Patent Publication Number: US-2021177896-A1

Title: Therapeutic regimens for chimeric antigen receptor (car)- expressing cells

Description:
This application is a U.S. National Stage Application under 35 U.S.C. § 371 of International Application No. PCT/US2017/035778, filed Jun. 2, 2017, which claims priority to U.S. Ser. No. 62/344,958 filed Jun. 2, 2016, U.S. Ser. No. 62/381,163 filed Aug. 30, 2016, U.S. Ser. No. 62/429,294 filed Dec. 2, 2016, U.S. Ser. No. 62/434,974 filed Dec. 15, 2016, U.S. Ser. No. 62/455,547 filed Feb. 6, 2017, U.S. Ser. No. 62/490,911 filed Apr. 27, 2017, and U.S. Ser. No. 62/492,784 filed May 1, 2017, the contents of all of which are incorporated herein by reference in their entireties. 
    
    
     SEQUENCE LISTING 
     The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Sep. 12, 2017, is named N2067-7110WO_SL.TXT and is 1,007,053 bytes in size. 
     FIELD OF THE INVENTION 
     The present invention relates, at least in part, to dosage regimens for immune cells engineered to express a Chimeric Antigen Receptor (CAR). 
     BACKGROUND OF THE INVENTION 
     Many patients with B cell malignancies are incurable with standard therapy. In addition, traditional treatment options often have serious side effects. Attempts have been made in cancer immunotherapy, however, several obstacles render this a very difficult goal to achieve clinical effectiveness. Although hundreds of so-called tumor antigens have been identified, these are generally derived from self and thus are poorly immunogenic. Furthermore, tumors use several mechanisms to render themselves hostile to the initiation and propagation of immune attack. 
     Recent developments using chimeric antigen receptor (CAR) modified autologous T cell (CART) therapy, which relies on redirecting T cells to a suitable cell-surface molecule on cancer cells such as B cell malignancies, show promising results in harnessing the power of the immune system to treat B cell malignancies and other cancers (see, e.g., Sadelain et al., Cancer Discovery 3:388-398 (2013)). The clinical results of the murine derived CART19 (i.e., “CTL019”) have shown promise in establishing complete remissions in patients suffering with CLL as well as in childhood ALL (see, e.g., Kalos et al., Sci Transl Med 3:95ra73 (2011), Porter et al., NEJM 365:725-733 (2011), Grupp et al., NEJM 368:1509-1518 (2013)). Besides the ability for the chimeric antigen receptor on the genetically modified T cells to recognize and destroy the targeted cells, a successful therapeutic T cell therapy needs to have the ability to proliferate and persist over time, in order to survey for leukemic relapse. The variable quality of T cells, resulting from anergy, suppression, or exhaustion, will have effects on CAR-transformed T cells&#39; performance, over which skilled practitioners have limited control at this time. To be effective, CAR transformed patient T cells need to persist and maintain the ability to proliferate in response to the cognate antigen. It has been shown that ALL patient T cells perform can do this with CART19 comprising a murine scFv (see, e.g., Grupp et al., NEJM 368:1509-1518 (2013)). 
     SUMMARY OF THE INVENTION 
     The disclosure features, at least in part, CAR dosage regimens that maintain efficacy while reducing side effects. In one embodiment, the invention pertains to a method of treating a subject having a cancer (e.g., a hematological cancer), comprising administering to the subject a plurality of cells comprising a CAR molecule. In another embodiment, the plurality of CAR-expressing cells is administered as a single dose, e.g., a single dose as described herein. In other embodiments, the plurality of CAR-expressing cells are administered as multiple doses, e.g., a first dose, a second dose, and optionally a third dose, e.g., as described herein. Additionally disclosed are assays and methods for evaluating responsiveness to a CAR therapy or monitoring a subject undergoing a CAR therapy, e.g., a B cell-targeting CAR therapy, by detecting the level of soluble BCMA; or methods of evaluating the suitability for manufacturing of a CAR therapy. Accordingly, methods and compositions comprising a plurality of CAR-expressing cells, as well as methods of monitoring, or making, a CAR therapy are disclosed. 
     Accordingly, in one aspect, disclosed herein is a plurality of cells that express a chimeric antigen receptor (CAR) molecule for use in the treatment of a subject having hematological cancer. In embodiments, the CAR molecule binds to a B-cell antigen, e.g., a CD19, BCMA, CD20, CD10, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. In one embodiment, the CAR molecule is: 
     (i) a murine CAR molecule that binds to CD19, and wherein the hematological cancer is acute lymphoid leukemia (ALL); 
     (ii) a humanized CAR molecule that binds to CD19; or 
     (iii) a CAR molecule that binds to BCMA. 
     In one embodiment, the plurality of CAR-expressing cells are administered at a dose of about 0.2×10 6  to 5.0×10 6  (e.g., 0.2×10 6  to 5.0×10 6 ) viable CAR-expressing cells/kg, e.g., when the subject weighs ≤50 kg; or at a dose of about 0.1×10 8  to 2.5×10 8  (e.g., 0.1×10 8  to 2.5×10 8 ) viable CAR-expressing cells, e.g., when the subject weighs &gt;50 kg. 
     In one aspect, disclosed herein is a method of treating a subject having a hematological cancer, comprising administering to the subject in need thereof a plurality of cells that express a chimeric antigen receptor (CAR) molecule. In embodiments, the CAR molecule binds to a B-cell antigen, e.g., a CD19, BCMA, CD20, CD10, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. In one embodiment, the CAR molecule is: 
     (i) a murine CAR molecule that binds to CD19, and wherein the hematological cancer is acute lymphoid leukemia (ALL); 
     (ii) a humanized CAR molecule that binds to CD19; or 
     (iii) a CAR molecule that binds to BCMA. 
     In one embodiment, the plurality of cells is administered at: 
     at a dose of about 0.2×10 6  to 5.0×10 6  (e.g., 0.2×10 6  to 5.0×10 6 ) viable CAR-expressing cells/kg, e.g., when the subject weighs ≤50 kg; or at a dose of about 0.1×10 8  to 2.5×10 8  (e.g., 0.1×10 8  to 2.5×10 8 ) viable CAR-expressing cells, e.g., when the subject weighs &gt;50 kg. 
     In one embodiment, the plurality of cells is administered at: 
     (i) a dose of about 0.2×10 6  to 2.0×10 6  (e.g., 0.2×10 6  to 2.0×10 6 ), about 0.2×10 6  to 1.8×10 6  (e.g., 0.2×10 6  to 1.8×10 6 ), about 0.2×10 6  to 1.6×10 6  (e.g., 0.2×10 6  to 1.6×10 6 ), about 0.2×10 6  to 1.4×10 6  (e.g., 0.2×10 6  to 1.4×10 6 ), about 0.2×10 6  to 1.2×10 6  (e.g., 0.2×10 6  to 1.2×10 6 ), about 0.2×10 6  to 1.0×10 6  (e.g., 0.2×10 6  to 1.0×10 6 ), about 0.2×10 6  to 0.8×10 6  (e.g., 0.2×10 6  to 0.8×10 6 ), about 0.2×10 6  to 0.6×10 6  (e.g., 0.2×10 6  to 0.6×10 6 ), or about 0.2×10 6  to 0.4×10 6  (e.g., 0.2×10 6  to 0.4×10 6 ) viable CAR-expressing cells/kg, e.g., when the subject weighs ≤50 kg; 
     (ii) a dose of about 0.2×10 6  (e.g., 0.2×10 6 ), about 0.4×10 6  (e.g., 0.4×10 6 ), about 0.6×10 6  (e.g., 0.6×10 6 ), about 0.8×10 6  (e.g., 0.8×10 6 ), about 1.0×10 6  (e.g., about 1.0×10 6 ), about 1.5×10 6  (e.g., 1.5×10 6 ), about 2.0×10 6  (e.g., 2.0×10 6 ), about 2.5×10 6  (e.g., 2.5×10 6 ), about 3.0×10 6  (e.g., 3.0×10 6 ), about 3.5×10 6  (e.g., 3.5×10 6 ), about 4.0×10 6  (e.g., 4.0×10 6 ), about 4.5×10 6  (e.g., 4.5×10 6 ), or about 5.0×10 6  (e.g., 5.0×10 6 ) viable CAR-expressing cells/kg, e.g., when the subject weighs ≤50 kg; 
     (iii) a dose of about 0.1×10 8  to 1.0×10 8  (e.g., 0.1×10 8  to 1.0×10 8 ), about 0.1×10 8  to 0.9×10 8  (e.g., 0.1×10 8  to 0.9×10 8 ), about 0.1×10 8  to 0.8×10 8  (e.g., 0.1×10 8  to 0.8×10 8 ), about 0.1×10 8  to 0.6×10 8  (e.g., 0.1×10 8  to 0.6×10 8 ), about 0.1×10 8  to 0.4×10 8  (e.g., 0.1×10 8  to 0.4×10 8 ), about 0.1×10 8  to 0.2×10 8  (e.g., 0.1×10 8  to 0.2×10 8 ), about 0.2×10 8  to 1.0×10 8  (e.g., 0.2×10 8  to 1.0×10 8 ), about 0.2×10 8  to 0.9×10 8  (e.g., 0.2×10 8  to 0.9×10 8 ), about 0.2×10 8  to 0.8×10 8  (e.g., 0.2×10 8  to 0.8×10 8 ), about 0.2×10 8  to 0.6×10 8  (e.g., 0.2×10 8  to 0.6×10 8 ), or about 0.2×10 8  to 0.4×10 8  (e.g., 0.2×10 8  to 0.4×10 8 ) viable CAR-expressing cells, e.g., when the subject weighs &gt;50 kg; or 
     (iv) a dose of about 0.1×10 8  (e.g., 0.1×10 8 ), about 0.2×10 8  (e.g., 0.2×10 8 ), about 0.4×10 8  (e.g., 0.4×10 8 ), about 0.6×10 8  (e.g., 0.6×10 8 ), about 0.8×10 8  (e.g., 0.8×10 8 ), about 1.0×10 8  (e.g., 1.0×10 8 ), about 1.5×10 8  (e.g., 1.5×10 8 ), about 2.0×10 8  (e.g., 2.0×10 8 ), or about 2.5×10 8  (e.g., 2.5×10 8 ) viable CAR-expressing cells, e.g., when the subject weighs &gt;50 kg. 
     In one embodiment, the subject is a pediatric or young adult. In one embodiment, the subject is aged about 3 to 23 years, e.g., aged 3 to 23 years. In one embodiment, the subject is aged about 1 to 24 years, e.g., aged 1 to 24 years. In one embodiment, the subject is aged about 3 to 25 years, e.g., aged 3 to 25 years. 
     In one embodiment, the subject is an adult. 
     In one embodiment, the hematological cancer is chosen from acute leukemia, B-cell acute lymphoid leukemia (BALL), T-cell acute lymphoid leukemia (TALL), small lymphocytic leukemia (SLL), acute lymphoid leukemia (ALL), chronic leukemia, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma, or multiple myeloma. In one embodiment, the hematological cancer is acute lymphoid leukemia (ALL), e.g., relapsed or refractory B-cell ALL. In one embodiment, the hematological cancer is relapsed or refractory CD19+ ALL. In one embodiment, the hematological cancer has CNS involvement. 
     In one aspect, disclosed herein is a container (e.g., an infusion bag) comprising a plurality of cells that express a chimeric antigen receptor (CAR) molecule. In embodiments, the CAR molecule binds to a B-cell antigen, e.g., a CD19, BCMA, CD20, CD10, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. In one embodiment, the CAR molecule is: 
     (i) a murine CAR molecule that binds to CD19, and wherein the hematological cancer is acute lymphoid leukemia (ALL); 
     (ii) a humanized CAR molecule that binds to CD19; or 
     (iii) a CAR molecule that binds to BCMA. 
     In embodiments, the container is suitable for administration to a subject having hematological cancer at a dose of about 0.2×10 6  to 5.0×10 6  viable CAR-expressing cells/kg, e.g., when the subject weighs ≤50 kg; or a dose of about 0.1×10 8  to 2.5×10 8  viable CAR-expressing cells, e.g., when the subject weighs &gt;50 kg. 
     In one embodiment, the container (e.g., an infusion bag) is suitable for administration at: 
     (i) a dose of about 0.2×10 6  to 2.0×10 6  (e.g., 0.2×10 6  to 2.0×10 6 ), about 0.2×10 6  to 1.8×10 6  (e.g., 0.2×10 6  to 1.8×10 6 ), about 0.2×10 6  to 1.6×10 6  (e.g., 0.2×10 6  to 1.6×10 6 ), about 0.2×10 6  to 1.4×10 6  (e.g., 0.2×10 6  to 1.4×10 6 ), about 0.2×10 6  to 1.2×10 6  (e.g., 0.2×10 6  to 1.2×10 6 ), about 0.2×10 6  to 1.0×10 6  (e.g., 0.2×10 6  to 1.0×10 6 ), about 0.2×10 6  to 0.8×10 6  (e.g., 0.2×10 6  to 0.8×10 6 ), about 0.2×10 6  to 0.6×10 6  (e.g., 0.2×10 6  to 0.6×10 6 ), or about 0.2×10 6  to 0.4×10 6  (e.g., 0.2×10 6  to 0.4×10 6 ) viable CAR-expressing cells/kg, e.g., when the subject weighs ≤50 kg; 
     (ii) a dose of about 0.2×10 6  (e.g., 0.2×10 6 ), about 0.4×10 6  (e.g., 0.4×10 6 ), about 0.6×10 6  (e.g., 0.6×10 6 ), about 0.8×10 6  (e.g., 0.8×10 6 ), about 1.0×10 6  (e.g., about 1.0×10 6 ), about 1.5×10 6  (e.g., 1.5×10 6 ), about 2.0×10 6  (e.g., 2.0×10 6 ), about 2.5×10 6  (e.g., 2.5×10 6 ), about 3.0×10 6  (e.g., 3.0×10 6 ), about 3.5×10 6  (e.g., 3.5×10 6 ), about 4.0×10 6  (e.g., 4.0×10 6 ), about 4.5×10 6  (e.g., 4.5×10 6 ), or about 5.0×10 6  (e.g., 5.0×10 6 ) viable CAR-expressing cells/kg, e.g., when the subject weighs ≤50 kg; 
     (iii) a dose of about 0.1×10 8  to 1.0×10 8  (e.g., 0.1×10 8  to 1.0×10 8 ), about 0.1×10 8  to 0.9×10 8  (e.g., 0.1×10 8  to 0.9×10 8 ), about 0.1×10 8  to 0.8×10 8  (e.g., 0.1×10 8  to 0.8×10 8 ), about 0.1×10 8  to 0.6×10 8  (e.g., 0.1×10 8  to 0.6×10 8 ), about 0.1×10 8  to 0.4×10 8  (e.g., 0.1×10 8  to 0.4×10 8 ), about 0.1×10 8  to 0.2×10 8  (e.g., 0.1×10 8  to 0.2×10 8 ), about 0.2×10 8  to 1.0×10 8  (e.g., 0.2×10 8  to 1.0×10 8 ), about 0.2×10 8  to 0.9×10 8  (e.g., 0.2×10 8  to 0.9×10 8 ), about 0.2×10 8  to 0.8×10 8  (e.g., 0.2×10 8  to 0.8×10 8 ), about 0.2×10 8  to 0.6×10 8  (e.g., 0.2×10 8  to 0.6×10 8 ), or about 0.2×10 8  to 0.4×10 8  (e.g., 0.2×10 8  to 0.4×10 8 ) viable CAR-expressing cells, e.g., when the subject weighs &gt;50 kg; or 
     (iv) a dose of about 0.1×10 8  (e.g., 0.1×10 8 ), about 0.2×10 8  (e.g., 0.2×10 8 ), about 0.4×10 8  (e.g., 0.4×10 8 ), about 0.6×10 8  (e.g., 0.6×10 8 ), about 0.8×10 8  (e.g., 0.8×10 8 ), about 1.0×10 8  (e.g., 1.0×10 8 ), about 1.5×10 8  (e.g., 1.5×10 8 ), about 2.0×10 8  (e.g., 2.0×10 8 ), or about 2.5×10 8  (e.g., 2.5×10 8 ) viable CAR-expressing cells, e.g., when the subject weighs &gt;50 kg. 
     In one aspect, disclosed herein is a kit comprising: 
     (i) a container (e.g., an infusion bag) comprising a plurality of cells that express a chimeric antigen receptor (CAR) molecule; and 
     (ii) instructions for administration. 
     In embodiments, the CAR molecule binds to a B-cell antigen, e.g., a CD19, BCMA, CD20, CD10, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. In one embodiment, the CAR molecule is: 
     (a) a murine CAR molecule that binds to CD19, and wherein the hematological cancer is acute lymphoid leukemia (ALL); 
     (b) a humanized CAR molecule that binds to CD19; or 
     (c) a CAR molecule that binds to BCMA, 
     In embodiments, the container is suitable for administration to a subject having hematological cancer at a dose of about 0.2×10 6  to 5.0×10 6  (e.g., 0.2×10 6  to 5.0×10 6 ) viable CAR-expressing cells/kg, e.g., when the subject weighs ≤50 kg; or a dose of about 0.1×10 8  to 2.5×10 8  (e.g., 0.1×10 8  to 2.5×10 8 ) viable CAR-expressing cells, e.g., when the subject weighs &gt;50 kg. 
     In one aspect, disclosed herein are a plurality of cells that express a chimeric antigen receptor (CAR) molecule for use in the treatment of a subject having hematological cancer. In embodiments, the CAR molecule binds to a B-cell antigen, e.g., a CD19, BCMA, CD20, CD10, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. In one embodiment, the CAR molecule is: 
     (i) a murine CAR molecule that binds to CD19, and wherein the hematological cancer is acute lymphoid leukemia (ALL); 
     (ii) a humanized CAR molecule that binds to CD19; or 
     (iii) a CAR molecule that binds to BCMA. 
     In embodiments, the plurality of cells are administered in at least two (e.g., three) doses, which together add up to a total dose of, e.g., at least about 0.2×10 6  (e.g., 0.2×10 6 ) viable CAR-expressing cells/kg, e.g., when the subject weighs ≤50 kg; or a total dose of at least about 0.1×10 8  (e.g., 0.1×10 8 ) viable CAR-expressing cells, e.g., when the subject weighs &gt;50 kg. 
     In one aspect, disclosed herein is a method of treating a subject having hematological cancer, comprising administering to the subject at least two (e.g., three) doses of a plurality of cells that express a chimeric antigen receptor (CAR) molecule. In embodiments, the CAR molecule binds to a B-cell antigen, e.g., a CD19, BCMA, CD20, CD10, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. In one embodiment, the CAR molecule is: 
     (i) a murine CAR molecule that binds to CD19, and wherein the hematological cancer is acute lymphoid leukemia (ALL); 
     (ii) a humanized CAR molecule that binds to CD19; or 
     (iii) a CAR molecule that binds to BCMA, In embodiments, the at least two (e.g., three) doses together add up to a total dose of at least about 0.2×10 6  (e.g., 0.2×10 6 ) viable CAR-expressing cells/kg, e.g., when the subject weighs ≤50 kg; or a total dose of at least about 0.1×10 8  (e.g., 0.1×10 8 ) viable CAR-expressing cells, e.g., when the subject weighs &gt;50 kg. 
     In one embodiment, the at least two (e.g., three) doses are administered separately with a time interval of about one day. 
     In one embodiment, the at least two (e.g., three) doses comprise a first dose, a second dose, and a third dose, wherein the first dose is administered on a first day of treatment, the second dose is administered on a subsequent (e.g., second, third, fourth, fifth, sixth, or seventh or later) day of treatment, and the third dose is administered on a yet subsequent (e.g., third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or later) day of treatment. 
     In one embodiment, the at least two (e.g., three) doses comprise a first dose, a second dose, and a third dose, wherein the first dose is administered on the first day of treatment, the second dose is administered on the second day of treatment, and the third dose is administered on the third day of treatment. 
     In one embodiment, the at least two (e.g., three) doses comprise a first dose, a second dose, and a third dose, wherein the first dose is about 10% (e.g., 10%) of the total dose, the second dose is about 30% (e.g., 30%) of the total dose, and the third dose is about 60% (e.g., 60%) of the total dose. 
     In one embodiment, the total dose is about 5×10 7  to 5×10 8  viable CAR-expressing cells (e.g., about 5×10 7 , e.g., 5×10 7 , or about 5×10 8 , e.g., 5×10 8 , viable CAR-expressing cells). 
     In embodiments, the CAR-expressing cells (e.g., CD19 CAR-expressing cells or BCMA CAR-expressing cells) are administered to the subject according to a dosing regimen comprising a total dose of cells administered to the subject by dose fractionation, e.g., one, two, three or more separate administration of a partial dose. In embodiments, a first percentage of the total dose is administered on a first day of treatment, a second percentage of the total dose is administered on a subsequent (e.g., second, third, fourth, fifth, sixth, or seventh or later) day of treatment, and optionally, a third percentage (e.g., the remaining percentage) of the total dose is administered on a yet subsequent (e.g., third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or later) day of treatment. For example, 10% of the total dose of cells is delivered on the first day, 30% of the total dose of cells is delivered on the second day, and the remaining 60% of the total dose of cells is delivered on the third day of treatment. For example, a total cell dose includes 1 to 5×10 7  or 1 to 5×10 8  CAR-expressing cells (e.g., CD19 CAR-expressing cells or BCMA CAR-expressing cells). 
     In one embodiment of the preceding methods, the plurality of cells comprise T cells or NK cells. 
     In embodiments, the subject is a mammal, e.g., a human. 
     In one embodiment, the subject is a pediatric or young adult. In one embodiment, the subject is aged about 3 to 23 years, e.g., aged 3 to 23 years. In one embodiment, the subject is aged about 1 to 24 years, e.g., aged 1 to 24 years. In one embodiment, the subject is aged about 3 to 25 years, e.g., aged 3 to 25 years. 
     In one embodiment, the subject is an adult. 
     In one embodiment, the hematological cancer is chosen from acute leukemia, B-cell acute lymphoid leukemia (BALL), T-cell acute lymphoid leukemia (TALL), small lymphocytic leukemia (SLL), acute lymphoid leukemia (ALL), chronic leukemia, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma, or multiple myeloma. In one embodiment, the hematological cancer is acute lymphoid leukemia (ALL), e.g., relapsed or refractory B-cell ALL. In one embodiment, the hematological cancer is relapsed or refractory CD19+ ALL. In one embodiment, the hematological cancer has CNS involvement. 
     CRS Treatment 
     The disclosure also features, at least in part, CAR dosage regimens that maintain efficacy while reducing the risk of CRS (cytokine release syndrome). In one embodiment shown in Example 26, dividing a dose of CAR expressing cells for administration in three increments can produce as good efficacy as a single dose, but without a concomitant increase in severe CRS. 
     In embodiments, the subject is evaluated for CRS after receiving a dose, e.g., after receiving the first dose, the second dose, and/or the third dose. 
     In embodiments, the subject receives a CRS treatment, e.g., tocilizumab, bazedoxifene, a corticosteroid, etanercept, or siltuximab. In embodiments, the CRS treatment is administered before or after the first dose of cells comprising the CAR molecule. In embodiments, the CRS treatment is administered before or after the second dose of cells comprising the CAR molecule. In embodiments, the CRS treatment is administered before or after the third dose of cells comprising the CAR molecule. In embodiments, the CRS treatment is administered between the first and second doses of cells comprising the CAR molecule, and/or between the second and third doses of cells comprising the CAR molecule. 
     In embodiments, in a subject having CRS after the first dose, e.g., CRS grade 1, 2, 3, or 4, the second dose is administered at least 2, 3, 4, or 5 days after the first dose. In embodiments, in a subject having CRS after the second dose, e.g., CRS grade 1, 2, 3, or 4, the third dose is administered at least 2, 3, 4, or 5 days after the second dose. In embodiments, in a subject having CRS after the first dose, the second dose of CAR-expressing cells is delayed relative to when the second dose would have been administered had the subject not had CRS. In embodiments, in a subject having CRS after the second dose, the third dose of CAR-expressing cells is delayed relative to when the third dose would have been administered had the subject not had CRS. 
     In embodiments, the subject has a cancer with a high disease burden before the first dose is administered. In embodiments, the subject has bone marrow blast levels of at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%, e.g., at least 5%. In embodiments, the subject has a cancer in stage I, II, III, or IV. In embodiments, the subject has a tumor mass of at least 1, 2, 5, 10, 20, 50, 100, 200, 500, or 1000 g, e.g., in a single tumor or a plurality of tumors. 
     In some embodiments, the subject has cancer (e.g., a solid cancer or a hematological cancer as described herein). In an embodiment, the subject has CLL. In embodiments, the subject has ALL. In other embodiments, the subject has multiple myeloma. 
     In one embodiment, the cancer is a disease associated with CD19 expression, e.g., as described herein. 
     In other embodiments, the cancer is a disease associated with a tumor antigen, e.g., a B-cell antigen as described herein. In embodiments, the CAR molecule is a CAR molecule as described herein (e.g., a CAR molecule that binds to a B-cell antigen, e.g., CD19 CAR or a BCMA CAR described herein). 
     Additional Therapeutic Methods 
     In another aspect, the present disclosure provides a method of treating a subject having a hematological cancer with CNS (central nervous system) involvement. The present disclosure also provides, in some aspects, a method of reducing CNS involvement or preventing a relapse of CNS involvement in a subject having a hematologic cancer. The method comprises administering to the subject in need thereof an effective number of immune effector cells expressing a CAR molecule, e.g., a CAR molecule that binds to a B-cell antigen, e.g., CD19 or BCMA. In some embodiments, the hematological cancer is a leukemia, e.g., acute lymphoid leukemia (ALL), e.g, relapsed or refractory ALL. In embodiments, the hematological cancer is a metastatic hematological cancer, e.g., a metastatic leukemia or lymphoma. In other embodiments, the hematological cancer is chosen from CNS lymphoma, CNS leukemia, or CNS AML. In some embodiments, the subject is a pediatric or young adult subject. 
     In one embodiment, CNS involvement is determined by measuring the presence of hematological cancer cells (e.g., blast cells) in cerebral spinal fluid (CSF). 
     In some embodiments, the subject has, or is identified as having, a hematological cancer with CNS involvement, e.g., a relapsed or refractory hematological cancer with CNS involvement. In some embodiments, the subject has, or is identified as having, relapsed or refractory ALL with CNS involvement. In some embodiments, the subject has, or is identified as having, active CNS3 status. In some embodiments, the subject is a pediatric or young adult subject. 
     In embodiments, the subject has, or is identified as having, one or more of: a CNS relapse, combined BM/CNS relapse, ocular involvement, or parenchymal changes of brain or spine. In one embodiment, the subject has or is identified as having a CNS relapse, e.g., having a score of CNS3 by lumbar puncture (LP) (e.g., ≥5 WBC/mL with blasts), or by detecting brain/ocular involvement, e.g., by imaging. In embodiments, the subject has, or is identified as having, &lt;0.01% blasts, 0.01-5% blasts, &gt;5% blasts, 5-50% blasts, or &gt;50% blasts. In embodiments, the leukemia is Philadelphia chromosome positive. In embodiments, the subject is at a first or subsequent relapse (e.g., 2nd, 3rd, 4th, 5th, 6th, or 7th relapse). In embodiments, the subject was previously treated with radiation or bone marrow transplant. In embodiments, the subject was previously treated with chemotherapy or radiation. 
     In embodiments, the subject undergoes lymphodepletion (e.g., with fludarabine and/or cyclophosphamide) before administration of the immune effector cells. 
     In embodiments, after administration, the subject experiences complete response (CR), e.g., at day 28 after the administration. In embodiments, the subject has &lt;0.01% minimal residual disease (MRD) (e.g., by flow cytometry), e.g., at day 28 after the administration or 3 months after the administration, e.g., without further anticancer therapy. In embodiments, the subject has CR with MRD (e.g., &gt;0.01%), e.g., at day 28 after the administration or 3 months after the administration, e.g., without further anticancer therapy. In embodiments, after the administration, the subject has no CNS involvement. In embodiments, after the administration, the subject experiences a reduction in CNS status, e.g., from CNS3 to CNS2 or CNS1, or from CNS2 to CNS1. In embodiments, a subject having CNS1 has no detectable blast cells in CSF, a subject having CNS2 has &lt;5 WBC/μl CSF with blast cells; and a subject having CNS3 has ≥5 WBC/μl CSF with blast cells. In embodiments, the subject is in CR at least at 8, 23, or 31 months after the administration, or at least at 2, 4, 6, 8, 12, 18, 24, 30, or 36 months after the administration. In embodiments, the subject experiences CR for a duration of at least 8, 23, or 31 months after the administration, or at least 2, 4, 6, 8, 12, 18, 24, 30, or 36 months after the administration. 
     In embodiments, the method further comprises testing a subject for CNS involvement, e.g., by lumbar puncture and/or by imaging to detect brain or ocular involvement, before or after the administration. In embodiments, the method further comprises testing a subject for bone marrow disease or MRD, before or after the administration. In embodiments, the testing is performed at one or more of 1, 3, 6, 9, or 12 months after the administration. 
     In embodiments, after the administration, the subject does not experience one or more of: CRS, severe CRS, encephalopathy (e.g., encephalopathy grade 2-3), seizures (e.g., seizures grade 2-4), vision disturbance, speech disturbance, trigeminal neuralgia, confusion, dizziness, ataxia, or agitation. 
     In some embodiments, the immune effector cell is an immune effector cell described herein. In some embodiments, the CAR molecule is a CAR molecule described herein. In some embodiments, the CAR molecule comprises the amino acid sequence of residues 22-486 of SEQ ID NO: 58, residues 22-486 of any one of SEQ ID NOs: 31-34 or 42, or residues 22-491 of any one of SEQ ID NOs: 35-41. In some embodiments the CAR molecule comprises an antigen binding domain comprising one or more sequence selected from SEQ ID NOS:1-12. In embodiments, the immune effector cells are administered as a monotherapy. 
     In embodiments, a CAR therapy described herein can be used in lieu of a standard of care for CNS involvement, e.g., radiation therapy. 
     In yet another aspect, the present disclosure provides a method of treating one or more of a neurological toxicity, CRS, or posterior reversible encephalopathy syndrome (PRES). The method comprises administering to a subject in need thereof a therapeutically effective amount of cyclophosphamide. In related aspects, the present disclosure provides cyclophosphamide for use in treating neurological toxicity, CRS, or posterior reversible encephalopathy syndrome (PRES). In embodiments, the administration of cyclophosphamide is subsequent to a cell-based therapy, e.g., a cell-based therapy for cancer (e.g., a CD19-inhibiting therapy, or a CD19-depleting therapy), or the subject has been previously treated with a cell-based therapy, e.g., a cell-based therapy for cancer, a CD19-inhibiting therapy, or a CD19-depleting therapy. In embodiments, the administration of cyclophosphamide is prior to, at the same time as, or after the cell-based therapy. 
     In embodiments, the patient has, or is identified as having, CRS, PRES, or both. In some embodiments, the subject has been treated with a CD19 inhibiting or depleting therapy. In some embodiments, the CD19 inhibitor is a CD19 antibody, e.g., a CD19 bispecific antibody (e.g., a bispecific T cell engager that targets CD19, e.g., blinatumomab). In some embodiments, the therapy comprises a CAR-expressing cell, e.g., an anti-CD19 CAR. In embodiments, the subject suffers from a neurological toxicity, e.g., focal deficits (e.g., cranial nerve palsy or hemiparesis) or global abnormalities (e.g., generalized seizures, confusion), or status epilepticus. In embodiments, the subject does not have any clinical symptoms of CRS. In embodiments, the subject has one or more clinical symptoms of CRS. In embodiments, the subject has, or is identified as having, elevated IL-6 relative to a reference, e.g., to the subject&#39;s level of IL-6 prior to therapy with a CAR-expressing cell. In embodiments, the subject has, or is identified as having, elevated serum levels of a cytokine associated with CRS (e.g., IL-6 and/or IL-8) relative to a reference. In embodiments, the subject has, or is identified as having, elevated levels of a cytokine associated with CRS (e.g., CSF IL-6 and/or IL-8) relative to a reference. In embodiments, the subject is treated or has been treated with a therapy for CRS such as tocilizumab or a corticosteroid (e.g., methylprednisolone, hydrocortisone, or both). In embodiments, the subject has, or is identified as having, an increase in circulating, activated CAR-expressing cells. In embodiments, the subject has, or is identified as having, CAR-expressing cells in the CSF. 
     In some aspects, the present disclosure also provides a method of treating a human subject (e.g., a pediatric or young adult subject) having acute lymphoid leukemia (ALL), comprising: administering to the subject immune effector cells expressing a CAR molecule that binds to CD19, wherein said CAR molecule comprises the amino acid sequence of residues 22-486 of SEQ ID NO: 58, residues 22-486 of any one of SEQ ID NOs: 31-34 or 42, or residues 22-491 of any one of SEQ ID NOs: 35-41, at a dose of 2.0-5.0×10 6  cells/kg (e.g., when the subject weighs ≤50 kg) or a dose of 1.0-2.5×10 8  cells (e.g., when the subject weighs &gt;50 kg). In a related aspect, the present disclosure provides a method of selecting a dose of subject immune effector cells expressing a CAR molecule that binds to CD19, wherein said CAR molecule comprises the amino acid sequence of residues 22-486 of SEQ ID NO: 58, residues 22-486 of any one of SEQ ID NOs: 31-34 or 42, or residues 22-491 of any one of SEQ ID NOs: 35-41 for a subject having ALL, wherein (i) if the subject weighs ≤50 kg, selecting a dose of 2.0-5.0×10 6  cells/kg, and (ii) if the subject weighs &gt;50 kg, selecting a dose of 1.0-2.5×10 8  cells. 
     In embodiments, the subject experiences remission (e.g., CR or CRi) after the administration of the immune effector cells. In embodiments, the subject is treated with lymphodepleting chemotherapy before the administration of the immune effector cells. 
     In embodiments, the dose of immune effector cells is about 2.0-3.0×10 6 , 2.0-4.0×10 6 , 2.0-5.0×10 6 , 3.0-4.0×10 6 , 3.0-5.0×10 6 , or 4.0-5.0×10 6  cells/kg. In embodiments, the dose of immune effector cells is about 2.0×10 6 , 3.0×10 6 , or 4.0×10 6  cells/kg. In embodiments, the dose of immune effector cells is about 1.0-1.5×10 8 , 1.0-2.0×10 8 , 1.0-2.5×10 8 , 1.5-2.0×10 8 , 1.5-2.5×10 8 , or 2.0-2.5×10 8  cells. In embodiments, the dose of immune effector cells is about 1.0×10 8 , 1.5×10 8 , or 2.0-2.5×10 8  cells. In embodiments, the subject receives a single dose of cells. In embodiments, the subject weighs ≤50 kg. In embodiments, the subject weighs &gt;50 kg. 
     In other aspects, the disclosure provides a method of treating GC (germinal center)-DLBCL, NGC (non-germinal center)-DLBCL, transformed FL, or double hit DLBCL, comprising administering to a patient in need thereof a CD19 CAR-expressing cell, thereby treating the GC-DLBCL, NGC-DLBCL, transformed FL, or double hit DLBCL. 
     In some embodiments, the CD19 CAR (or a nucleic acid encoding it) comprises a sequence set out in any of Table 2, Table 3, Table 4, or Table 5. In embodiments, the CD19 CAR is CTL019. In other embodiments, the CD19 CAR is CTL119. In embodiments, the double hit DLBCL is DLBCL having chromosomal breakpoints affecting the MYC/8q24 locus and a second oncogene locus and arising either from transformation of follicular lymphoma or de novo. In embodiments, the DLBCL is a CD19+ DLBCL. In embodiments, the DLBCL is stage I, II, III, or IV. In embodiments, the DLBCL has bone marrow involvement. In embodiments, the DLBCL is GC-DLBCL or NGC-DLBCL. In embodiments, the second oncogene locus is BCL2 or BCL6. In embodiments, the patient received lymphodepleting chemotherapy prior to administration of the CD19 CAR-expressing cell. In embodiments, a single dose of CD19 CAR-expressing cells are administered. In embodiments, the patient experiences CRS. In embodiments, the patient experiences a response, e.g., complete response. In embodiments, the subject is administered a single dose of CD19 CAR-expressing cells. In embodiments, the CD19 CAR-expressing cells (e.g., CTL019 cells) are administered at a dose of about 5×10 8  cells, e.g., about 4-6×10 8  cells. In embodiments, the CD19 CAR-expressing cells (e.g., CTL019 cells) are administered at a dose of about 5-7×10 6  cells/kg. In embodiments, the CD19 CAR-expressing cells (e.g., CTL019 cells) are administered at a dose of about 2×10 8  cells, e.g., about 1-3×10 8  cells. In embodiments, the CD19 CAR-expressing cells (e.g., CTL019 cells) are administered at a dose of about 3×10 6  cells/kg, e.g., about 2-4×10 6  cells/kg. 
     Methods of Evaluating and Monitoring a Patient 
     The disclosure also features a method of evaluating, or monitoring, a subject receiving or who has received a chimeric antigen receptor (CAR) cell therapy for the effectiveness of the therapy using soluble BCMA (sBCMA) as a biomarker. In one embodiment, the CAR therapy is a CAR molecule that binds to a B-cell antigen, e.g., a CD19, BCMA, CD20, CD10, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. In one embodiment, the CAR therapy is a CD19 CAR therapy or a BCMA CAR therapy. 
     In one aspect, disclosed herein is a method of evaluating the effectiveness of a CAR-expressing cell therapy in a subject having hematological cancer, who has received or is receiving the CAR-expressing cell therapy, comprising measuring soluble BCMA (sBCMA) level or activity (e.g., level) in the subject (e.g., in the serum of the subject) at at least two time points after the beginning of the CAR-expressing cell therapy, e.g., using a method described herein, e.g., ELISA, wherein: 
     (i) a decrease in the sBCMA level or activity over time indicates that the CAR-expressing cell therapy is effective in the subject (e.g., the subject responds to the CAR-expressing cell therapy); and 
     (ii) the absence of a decrease in the sBCMA level or activity over time indicates that the CAR-expressing cell therapy has reduced efficacy, e.g., is ineffective or is minimally effective, in the subject (e.g., the subject does not respond or only minimally responds to the CAR-expressing cell therapy), thereby evaluating the subject. 
     In one embodiment, 
     (i) a decrease in the sBCMA level or activity at a subsequent (e.g., second, third, fourth, fifth, sixth, or seventh or later) time point relative to a prior (e.g., first, second, third, fourth, fifth, or sixth or later) time point, among the at least two time points, indicates that the CAR-expressing cell therapy is effective in the subject (e.g., the subject responds to the CAR-expressing cell therapy); and 
     (ii) the absence of a decrease in the sBCMA level or activity at a subsequent (e.g., second, third, fourth, fifth, sixth, or seventh or later) time point relative to a prior (e.g., first, second, third, fourth, fifth, or sixth or later) time point, among the at least two time points, indicates that the CAR-expressing cell therapy has reduced efficacy, e.g., is ineffective or is minimally effective, in the subject (e.g., the subject does not respond or only minimally responds to the CAR-expressing cell therapy). 
     In one embodiment, the CAR-expressing cell therapy comprises a plurality of cells that express a CAR molecule, wherein: 
     (i) a decrease in the sBCMA level or activity over time indicates that the plurality of cells that express a CAR molecule expand and/or persist in the subject; and 
     (ii) the absence of a decrease in the sBCMA level or activity over time indicates that the plurality of cells that express a CAR molecule do not expand and/or persist in the subject. 
     In one embodiment, 
     (i) a decrease in the sBCMA level or activity at a subsequent (e.g., second, third, fourth, fifth, sixth, or seventh or later) time point relative to a prior (e.g., first, second, third, fourth, fifth, or sixth or later) time point, among the at least two time points, indicates that the plurality of cells that express a CAR molecule expand and/or persist in the subject; and 
     (ii) the absence of a decrease in the sBCMA level or activity at a subsequent (e.g., second, third, fourth, fifth, sixth, or seventh or later) time point relative to a prior (e.g., first, second, third, fourth, fifth, or sixth or later) time point, among the at least two time points, indicates that the plurality of cells that express a CAR molecule do not expand and/or persist in the subject. 
     In one aspect, disclosed herein is a method of evaluating the effectiveness of a CAR-expressing cell therapy in a subject having hematological cancer, who has received or is receiving the CAR-expressing cell therapy, comprising: 
     (i) measuring soluble BCMA (sBCMA) level or activity (e.g., level) in the subject (e.g., in the serum of the subject) at at least one time point after the beginning of the CAR-expressing cell therapy, e.g., using a method described herein, e.g., ELISA, and 
     (ii) (optionally) comparing the sBCMA level or activity (e.g., level) (“sample value”) at the at least one time point with a reference sBCMA level or activity (e.g., level) (“reference value”), wherein: 
     (a) a decrease from the reference value to the sample value indicates that the CAR-expressing cell therapy is effective in the subject (e.g., the subject responds to the CAR-expressing cell therapy); and 
     (b) the absence of a decrease from the reference value to the sample value indicates that the CAR-expressing cell therapy has reduced efficacy, e.g., is ineffective or is minimally effective in the subject (e.g., the subject does not respond or only minimally responds to the CAR-expressing cell therapy), thereby evaluating the subject. 
     In one embodiment, the reference value is a sBCMA level or activity (e.g., level) of a sample taken from the subject prior to the at least one time point (e.g., a sample taken from the subject prior to the beginning of the CAR-expressing cell therapy, or a sample taken from the subject after the beginning of the CAR-expressing cell therapy but prior to measuring the sBCMA level or activity at the at least one time point). 
     In one embodiment, the reference value is a sBCMA level or activity (e.g., level) of a sample taken from a different subject having hematological cancer (e.g., the same or a different hematological cancer). 
     In one embodiment, the reference value is an average sBCMA level or activity (e.g., level) of samples taken from a population of subjects having hematological cancer (e.g., the same or a different hematological cancer). 
     In one embodiment, the CAR-expressing cell therapy comprises a plurality of cells that express a CAR molecule, wherein: 
     (i) a decrease from the reference value to the sample value indicates that the plurality of cells that express a CAR molecule expand and/or persist in the subject; and 
     (ii) the absence of a decrease from the reference value to the sample value indicates that the plurality of cells that express a CAR molecule do not expand and/or persist in the subject. 
     In one aspect, disclosed herein is a method of treating a subject having hematological cancer, who has received or is receiving a first CAR-expressing cell therapy, comprising measuring soluble BCMA (sBCMA) level or activity (e.g., level) in the subject (e.g., in the serum of the subject) at at least two time points after the beginning of the first CAR-expressing cell therapy, e.g., using a method described herein, e.g., ELISA, wherein if the sBCMA level or activity does not decrease over time, administer a second therapy to the subject, thereby treating the subject. 
     In one embodiment, if the sBCMA level or activity does not decrease at a subsequent (e.g., second, third, fourth, fifth, sixth, or seventh or later) time point relative to a prior (e.g., first, second, third, fourth, fifth, or sixth or later) time point, among the at least two time points, administer a second therapy to the subject. 
     In one aspect, disclosed herein is a method of treating a subject having hematological cancer, who has received or is receiving a first CAR-expressing cell therapy, comprising: 
     (i) measuring soluble BCMA (sBCMA) level or activity (e.g., level) in the subject (e.g., in the serum of the subject) at at least one time point after the beginning of the first CAR-expressing cell therapy, e.g., using a method described herein, e.g., ELISA, and 
     (ii) (optionally) comparing the sBCMA level or activity (e.g., level) (“sample value”) at the at least one time point with a reference sBCMA level or activity (e.g., level) (“reference value”), 
     wherein if the sample value does not decrease from the reference value, administer a second therapy to the subject, thereby treating the subject. 
     In one embodiment, the reference value is a sBCMA level or activity (e.g., level) of a sample taken from the subject prior to the at least one time point (e.g., a sample taken from the subject prior to the beginning of the CAR-expressing cell therapy, or a sample taken from the subject after the beginning of the CAR-expressing cell therapy but prior to measuring the sBCMA level or activity at the at least one time point). 
     In one embodiment, the reference value is a sBCMA level or activity (e.g., level) of a sample taken from a different subject having hematological cancer (e.g., the same or a different hematological cancer). 
     In one embodiment, the reference value is an average sBCMA level or activity (e.g., level) of samples taken from a population of subjects having hematological cancer (e.g., the same or a different hematological cancer). 
     In one embodiment, the CAR-expressing cell therapy comprises a plurality of cells that express a CAR molecule, wherein: 
     (i) a decrease from the reference value to the sample value indicates that the plurality of cells that express a CAR molecule expand and/or persist in the subject; and 
     (ii) the absence of a decrease from the reference value to the sample value indicates that the plurality of cells that express a CAR molecule do not expand and/or persist in the subject. 
     In one aspect, disclosed herein is a method of treating a subject having hematological cancer, comprising: 
     in response to a determination that the subject, after being administered a first CAR-expressing cell therapy, has not achieved, or has not been identified as having achieved, a decrease in soluble BCMA (sBCMA) level or activity (e.g., level), e.g., in the serum of the subject, e.g., as measured by a method described herein, e.g., ELISA, administering a second therapy to the subject, thereby treating the subject. 
     The disclosure also features a method of monitoring a subject having responded or partially responded to a chimeric antigen receptor (CAR) cell therapy for minimal residual disease using soluble BCMA (sBCMA) as a biomarker. 
     In one aspect, disclosed herein is a method of monitoring cancer relapse in a subject having hematological cancer, who has responded or partially responded to a CAR-expressing cell therapy, comprising measuring soluble BCMA (sBCMA) level or activity (e.g., level) in the subject (e.g., in the serum of the subject) at at least two time points after the subject responded or partially responded to the CAR-expressing cell therapy, e.g., using a method described herein, e.g., ELISA, wherein: 
     (i) an increase in the sBCMA level or activity over time indicates that the cancer is relapsing; 
     (ii) the absence of an increase, e.g., a decrease, in the sBCMA level or activity over time indicates that the cancer is not relapsing. 
     In one embodiment, 
     (i) an increase in the sBCMA level or activity at a subsequent (e.g., second, third, fourth, fifth, sixth, or seventh or later) time point relative to a prior (e.g., first, second, third, fourth, fifth, or sixth or later) time point, among the at least two time points, indicates that the cancer is relapsing; and 
     (ii) the absence of an increase in the sBCMA level or activity at a subsequent (e.g., second, third, fourth, fifth, sixth, or seventh or later) time point relative to a prior (e.g., first, second, third, fourth, fifth, or sixth or later) time point, among the at least two time points, indicates that the cancer is not relapsing. 
     In one aspect, disclosed herein is a method of monitoring cancer relapse in a subject having hematological cancer, who has responded or partially responded to a CAR-expressing cell therapy, comprising: 
     (i) measuring soluble BCMA (sBCMA) level or activity (e.g., level) in the subject (e.g., in the serum of the subject) at at least one time point after the subject responded or partially responded to the CAR-expressing cell therapy, e.g., using a method described herein, e.g., ELISA, and 
     (ii) (optionally) comparing the sBCMA level or activity (e.g., level) (“sample value”) at the at least one time point with a reference sBCMA level or activity (e.g., level) (“reference value”), wherein: 
     (a) an increase from the reference value to the sample value indicates that the cancer is relapsing; and 
     (b) the absence of an increase from the reference value to the sample value indicates that indicates that the cancer is not relapsing. 
     In one embodiment, the reference value is a sBCMA level or activity (e.g., level) of a sample taken from a subject not having hematological cancer (e.g., a healthy subject). In one embodiment, the reference value is an average sBCMA level or activity (e.g., level) of samples taken from a population of subjects not having hematological cancer (e.g., healthy subjects). 
     In one aspect, disclosed herein is a method of treating a subject having hematological cancer, who has responded or partially responded to a first CAR-expressing cell therapy, comprising measuring soluble BCMA (sBCMA) level or activity (e.g., level) in the subject (e.g., in the serum of the subject) at at least two time points after the subject responded or partially responded to the CAR-expressing cell therapy, e.g., using a method described herein, e.g., ELISA, wherein if the sBCMA level or activity increases over time, administer a second therapy. 
     In one embodiment, if the sBCMA level or activity increases at a subsequent (e.g., second, third, fourth, fifth, sixth, or seventh or later) time point relative to a prior (e.g., first, second, third, fourth, fifth, or sixth or later) time point, among the at least two time points, administer a second therapy to the subject. 
     In one aspect, disclosed herein is a method of treating a subject having hematological cancer, who has responded or partially responded to a first CAR-expressing cell therapy, comprising: 
     (i) measuring soluble BCMA (sBCMA) level or activity (e.g., level) in the subject (e.g., in the serum of the subject) at at least one time point after the subject responded or partially responded to the CAR-expressing cell therapy, e.g., using a method described herein, e.g., ELISA, and 
     (ii) (optionally) comparing the sBCMA level or activity (e.g., level) (“sample value”) at the at least one time point with a reference sBCMA level or activity (e.g., level) (“reference value”), wherein if the sample value increases from the reference value, administer a second therapy to the subject, thereby treating the subject e, administer a second therapy. 
     In one embodiment, the reference value is a sBCMA level or activity (e.g., level) of a sample taken from a subject not having hematological cancer (e.g., a healthy subject). In one embodiment, the reference value is an average sBCMA level or activity (e.g., level) of samples taken from a population of subjects not having hematological cancer (e.g., healthy subjects). 
     In one aspect, disclosed herein is a method of treating a subject having hematological cancer, comprising: 
     in response to a determination that the subject, after having responded or partially responded to a first CAR-expressing cell therapy, has experienced, or has been identified as having experienced an increase in soluble BCMA (sBCMA) level or activity (e.g., level), e.g., in the serum of the subject, e.g., as measured by a method described herein, e.g., ELISA, administering a second therapy to the subject, thereby treating the subject. 
     In one embodiment of the preceding methods, the increase and/or decrease in soluble BCMA (sBCMA) level or activity (e.g., level) is measured by, e.g., multiplexed ELISA, single analyte ELISA, single analyte Luminex, ProteinSimple, Simoa, SomaLogic, Singulex, or Olink. 
     In one embodiment of the preceding methods, the second therapy comprises a B cell inhibitor. In one embodiment, the B cell inhibitor is a checkpoint inhibitor. In one embodiment, the B cell inhibitor is a second CAR-expressing cell therapy, wherein: 
     (i) the second CAR-expressing cell therapy is the same as the first CAR-expressing cell therapy (e.g., the second CAR-expressing cell therapy is administered at a different dose from the first CAR-expressing cell therapy); or 
     (ii) the second CAR-expressing cell therapy is different from the first CAR-expressing cell therapy. 
     In one embodiment, the preceding methods comprise discontinuing the first CAR-expressing cell therapy. 
     In one embodiment of the preceding methods, the CAR-expressing cell therapy, the first CAR-expressing cell therapy, or the second CAR-expressing cell therapy comprises a plurality of cells that express a CAR molecule. In some embodiments, the CAR molecule is a CAR molecule that binds to a B-cell antigen, e.g., a CD19, BCMA, CD20, CD10, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. 
     In one embodiment, the CAR molecule is: 
     (i) a murine CAR molecule that binds to CD19, and wherein the hematological cancer is acute lymphoid leukemia (ALL); 
     (ii) a humanized CAR molecule that binds to CD19; or 
     (iii) a CAR molecule that binds to BCMA. 
     In embodiments of any of the preceding methods, the hematological cancer is a B cell malignancy, e.g., chosen from multiple myeloma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or non-Hodgkins lymphoma. In one embodiment, the hematological cancer is multiple myeloma. 
     In embodiments of any of the preceding methods, the at least one or at least two time points are determined at predetermined time intervals, e.g., at an initial phase or a maintenance phase of administration of the CAR molecule. In some embodiments, the at least one or at least two time points (e.g., the sample or reference values) are determined on a weekly basis, e.g., for the first month of CAR therapy, on a monthly basis, e.g., up to six months after initiation of the CAR therapy, or every three months, e.g., up to one, two, three or more years after initiation of the CAR therapy. In some embodiments, the at least two time points (e.g., the sample or reference values) are determined at any combination of the aforesaid time intervals, e.g., such that the first sample or time point is obtained on a weekly basis and the second sample or time point on a monthly basis. Alternatively, the first sample or time point is obtained on a monthly basis and the second sample or time point is obtained every three months, and so on. 
     In some embodiments, the soluble BCMA (sBCMA) level or activity (e.g., level) is measured in the subject (e.g., in the serum of the subject), e.g., once every week, e.g., for the first month after the beginning of the CAR-expressing cell therapy, once every month, e.g., up to six months after the beginning of the CAR-expressing cell therapy, or once every three months, e.g., up to one, two, three or more years after the beginning of the CAR-expressing cell therapy. 
     In some embodiments, the soluble BCMA (sBCMA) level or activity (e.g., level) is measured in the subject (e.g., in the serum of the subject), e.g., once every week, e.g., for the first month after the beginning of the CAR-expressing cell therapy, once every month, e.g., from the second month to the sixth month after the beginning of the CAR-expressing cell therapy, and/or once every three months, e.g., from the seventh month up to one, two, three or more years after the beginning of the CAR-expressing cell therapy. 
     In some embodiments, an increase in sBCMA level from the reference value or prior time point is indicative of relapse of disease, or minimal residual disease (MRD). In embodiments, an increase in sBCMA level is indicative of MRD after a B cell therapy, e.g., a CD19-targeting therapy or a BCMA-targeting therapy, in B cell malignancies. 
     In other aspects, the present disclosure provides a method of evaluating a subject, e.g., evaluating or monitoring the effectiveness of a CAR-expressing cell therapy in a subject, having a cancer, comprising acquiring a value of a soluble BCMA (sBCMA) level or activity in the subject, wherein said value is indicative of the subject&#39;s responsiveness or relapsing status to the CAR-expressing cell therapy, thereby evaluating the subject. 
     In some aspects, the present disclosure provides a CAR-expressing cell therapy, for use in the treatment of a subject that has been identified as being responsive (e.g., identified as a complete responder, partial responder or a non-relapser) to a therapy comprising a CAR-expressing cell population (e.g., a CAR19-expressing cell population or BCMA-expressing cell population), wherein said identifying comprises acquiring a value of a sBCMA level or activity in the subject. 
     In some aspects, the present disclosure provides a method for treating a subject having a cancer, comprising administering to the subject a therapeutically effective dose of a CAR-expressing cell therapy, if the subject is identified as being responsive (e.g., identified as a complete responder, partial responder or a non-relapser) to a therapy comprising a CAR-expressing cell population (e.g., a CAR19-expressing cell population or BCMA-expressing cell population), wherein said identifying comprises acquiring a value of a sBCMA level or activity in the subject, thereby treating the subject. 
     In some aspects, the present disclosure provides a method of treating a cancer in a subject, comprising: 
     acquiring a value of a sBCMA level or activity in the subject, wherein said value is indicative of the subject&#39;s responsiveness or relapsing status to the CAR-expressing cell therapy, and 
     responsive to said value, performing one, two, three, four, five, six, seven, or more (e.g., all) of: 
     identifying the subject as a responder (e.g., complete responder or partial responder) or non-responder, or a relapser or a non-relapser; 
     administering e.g., to a responder or a non-relapser, a CAR-expressing cell therapy; 
     administering an altered dosing of a CAR-expressing cell therapy; 
     altering the schedule or time course of a CAR-expressing cell therapy; 
     administering, e.g., to a non-responder or a partial responder, an additional agent in combination with a CAR-expressing cell therapy, e.g., a checkpoint inhibitor, e.g., a checkpoint inhibitor described herein; 
     administering to a non-responder or partial responder a therapy that increases the number of younger T cells or naïve T cells in the subject prior to treatment with a CAR-expressing cell therapy; 
     modifying a manufacturing process of a CAR-expressing cell therapy, e.g., enriching for younger T cells or naïve T cells prior to introducing a nucleic acid encoding a CAR, or increasing the transduction efficiency, e.g., for a subject identified as a non-responder or a partial responder; 
     administering an alternative therapy, e.g., for a non-responder or partial responder or relapser, e.g., a standard of care for a particular cancer type; or 
     if the subject is, or is identified as, a non-responder or a relapser, decreasing the T REG  cell population and/or T REG  gene signature, e.g., by depleting CD25 cells, or administration of cyclophosphamide, an anti-GITR antibody, an mTOR inhibitor, or a combination thereof. 
     The disclosure also provides, in certain aspects, a kit for providing a prognosis for success rate of a CAR-expressing cell therapy in a subject having cancer, said kit comprising: 
     a reagent that specifically detects the level or activity of sBCMA, and instructions for using said kit; 
     wherein said instructions for use provide that if one or more of the detected expression levels is different from, e.g., lower than a reference level, the subject is more likely to respond positively to a CAR-expressing cell therapy. 
     The disclosure also provides, in certain aspects, a system for evaluating cancer in a subject, comprising: 
     at least one processor operatively connected to a memory, the at least one processor when executing is configured to: 
     acquire a value of a sBCMA level or activity in the subject, and 
     responsive to a determination of the value, perform one, two, three, four, five, six, seven, or more (e.g., all) of: 
     identify the subject as a responder (e.g., complete responder or partial responder), non-responder, relapser or non-relapser; 
     recommend administering a CAR-expressing cell therapy; 
     recommend a selection or alteration of a dosing of a CAR-expressing cell therapy; 
     recommend a selection or alteration of a schedule or time course of a CAR-expressing cell therapy; 
     recommend administering, e.g., to a non-responder or a partial responder, an additional agent in combination with a CAR-expressing cell therapy, e.g., a checkpoint inhibitor, e.g., a checkpoint inhibitor described herein; 
     recommend administering to a non-responder or partial responder a therapy that increases the number of naïve T cells in the subject prior to treatment with a CAR-expressing cell therapy; 
     recommend modifying a manufacturing process of a CAR-expressing cell therapy, e.g., enrich for naïve T cells prior to introducing a nucleic acid encoding a CAR, e.g., for a subject identified as a non-responder or a partial responder; 
     recommend modifying the CAR-expressing cell product prior to infusion into the patient; recommend adjusting the CAR-expressing cell infusion dose to achieve clinical efficacy; recommend administering an alternative therapy, e.g., for a non-responder or partial responder or relapser; 
     recommend a selection of an alternative therapy, e.g., for a non-responder or partial responder, e.g., a standard of care for a particular cancer type; or 
     if the subject is, or is identified as, a non-responder or a relapser, recommend decreasing the T REG  cell population and/or T REG  gene signature, e.g., by CD25 depletion, administration of cyclophosphamide, an anti-GITR antibody, an mTOR inhibitor, or a combination thereof. 
     In some aspects, the present disclosure provides a method of evaluating a subject, e.g., evaluating or monitoring CRS status (e.g., the risk or level of CRS) or the effectiveness of a CAR-expressing cell therapy in a subject, having a cancer. The method comprises acquiring a value of a level or activity of one or both of APRIL or BAFF in the subject, wherein said value is indicative of the subject&#39;s CRS status, or responsiveness or relapsing status to the CAR-expressing cell therapy, thereby evaluating the subject. 
     In some aspects, the present disclosure provides a method of evaluating a subject, e.g., evaluating or monitoring the effectiveness of a CAR-expressing cell therapy in a subject, having a cancer, comprising acquiring a value of an anti-Sox2 antibody level or activity in the subject, wherein said value is indicative of the subject&#39;s responsiveness or relapsing status to the CAR-expressing cell therapy, thereby evaluating the subject. 
     In some aspects, the present disclosure provides a method of detecting Sox2 antibodies in a subject treated with a CAR-expressing cell therapy, comprising obtaining a biological sample from the subject and contacting the biological sample with an agent that binds Sox2 antibodies, and detecting binding of the agent to a Sox2 antibody. 
     The following embodiments can be combined with any of the aspects herein, e.g., any of the BCMA-related or Sox2-related aspects described herein, e.g., any of the BCMA-related or Sox2-related aspects above. 
     In embodiments, e.g., embodiments wherein sBCMA is detected, the cancer is multiple myeloma. In another embodiment wherein sBCMA is detected the cancer is a leukemia, e.g., CLL. In another embodiment wherein sBCMA is detected the cancer is ALL or NHL. 
     In embodiments, sBCMA is detected using an ELISA assay (e.g., multiplex or single plate), single analyte Luminex assay, ProteinSimple, Simoa, SomaLogic, Singulex, or Olink. 
     In embodiments, the value of sBCMA level or activity is obtained from a blood sample, e.g., a serum sample, e.g., a peripheral serum sample. In embodiments, the value of sBCMA level or activity is not obtained from a bone marrow sample. In embodiments, the method comprises obtaining a blood sample from a subject. In embodiments, the method does not comprise obtaining a bone marrow sample from the subject. 
     In embodiments, a responder (e.g., complete responder or partial responder, e.g., wherein the cancer is multiple myeloma or CLL) has, or is identified as having, a lower level of sBCMA compared to a reference value, e.g., a non-responder level of sBCMA. 
     In other embodiments, a responder (e.g., complete responder or partial responder, e.g., wherein the cancer is ALL or NHL) has, or is identified as having, a higher level of sBCMA compared to a reference value, e.g., a non-responder level of sBCMA. In embodiments, a subject having ALL or NHL has a lower level of sBCMA compared to a reference value, e.g., a level of sBCMA in a non-disease subject. 
     In embodiments, the CAR-expressing cell therapy is a BCMA CAR-expressing cell therapy (e.g., for treating multimple myeloma) or a CD19-expressing cell therapy (e.g., for treating multimple myeloma or CLL). 
     In embodiments, the method further comprises performing one, two, three, four, five, six, seven, or more (e.g., all) of: 
     identifying the subject as a responder (e.g., complete responder or partial responder) or non-responder, or a relapser or a non-relapser; 
     administering a CAR-expressing cell therapy; 
     administered an altered dosing of a CAR-expressing cell therapy; 
     altering the schedule or time course of a CAR-expressing cell therapy; 
     administering, e.g., to a non-responder or a partial responder, an additional agent in combination with a CAR-expressing cell therapy, e.g., a checkpoint inhibitor, e.g., a checkpoint inhibitor described herein; 
     administering to a non-responder or partial responder a therapy that increases the number of younger T cells in the subject prior to treatment with a CAR-expressing cell therapy; 
     modifying a manufacturing process of a CAR-expressing cell therapy, e.g., enriching for younger T cells prior to introducing a nucleic acid encoding a CAR, or increasing the transduction efficiency, e.g., for a subject identified as a non-responder or a partial responder; 
     modifying the CAR-expressing cell product prior to infusion into the patient; 
     adjusting the CAR-expressing cell infusion dose to achieve clinical efficacy; 
     administering an alternative therapy, e.g., for a non-responder or partial responder or relapser; 
     administering an alternative therapy, e.g., for a non-responder or partial responder, e.g., a standard of care for a particular cancer type; or 
     if the subject is, or is identified as, a non-responder or a relapser, decreasing the T REG  cell population and/or T REG  gene signature, e.g., by CD25 depletion, administration of cyclophosphamide, anti-GITR antibody, mTOR inhibitor, or a combination thereof. 
     In embodiments, the CAR-expressing cell therapy comprises a plurality of CAR-expressing immune effector cells. In embodiments, the CAR-expressing cell therapy is a CAR19 therapy (e.g., CTL019 therapy). 
     In embodiments, the value of sBCMA level or activity is obtained from an apheresis sample acquired from the subject, wherein optionally the apheresis sample is evaluated prior to infusion or re-infusion. 
     In embodiments, the subject is evaluated prior to, during, or after receiving the CAR-expressing cell therapy. 
     In embodiments, the subject is a human patient. 
     In embodiments, the method further comprises identifying the subject as a responder (e.g., a complete or partial responder), a non-responder, a relapser or a non-relapser, based on the value of sBCMA level or activity or the value of Sox2 antibody level or activity. 
     In embodiments, the kit comprises a reagent for detecting sBCMA protein levels, e.g., an anti-sBCMA antibody molecule. 
     In embodiments, Sox2 antibody level or activity is measured in a sample taken from a subject that has received at least one dose of a CAR-expressing cell therapy. 
     In embodiments, e.g., embodiments wherein Sox2 antibody is measured, the cancer is multiple myeloma. 
     In some aspects, the present disclosure provides a method of evaluating a subject, e.g., evaluating or monitoring the effectiveness of a CAR-expressing cell therapy (e.g., CD19 CAR, e.g., CTL019) in a subject, having a cancer, comprising acquiring a value of a CAR-expressing cell therapy pharmacokinetic measure in the subject, wherein the pharmacokinetic measure is selected from: 
     a) peak expansion of CAR-expressing cells, e.g., wherein a peak expansion of over about 3, 3.5, 4, 4.5, or 5 (and optionally up to 6) log 10  CAR copies/μg genomic DNA is indicative of response, e.g., CR, PR TD , or PR; 
     b) persistence of CAR-expressing cells, e.g., wherein an AUC of over about 300, 350, 400, 450, or 500 (and optionally up to 600 or 700) log 10  CAR copies/μg genomic DNA over time (e.g., over 12 months) is indicative of response, e.g., CR, PR TD , or PR; or 
     c) in vitro proliferation of CAR-expressing cells, e.g., wherein a CAR-expressing cell fold-expansion of over about 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100 (and optionally up to 100 or 150) fold expansion is indicative of CR, PR TD ; 
     wherein said value is indicative of the subject&#39;s responsiveness or relapsing status to the CAR-expressing cell therapy, thereby evaluating the subject. 
     In some aspects, the present disclosure provides a method of evaluating a subject, e.g., evaluating or monitoring the effectiveness of a CAR-expressing cell therapy in a subject, having a cancer, comprising acquiring a value of a pro-apoptotic signalling molecule level or activity in the subject, wherein said value is indicative of the subject&#39;s responsiveness or relapsing status to the CAR-expressing cell therapy, thereby evaluating the subject. 
     Manufacturing 
     In certain aspects, the disclosure provides a method of making a cell, comprising transducing an immune effector cell, e.g., a T cell or NK cell, with a vector as described herein, e.g., a vector encoding a CAR. In certain aspects, the disclosure provides a method of making a cell, comprising introducing a nucleic acid as described herein (e.g., a nucleic acid encoding a CAR) into an immune effector cell, e.g., a T cell or NK cell. In certain aspects, the disclosure provides a method of generating a population of RNA-engineered cells comprising introducing an in vitro transcribed RNA or synthetic RNA into a cell, where the RNA comprises a nucleic acid as described herein, e.g., a nucleic acid encoding a CAR. 
     In some embodiments, the methods of making disclosed herein further comprise contacting the population of cells, (e.g., CD19 CAR-expressing cells, CD20 CAR-expressing cells, CD22 CAR-expressing cells, B-cell inhibitor cells, or both of CD19 CAR-expressing cells and B-cell inhibitor cells), with a nucleic acid encoding a telomerase subunit, e.g., hTERT. The nucleic acid encoding the telomerase subunit can be DNA. 
     In some embodiments, the method of making disclosed herein further comprises culturing the population of cells, (e.g., a population of CAR-expressing cells, e.g., CD19 CAR-expressing cells, or BCMA CAR-expressing cells), in serum comprising 2% hAB serum. 
     In some aspects, the present disclosure provides a method of evaluating suitability for manufacturing, e.g., high or low suitability for manufacturing (e.g., predicting high manufacturing success or low manufacturing success, e.g., manufacturing fail) of a CAR-expressing cell product, e.g., CAR19-expressing cell product sample (e.g., CTL019 or CTL119), or BCMA-expressing cell product sample. The method comprises: 
     (1) acquiring a sample comprising immune effector cells (e.g., a whole blood sample, peripheral blood sample, or apheresis sample) from a patient having a cancer, e.g., NHL; and 
     (2) evaluating the suitability for manufacturing by determining, from the sample, one, two, three, four, five, six, seven, eight, nine or more (e.g., all) of:
         (i) complete blood count, e.g., complete blood count with differential;   (ii) absolute lymphocyte count (ALC);   (iii) absolute monocyte count (AMC);   (iv) percent or number of lymphocytes;   (v) percent or number of neutrophils;   (vi) percent or number of CD3+CD45+ cells;   (vii) percent or number of monocytes;   (viii) percent or number of CD45 dim or CD45 negative cells;   (ix) percent or number of CD15+ and/or CXCR2+ cells; or   (x) percent or number of suppressive non-lymphoid cell, e.g., myeloid derived suppressor cells (MDSC);   wherein low levels of (i), (ii), (iii), (iv), or (vi) or high levels of (v), (vii), (viii), (ix) or (x) are indicative of low suitability for manufacturing, or   wherein high levels of (i), (ii), (iii), (iv), or (vi) or low levels of (v), (vii), (viii), (ix) or (x) are indicative of high suitability for manufacturing,
 
thereby evaluating the suitability for manufacturing of the CAR-expressing cell product.
       

     In some aspects, the present disclosure provides a method of evaluating a sample, or a method of manufacturing CAR-expressing cells, comprising: 
     (1) acquiring a sample comprising immune effector cells (e.g., a whole blood sample, peripheral blood sample, or apheresis sample) from a patient having a cancer, e.g., NHL; and 
     (2) evaluating one, two, three, four, five, six, seven, eight, nine or more (e.g., all) of:
         (i) complete blood count, e.g., complete blood count with differential;   (ii) absolute lymphocyte count;   (iii) absolute monocyte count;   (iv) percent or number of lymphocytes;   (v) percent or number of neutrophils;   (vi) percent or number of CD3+CD45+ cells;   (vii) percent or number of monocytes;   (viii) percent or number of CD45 dim or CD45 negative cells;   (ix) percent or number of CD15+ and/or CXCR2+ cells; or   (x) percent or number of suppressive non-lymphoid cell, e.g., myeloid derived suppressor cells (MDSC); and       

     (3) optionally contacting the cell sample with a nucleic acid encoding CAR molecule, e.g., a CAR molecule described herein, e.g., a CD19 CAR or a BCMA CAR. 
     In embodiments of any of the manufacturing or evaluating aspects herein, low levels of (i), (ii), (iii), (iv), or (vi) or high levels of (v) or (vii), (viii), (ix) or (x) are indicative of low suitability for manufacturing. 
     In embodiments of any of the manufacturing or evaluating aspects herein, high levels of (i), (ii), (iii), (iv), or (vi) or low levels of (v), (vii), (viii), (ix) or (x) are indicative of high suitability for manufacturing. 
     In embodiments of any of the manufacturing or evaluating aspects herein, the method comprises evaluating two of (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix) or (x). In embodiments, the method comprises evaluating three of (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix) or (x). In embodiments, the method comprises evaluating four of (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix) or (x). In embodiments, the method comprises evaluating five of (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix) or (x). In embodiments, the method comprises evaluating six of (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix) or (x). In embodiments, the method comprises evaluating seven of (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix) or (x). In embodiments, the method comprises evaluating eight of (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix) or (x). In embodiments, the method comprises evaluating nine of (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix) or (x). In embodiments, the method comprises evaluating all of (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix) or (x). 
     In embodiments of any of the manufacturing or evaluating aspects herein, wherein the absolute lymphocyte count is greater than or equal to 500/ul, the sample is suitable for manufacturing, e.g., the likelihood of manufacturing success is about 93%. In embodiments, wherein the absolute lymphocyte count is &lt;500/ul, there is a reduced suitability for manufacturing, e.g., the likelihood of manufacturing success is about 65%. In embodiments, wherein the absolute lymphocyte count is &lt;300/ul, there is a reduced suitability for manufacturing, e.g., the likelihood of manufacturing success is about 40%. In embodiments, wherein the absolute monocyte count is &lt;500/ul, there is a reduced suitability for manufacturing. In embodiments, wherein the percent lymphocytes is &lt;10%, there is a reduced suitability for manufacturing. In embodiments, wherein the percent lymphocytes is &lt;40%, there is a reduced suitability for manufacturing. In embodiments, wherein the percent neutrophils is &gt;60%, there is a reduced suitability for manufacturing. In embodiments, wherein the percent CD3+CD45+ cells (e.g., determined by flow cytometry) is &lt;25%, there is a reduced suitability for manufacturing. In embodiments, wherein the percent monocytes is &gt;60%, there is a reduced suitability for manufacturing. 
     In embodiments of any of the manufacturing or evaluating aspects herein, a sample with high suitability for manufacturing has an at least 50%, 60%, 70%, 80%, or 90% chance of manufacturing success. In embodiments, a sample with low suitability for manufacturing has less than 50%, 40%, 30%, 20%, or 10% chance of manufacturing success. In embodiment, evaluating the likelihood of manufacturing fail comprises identifying the sample as having at least a 50%, 60%, 70%, 80%, or 90% chance of undergoing manufacturing fail. In embodiment, evaluating the likelihood of manufacturing success comprises identifying the sample as having at least a 50%, 60%, 70%, 80%, or 90% chance of undergoing manufacturing success. 
     In embodiments of any of the manufacturing or evaluating aspects herein, e.g., embodiments where the sample has a high suitability for manufacturing, the method further comprises manufacturing one or more CAR-expressing cells from a sample from the subject. In one embodiment, the sample is the same sample that was assayed, and in another embodiment, the sample is a different sample from the subject. In embodiments, the method further comprises contacting a cell sample from the subject with a nucleic acid encoding CAR molecule, e.g., a CAR molecule described herein, e.g., a CD19 CAR or a BCMA CAR. In embodiments the method further comprises freezing and thawing the apheresis sample. In embodiments, the method further comprises determining manufacturing fail or manufacturing success, e.g., based on cell expansion, CAR expression, or transduction efficiency. In embodiments, the method further comprises administering the manufactured cells to the subject. 
     In embodiments of any of the manufacturing or evaluating aspects herein, (e.g., embodiments where the sample has a low suitability for manufacturing), the method further comprises performing a second apheresis collection from the subject. In embodiments (e.g., embodiments where the sample has a low suitability for manufacturing) the method further comprises performing an enrichment, e.g., a modified enrichment, on the apheresis sample, e.g., the first or second apheresis sample. In embodiments the method further comprises freezing and thawing the apheresis sample, e.g., the first or second apheresis sample. In embodiments, the method further comprises evaluating T cell enrichment and/or decrease in suppressive non-lymphoid cells, e.g., myeloid derived suppressor cells (MDSC), e.g., after the second apheresis collection, e.g., after the enrichment or freezing and thawing, of the sample. In embodiments, a decrease in the level, e.g., percent or number, of CD45 dim or CD45 negative cells, e.g., relative to a reference sample (e.g., the first apheresis collection) is indicative of high suitability for manufacturing. In other embodiments, a decrease in the level, e.g., percent or number, of CD15-positive and/or CXCR2-positive cells, e.g., relative to a reference sample (e.g., the first apheresis collection) is indicative of high suitability for manufacturing. 
     In embodiments, (e.g., embodiments where the sample has a low suitability for manufacturing) the method further comprises discarding the cells in the assayed sample. In embodiments, the method further comprises manufacturing one or more CAR-expressing cells from the second apheresis sample. In embodiments, the first apheresis sample underwent manufacturing fail and the second apheresis sample underwent manufacturing success. In embodiments (e.g., embodiments where the sample has a low suitability for manufacturing), the method further comprises manufacturing one or more CAR-expressing cells from a sample from the subject. In one embodiment, the sample is the same sample that was assayed, and in another embodiment, the sample is a different sample from the subject. 
     In embodiments of any of the manufacturing or evaluating aspects herein, the method comprises performing or determining one or more of: complete blood count, flow cytometry phenotyping, cell size, and processing pathway on an apheresis sample. 
     In embodiments of any of the manufacturing or evaluating aspects herein, the method can further include performing a small scale test expansion (TE) to evaluate manufacturing proliferative capacity, e.g., one or more of cell number, cell phenotype (e.g., a cell phenotype as described herein), or transduction efficiency. In embodiments wherein the absolute lymphocyte count is &lt;500/ul, the small scale test expansion can be used to evaluate suitability for manufacturing, e.g., high or low suitability for manufacturing. Small scale test expansion can be carried out, e.g., using the experimental conditions described in Example 37. For example, an aliquot of the apheresis sample can be obtained and cultured under small scale conditions similar to large scale manufacturing conditions. 
     In embodiments, a complete blood count with differential is a complete blood count that identifies the numbers or percentages of different types of blood cells, e.g., white blood cells, e.g., neutrophils, lymphocytes, monocytes, eosinophils, or basophils, in a sample. 
     In another aspect, the invention features a method of evaluating or monitoring the suitability of a sample (e.g., an apheresis sample or a manufactured CAR-expressing cell sample) for a CAR therapy (e.g., a CD19 CAR therapy or a BCMA CAR therapy). The method includes acquiring a value of sample suitability, wherein said value is indicative of the suitability of the CAR-expressing cell sample. In embodiments, the value of sample suitability, comprises a measure of the level or activity of a Stat3 signalling mediator (e.g., IL-6, IL-17, IL-22, IL-31, or CCL20 level or activity) in the CAR-expressing cell, wherein said value is indicative of a subject&#39;s responsiveness or relapsing status to the CAR-expressing cell, thereby evaluating the sample suitability. 
     In another aspect, the invention features a method of evaluating the suitability of a sample (e.g., an apheresis sample) for a CAR therapy (e.g., a CD19 CAR therapy or a BCMA CAR therapy). The method includes acquiring a value of sample suitability, wherein said value is indicative of the suitability of the CAR-expressing cell sample. In embodiments, the value of the sample suitability, comprises a measure of: 
     a) Ki-67 and/or granzyme B level, and 
     b) optionally, CD8 level, 
     c) optionally, CD45RO level, and/or 
     d) optionally, CD27 level, 
     wherein a Ki-67 level that is lower than a reference (e.g., lower than that in a CD8+CD45RO+CD27+ cell or population of cells) is indicative that a subject will be a CR or PR TD  to the CAR-expressing cell, and/or 
     wherein a granzyme B level that is higher than a reference (e.g., lower than that in a CD8+CD45RO+CD27+ cell or population of cells) is indicative that a subject will be a CR or PR TD  to the CAR-expressing cell. 
     In another aspect, the invention features a method of evaluating the suitability of a sample (e.g., an apheresis sample or a manufactured CAR-expressing cell sample) for a CAR therapy (e.g., a CD19 CAR therapy or a BCMA CAR therapy). The method includes acquiring a value of sample suitability, wherein said value is indicative of the suitability of the CAR-expressing cell therapy. 
     In embodiments, the value of sample suitability, comprises a measure of the level or activity of: 
     (i) CAR, 
     (ii) CD8, and 
     (iii) CD27, and/or PD1, 
     (e.g., CAR+CD8+CD27+PD1−) immune effector cells, e.g., in a T cell population, in a sample (e.g., an apheresis sample or a manufactured CAR-expressing cell product sample). 
     In some aspects, the present disclosure provides a method of evaluating a subject, e.g., evaluating or monitoring the effectiveness of a CAR-expressing cell therapy (e.g., CD19 CAR, (e.g., CTL019 or CTL119) or BCMA CAR) in a subject, having a cancer, comprising determining the persistence of the CAR-expressing cell in the subject (e.g., using qPCR or flow cytometry), wherein a persistence that is greater than a reference value (e.g., the average persistence in a NR or PD population) indicates a response, e.g., a complete response. 
     In embodiments, persistence is calculated by an area under the curve (AUC), e.g., AUC28 or AUC84. In embodiments (e.g., involving ALL), an AUC of above about 5×10 5  or 1×10 6  indicates CR. In embodiments (e.g., involving CLL), an AUC of above about 5×10 5  or 1×10 6  indicates CR or PR, and/or an AUC of below about 1×10 5  or 5×10 4  indicates NR/PD. 
     In embodiments, persistence is measured in the peripheral blood or bone marrow. 
     In embodiments, the AUC is determined at a preselected time period after administration of the CAR-expressing cell therapy. In some embodiments, the AUC is determined, e.g., between day 0 and day 45, between day 10 and day 40, between day 15 and day 35, between day 20 and day 30, or between day 0 and ending at day 25, 26, 27, 28, 29, or 30, after administration of the CAR-expressing cell therapy. In some embodiments, the AUC is determined, e.g., between day 0 and day 90, between, or between day 0 and ending at day 80, 82, 84, 85, 86, after administration of the CAR-expressing cell therapy. 
     Any of the aforesaid cell samples can be used in a method of treatment or medical use described herein. 
     CAR Molecules 
     In certain embodiments, the method of treatment comprises a CAR therapy, e.g., administration of one or more cells that express one or more CAR molecules. A cell expressing one or more CAR molecules can be an immune effector cell, e.g., a T cell or NK cell. In an embodiment, the subject is a human. 
     In one embodiment, the cell expressing the CAR molecule comprises a vector that includes a nucleic acid sequence encoding the CAR molecule. In one embodiment, the vector is selected from the group consisting of a DNA, an RNA, a plasmid, a lentivirus vector, adenoviral vector, or a retrovirus vector. In one embodiment, the vector is a lentivirus vector. In one embodiment, the vector further comprises a promoter. In one embodiment, the promoter is an EF-1 promoter. In one embodiment, the EF-1 promoter comprises a sequence of SEQ ID NO: 100. In one embodiment, the vector is an in vitro transcribed vector, e.g., a vector that transcribes RNA of a nucleic acid molecule described herein. In one embodiment, the nucleic acid sequence in the in vitro vector further comprises a poly(A) tail, e.g., a poly A tail described herein, e.g., comprising about 150 adenosine bases. In one embodiment, the nucleic acid sequence in the in vitro vector further comprises a 3′UTR, e.g., a 3′ UTR described herein, e.g., comprising at least one repeat of a 3′UTR derived from human beta-globulin. In one embodiment, the nucleic acid sequence in the in vitro vector further comprises promoter. In one embodiment, the nucleic acid sequence comprises a T2A sequence. 
     In one embodiment, the cell expressing the CAR molecule is a cell described herein, e.g., a human T cell or a human NK cell, e.g., a human T cell described herein or a human NK cell described herein. In one embodiment, the human T cell is a CD8+ T cell. In one embodiment, the human T cell is a CD4+ T cell. In one embodiment, the human T cell is a CD4+/CD8+ T cell. In one embodiment the human T cell is a mixture of CD8+ and CD4+ T cells. In one embodiment, the cell is an autologous T cell. In one embodiment, the cell is an allogeneic T cell. In one embodiment, the cell is a T cell and the T cell is diacylglycerol kinase (DGK) deficient. In one embodiment, the cell is a T cell and the T cell is Ikaros deficient. In one embodiment, the cell is a T cell and the T cell is both DGK and Ikaros deficient. 
     In another embodiment, the cell expressing the CAR molecule, e.g., as described herein, can further express another agent, e.g., an agent which enhances the activity of a CAR-expressing cell. 
     In one embodiment, the method includes administering a cell expressing the CAR molecule, as described herein, in combination with an agent which enhances the activity of a CAR-expressing cell, wherein the agent is a cytokine, e.g., IL-7, IL-15, IL-21, or a combination thereof. The cytokine can be delivered in combination with, e.g., simultaneously or shortly after, administration of the CAR-expressing cell. Alternatively, the cytokine can be delivered after a prolonged period of time after administration of the CAR-expressing cell, e.g., after assessment of the subject&#39;s response to the CAR-expressing cell. 
     For example, in one embodiment, the agent that enhances the activity of a CAR-expressing cell can be an agent which inhibits an immune inhibitory molecule. Examples of immune inhibitory molecules include PD1, PD-L1, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and TGF beta. In one embodiment, the agent that inhibits an immune inhibitory molecule comprises a first polypeptide, e.g., an inhibitory molecule, associated with a second polypeptide that provides a positive signal to the cell, e.g., an intracellular signaling domain described herein. In one embodiment, the agent comprises a first polypeptide, e.g., of an immune inhibitory molecule such as PD1, PD-L1, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGF beta, or a fragment of any of these (e.g., at least a portion of the extracellular domain of any of these), and a second polypeptide which is an intracellular signaling domain described herein (e.g., comprising a costimulatory domain (e.g., 41BB, CD27 or CD28, e.g., as described herein) and/or a primary signaling domain (e.g., a CD3 zeta signaling domain described herein). In one embodiment, the agent comprises a first polypeptide of PD1 or a fragment thereof (e.g., at least a portion of the extracellular domain of PD1), and a second polypeptide of an intracellular signaling domain described herein (e.g., a CD28 signaling domain described herein and/or a CD3 zeta signaling domain described herein). 
     In one embodiment, lymphocyte infusion, for example allogeneic lymphocyte infusion, is used in the treatment of the cancer, wherein the lymphocyte infusion comprises at least one CD19 CAR-expressing cell or BCMA CAR-expressing cell described herein and optionally at least one cell expressing a CAR directed against a B-cell antigen. In one embodiment, autologous lymphocyte infusion is used in the treatment of the cancer, wherein the autologous lymphocyte infusion comprises at least one CD19-expressing cell or at least one BCMA-expressing cell, and optionally at least one cell expressing a CAR directed against a B-cell antigen. 
     In one embodiment, the CAR expressing cell, e.g., T cell, is administered to a subject that has received a previous stem cell transplantation, e.g., autologous stem cell transplantation, or a subject that has received a previous dose of melphalan. 
     In one embodiment, the cell expressing the CAR molecule, e.g., a CAR molecule described herein, is administered in combination with an agent that ameliorates one or more side effect associated with administration of a cell expressing a CAR molecule or with administration of the B-cell inhibitor, e.g., an agent described herein. 
     In one embodiment, the cell expressing the CAR molecule, e.g., a CD19 CAR or BCMA CAR molecule described herein, and the B-cell inhibitor are administered in combination with an additional agent that treats the disease associated with CD19, e.g., an additional agent described herein. 
     In one embodiment, the cells expressing a CAR molecule, e.g., a CAR molecule described herein, are administered at a dose and/or dosing schedule described herein. 
     In one embodiment, the CAR molecule is introduced into T cells, e.g., using in vitro transcription, and the subject (e.g., human) receives an initial administration of cells comprising a CAR molecule, and one or more subsequent administrations of cells comprising a CAR molecule, wherein the one or more subsequent administrations are administered less than 15 days, e.g., 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 days after the previous administration. In one embodiment, more than one administration of cells comprising a CAR molecule are administered to the subject (e.g., human) per week, e.g., 2, 3, or 4 administrations of cells comprising a CAR molecule are administered per week. In one embodiment, the subject (e.g., human subject) receives more than one administration of cells comprising a CAR molecule per week (e.g., 2, 3 or 4 administrations per week) (also referred to herein as a cycle), followed by a week of no administration of cells comprising a CAR molecule, and then one or more additional administration of cells comprising a CAR molecule (e.g., more than one administration of the cells comprising a CAR molecule per week) is administered to the subject. In another embodiment, the subject (e.g., human subject) receives more than one cycle of cells comprising a CAR molecule, and the time between each cycle is less than 10, 9, 8, 7, 6, 5, 4, or 3 days. In one embodiment, the cells comprising a CAR molecule are administered every other day for 3 administrations per week. In one embodiment, the cells comprising a CAR molecule are administered for at least two, three, four, five, six, seven, eight or more weeks. 
     In one embodiment, a population of cells described herein is administered. In some embodiments the population of cells is isolated or purified. 
     In one embodiment, the 4-1BB costimulatory domain comprises a sequence of SEQ ID NO: 16. In one embodiment, the 4-1BB costimulatory domain comprises an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 20, 10 or 5 modifications (e.g., substitutions) of an amino acid sequence of SEQ ID NO: 16, or a sequence with at least 95%, e.g., 95-99%, identity to an amino acid sequence of SEQ ID NO:16. In one embodiment, the 4-1BB costimulatory domain is encoded by a nucleic acid sequence of SEQ ID NO:60, or a sequence with at least 95%, e.g., 95-99%, identity thereof. 
     In one embodiment, the CD27 costimulatory domain comprises a sequence of SEQ ID NO: 16. In one embodiment, the CD27 costimulatory domain comprises an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 20, 10 or 5 modifications (e.g., substitutions) of an amino acid sequence of SEQ ID NO: 16, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO:16. In one embodiment, the CD27 costimulatory domain is encoded by a nucleic acid sequence of SEQ ID NO:17, or a sequence with at least 95%, e.g., 95-99%, identity thereof. 
     In one embodiment, the CD28 costimulatory domain comprises a sequence of SEQ ID NO: 1317. In one embodiment, the CD28 costimulatory domain comprises an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 20, 10 or 5 modifications (e.g., substitutions) of an amino acid sequence of SEQ ID NO: 1317, or a sequence with at least 95%, e.g., 95-99%, identity to an amino acid sequence of SEQ ID NO:1317. In one embodiment, the CD28 costimulatory domain is encoded by a nucleic acid sequence of SEQ ID NO:1318, or a sequence with at least 95%, e.g., 95-99%, identity thereof. 
     In one embodiment, the wild-type ICOS costimulatory domain comprises a sequence of SEQ ID NO: 1319. In one embodiment, the wild-type ICOS costimulatory domain comprises an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 20, 10 or 5 modifications (e.g., substitutions) of an amino acid sequence of SEQ ID NO: 1319, or a sequence with at least 95%, e.g., 95-99%, identity to an amino acid sequence of SEQ ID NO: 1319. In one embodiment, the wild-type ICOS costimulatory domain is encoded by a nucleic acid sequence of SEQ ID NO: 1320, or a sequence with at least 95%, e.g., 95-99%, identity thereof. 
     In one embodiment, the Y to F mutant ICOS costimulatory domain comprises a sequence of SEQ ID NO: 1321. In one embodiment, the Y to F mutant ICOS costimulatory domain comprises an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 20, 10 or 5 modifications (e.g., substitutions) of an amino acid sequence of SEQ ID NO: 1321, or a sequence with at least 95%, e.g., 95-99%, identity to an amino acid sequence of SEQ ID NO: 1321. In one embodiment, the Y to F mutant ICOS costimulatory domain is encoded by a nucleic acid sequence with at least 95%, e.g., 95-99%, identity to a nucleic acid sequence of SEQ ID NO:1320 (wherein SEQ ID NO: 1320 encodes wild-type ICOS). 
     In embodiments, the primary signaling domain comprises a functional signaling domain of CD3 zeta. In embodiments, the functional signaling domain of CD3 zeta comprises SEQ ID NO: 17 (mutant CD3 zeta) or SEQ ID NO: 43 (wild-type human CD3 zeta). 
     In one embodiment, the method includes administering a population of cells wherein at least one cell in the population expresses a CAR, e.g., having an anti-CD19 domain described herein, and an agent which enhances the activity of a CAR-expressing cell, e.g., a second cell expressing the agent which enhances the activity of a CAR-expressing cell. For example, in one embodiment, the agent can be an agent which inhibits an immune inhibitory molecule. Examples of immune inhibitory molecules include PD1, PD-L1, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and TGF beta. In one embodiment, the agent that inhibits an immune inhibitory molecule comprises a first polypeptide, e.g., an inhibitory molecule, associated with a second polypeptide that provides a positive signal to the cell, e.g., an intracellular signaling domain described herein. In one embodiment, the agent comprises a first polypeptide, e.g., of an inhibitory molecule such as PD1, PD-L1, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGF beta, or a fragment of any of these (e.g., at least a portion of an extracellular domain of any of these), and a second polypeptide which is an intracellular signaling domain described herein (e.g., comprising a costimulatory domain (e.g., 41BB, CD27 or CD28, e.g., as described herein) and/or a primary signaling domain (e.g., a CD3 zeta signaling domain described herein). In one embodiment, the agent comprises a first polypeptide of PD1 or a fragment thereof (e.g., at least a portion of the extracellular domain of PD1), and a second polypeptide of an intracellular signaling domain described herein (e.g., a CD28 signaling domain described herein and/or a CD3 zeta signaling domain described herein). 
     In an embodiment, the method further comprises transplanting a cell, e.g., a hematopoietic stem cell, or a bone marrow, into the mammal. 
     In one embodiment, the method includes administering a population of cells comprising a CAR described herein, e.g., a CAR having an anti-CD19 domain described herein, and an agent which enhances the activity of a CAR-expressing cell, wherein the agent is a cytokine, e.g., IL-7, IL-15, IL-21, or a combination thereof. The cytokine can be delivered in combination with, e.g., simultaneously or shortly after, administration of the CAR-expressing cell(s). Alternatively, the cytokine can be delivered after a prolonged period of time after administration of the CAR-expressing cell(s), e.g., after assessment of the subject&#39;s response to the CAR-expressing cell(s). Related compositions for use and methods of making a medicament are also provided. 
     In an embodiment, the composition is a pharmaceutically acceptable composition. 
     In some embodiment, the CAR molecules described herein include a binding domain, e.g., a CD19- or BCMA-binding domain as described herein. 
     In one embodiment, the CAR molecule comprises a transmembrane domain of a protein selected from the group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154. In one embodiment, the transmembrane domain comprises a sequence of SEQ ID NO: 15. In one embodiment, the transmembrane domain comprises an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 20, 10 or 5 modifications (e.g., substitutions) of an amino acid sequence of SEQ ID NO: 15, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO: 15. 
     In one embodiment, the binding domain is connected to the transmembrane domain by a hinge region, e.g., a hinge region described herein. In one embodiment, the encoded hinge region comprises SEQ ID NO:14 or SEQ ID NO:45, or a sequence with 95-99% identity thereof. 
     In one embodiment, the CAR molecule further comprises a sequence encoding a costimulatory domain, e.g., a costimulatory domain described herein. In one embodiment, the costimulatory domain comprises a functional signaling domain of a protein selected from the group consisting of OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), and 4-1BB (CD137). In one embodiment, the costimulatory domain comprises a sequence of SEQ ID NO: 16. In one embodiment, the costimulatory domain comprises a sequence of SEQ ID NO:51. In one embodiment, the costimulatory domain comprises an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 20, 10 or 5 modifications (e.g., substitutions) of an amino acid sequence of SEQ ID NO: 16 or SEQ ID NO:51, or a sequence with at least 95%, e.g., 95-99%, identity to an amino acid sequence of SEQ ID NO: 16 or SEQ ID NO:51. In one embodiment, the costimulatory domain comprises a functional signaling domain of a protein selected from the group consisting of MHC class I molecule, TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CD11a/CD18), 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, and a ligand that specifically binds with CD83. In embodiments, the costimulatory domain comprises 4-1BB, CD27, CD28, or ICOS. 
     In one embodiment, the CAR molecule further comprises a sequence encoding an intracellular signaling domain, e.g., an intracellular signaling domain described herein. In one embodiment, the intracellular signaling domain comprises a functional signaling domain of 4-1BB and/or a functional signaling domain of CD3 zeta. In one embodiment, the intracellular signaling domain comprises the sequence of SEQ ID NO: 16 and/or the sequence of SEQ ID NO:17. In one embodiment, the intracellular signaling domain comprises the sequence of SEQ ID NO:16 and/or the sequence of SEQ ID NO:43. In one embodiment, the intracellular signaling domain comprises a functional signaling domain of CD27 and/or a functional signaling domain of CD3 zeta. In one embodiment, the intracellular signaling domain comprises the sequence of SEQ ID NO: 51 and/or the sequence of SEQ ID NO:17. In one embodiment, the intracellular signaling domain comprises the sequence of SEQ ID NO:51 and/or the sequence of SEQ ID NO:43. In one embodiment, the intracellular signaling domain comprises an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 20, 10 or 5 modifications (e.g., substitutions) of an amino acid sequence of SEQ ID NO:16 or SEQ ID NO:51 and/or an amino acid sequence of SEQ ID NO:17 or SEQ ID NO:43, or a sequence with at least 95%, e.g., 95-99%, identity to an amino acid sequence of SEQ ID NO:16 or SEQ ID NO:51 and/or an amino acid sequence of SEQ ID NO:17 or SEQ ID NO:43. In one embodiment, the intracellular signaling domain comprises the sequence of SEQ ID NO:16 or SEQ ID NO:51 and the sequence of SEQ ID NO: 17 or SEQ ID NO:43, wherein the sequences comprising the intracellular signaling domain are expressed in the same frame and as a single polypeptide chain. 
     In one embodiment, the CAR molecule further comprises a leader sequence, e.g., a leader sequence described herein. In one embodiment, the leader sequence comprises an amino acid sequence of SEQ ID NO: 13, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO:13. 
     In one aspect, the CAR (e.g., a CD19 CAR or a BCMA CAR) comprises an optional leader sequence (e.g., an optional leader sequence described herein), an extracellular antigen binding domain, a hinge (e.g., hinge described herein), a transmembrane domain (e.g., transmembrane domain described herein), and an intracellular stimulatory domain (e.g., intracellular stimulatory domain described herein). In one aspect an exemplary CAR construct comprises an optional leader sequence (e.g., a leader sequence described herein), an extracellular antigen binding domain, a hinge, a transmembrane domain, an intracellular costimulatory domain (e.g., an intracellular costimulatory domain described herein) and an intracellular stimulatory domain. 
     CAR which comprises a transmembrane domain that comprises a transmembrane domain of a protein selected from the group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154. In embodiments, the antigen binding domain is connected to the transmembrane domain by a hinge region. In embodiments, the hinge region comprises SEQ ID NO:14, or a sequence with 95-99% identity thereof. In embodiments, the costimulatory domain is a functional signaling domain obtained from a protein selected from the group consisting of OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), and 4-1BB (CD137). In embodiments, the costimulatory domain is a functional signaling domain obtained from a protein selected from the group consisting of MHC class I molecule, TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CD11a/CD18), 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, and a ligand that specifically binds with CD83. In embodiments, the costimulatory domain comprises a sequence of SEQ ID NO:16 or SEQ ID NO:51. In embodiments, the intracellular signaling domain comprises a functional signaling domain of 4-1BB and/or a functional signaling domain of CD3 zeta. 
     In embodiments, the intracellular signaling domain comprises the sequence of SEQ ID NO: 16 and/or the sequence of SEQ ID NO:17 or SEQ ID NO:43. In embodiments, the CAR further comprises a leader sequence. In embodiments, the leader sequence comprises SEQ ID NO: 13. 
     In embodiments, the cells that express the CAR molecule comprise T cells or NK cells. 
     CD19 Inhibitors 
     In embodiments, the CD19 inhibitor is a small molecule, an antibody, a fragment of an antibody, or a cell therapy, e.g., a cell that expresses a CAR molecule comprising an anti-CD19 binding domain. 
     In one embodiment, the cell expresses a CAR molecule comprising an anti-CD19 binding domain (e.g., a murine or humanized antibody or antibody fragment that specifically binds to CD19), a transmembrane domain, and an intracellular signaling domain (e.g., an intracellular signaling domain comprising a costimulatory domain and/or a primary signaling domain). In one embodiment, the CAR comprises an antibody or antibody fragment which includes an anti-CD19 binding domain described herein (e.g., a murine or humanized antibody or antibody fragment that specifically binds to CD19 as described herein), a transmembrane domain described herein, and an intracellular signaling domain described herein (e.g., an intracellular signaling domain comprising a costimulatory domain and/or a primary signaling domain described herein). 
     In one embodiment, the CAR molecule comprises an anti-CD19 binding domain comprising one or more (e.g., all three) light chain complementary determining region 1 (LC CDR1), light chain complementary determining region 2 (LC CDR2), and light chain complementary determining region 3 (LC CDR3) of an anti-CD19 binding domain described herein, and one or more (e.g., all three) heavy chain complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary determining region 3 (HC CDR3) of an anti-CD19 binding domain described herein, e.g., an anti-CD19 binding domain comprising one or more, e.g., all three, LC CDRs and one or more, e.g., all three, HC CDRs. In one embodiment, the anti-CD19 binding domain comprises one or more (e.g., all three) heavy chain complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary determining region 3 (HC CDR3) of an anti-CD19 binding domain described herein, e.g., the anti-CD19 binding domain has two variable heavy chain regions, each comprising a HC CDR1, a HC CDR2 and a HC CDR3 described herein. In one embodiment, the anti-CD19 binding domain comprises a murine light chain variable region described herein (e.g., in Table 3) and/or a murine heavy chain variable region described herein (e.g., in Table 3). In one embodiment, the anti-CD19 binding domain is a scFv comprising a murine light chain and a murine heavy chain of an amino acid sequence of Table 3. In an embodiment, the anti-CD19 binding domain (e.g., an scFv) comprises: a light chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a light chain variable region provided in Table 3, or a sequence with at least 95%, e.g., 95-99%, identity with an amino acid sequence of Table 3; and/or a heavy chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a heavy chain variable region provided in Table 3, or a sequence with 95-99% identity to an amino acid sequence of Table 3. In one embodiment, the anti-CD19 binding domain comprises a sequence of SEQ ID NO:59, or a sequence with at least 95%, e.g., 95-99%, identity thereof. In one embodiment, the anti-CD19 binding domain is a scFv, and a light chain variable region comprising an amino acid sequence described herein, e.g., in Table 3, is attached to a heavy chain variable region comprising an amino acid sequence described herein, e.g., in Table 3, via a linker, e.g., a linker described herein. In one embodiment, the anti-CD19 binding domain includes a (Gly 4 -Ser)n linker, wherein n is 1, 2, 3, 4, 5, or 6, e.g., 3 or 4 (SEQ ID NO: 53). The light chain variable region and heavy chain variable region of a scFv can be, e.g., in any of the following orientations: light chain variable region-linker-heavy chain variable region or heavy chain variable region-linker-light chain variable region. 
     In one embodiment, the CAR molecule comprises a humanized anti-CD19 binding domain that includes one or more (e.g., all three) light chain complementary determining region 1 (LC CDR1), light chain complementary determining region 2 (LC CDR2), and light chain complementary determining region 3 (LC CDR3) of a humanized anti-CD19 binding domain described herein, and one or more (e.g., all three) heavy chain complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary determining region 3 (HC CDR3) of a humanized anti-CD19 binding domain described herein, e.g., a humanized anti-CD19 binding domain comprising one or more, e.g., all three, LC CDRs and one or more, e.g., all three, HC CDRs. In one embodiment, the humanized anti-CD19 binding domain comprises at least HC CDR2. In one embodiment, the humanized anti-CD19 binding domain comprises one or more (e.g., all three) heavy chain complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary determining region 3 (HC CDR3) of a humanized anti-CD19 binding domain described herein, e.g., the humanized anti-CD19 binding domain has two variable heavy chain regions, each comprising a HC CDR1, a HC CDR2 and a HC CDR3 described herein. In one embodiment, the humanized anti-CD19 binding domain comprises at least HC CDR2. In one embodiment, the light chain variable region comprises one, two, three or all four framework regions of VK3_L25 germline sequence. In one embodiment, the light chain variable region has a modification (e.g., substitution, e.g., a substitution of one or more amino acid found in the corresponding position in the murine light chain variable region of SEQ ID NO: 58, e.g., a substitution at one or more of positions 71 and 87). In one embodiment, the heavy chain variable region comprises one, two, three or all four framework regions of VH4_4-59 germline sequence. In one embodiment, the heavy chain variable region has a modification (e.g., substitution, e.g., a substitution of one or more amino acid found in the corresponding position in the murine heavy chain variable region of SEQ ID NO: 58, e.g., a substitution at one or more of positions 71, 73 and 78). In one embodiment, the humanized anti-CD19 binding domain comprises a light chain variable region described herein (e.g., in Table 2) and/or a heavy chain variable region described herein (e.g., in Table 2). In one embodiment, the humanized anti-CD19 binding domain is a scFv comprising a light chain and a heavy chain of an amino acid sequence of Table 2. In an embodiment, the humanized anti-CD19 binding domain (e.g., an scFv) comprises: a light chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a light chain variable region provided in Table 2, or a sequence with at least 95%, e.g., 95-99%, identity with an amino acid sequence of Table 2; and/or a heavy chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a heavy chain variable region provided in Table 2, or a sequence with at least 95%, e.g., 95-99%, identity to an amino acid sequence of Table 2. In one embodiment, the humanized anti-CD19 binding domain comprises a sequence selected from a group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO: 4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12, or a sequence with 95-99% identity thereof. In one embodiment, the humanized anti-CD19 binding domain is a scFv, and a light chain variable region comprising an amino acid sequence described herein, e.g., in Table 2, is attached to a heavy chain variable region comprising an amino acid sequence described herein, e.g., in Table 2, via a linker, e.g., a linker described herein. In one embodiment, the humanized anti-CD19 binding domain includes a (Gly4-Ser)n linker, wherein n is 1, 2, 3, 4, 5, or 6, e.g., 3 or 4 (SEQ ID NO: 53). The light chain variable region and heavy chain variable region of a scFv can be, e.g., in any of the following orientations: light chain variable region-linker-heavy chain variable region or heavy chain variable region-linker-light chain variable region. 
     In one embodiment of the preceding methods, the murine CAR molecule that binds to CD19 comprises: 
     (i) one or more of (e.g., all three of) heavy chain complementary determining region 1 (HCDR1), HCDR2, and HCDR3 of any CD19 scFv domain amino acid sequence listed in Table 3 and one or more of (e.g., all three of) light chain complementary determining region 1 (LCDR1), LCDR2, and LCDR3 of any CD19 scFv domain amino acid sequence listed in Table 3, 
     (ii) a heavy chain variable region (VH) of any CD19 scFv domain amino acid sequence listed in Table 3 and a light chain variable region (VL) of any CD19 scFv domain amino acid sequence listed in Table 3, 
     (iii) a CD19 scFv domain amino acid sequence listed in Table 3 (e.g., SEQ ID NO: 59, 109, 111, or 114), or 
     (iv) a full-length CD19 CAR amino acid sequence listed in Table 3 (e.g., SEQ ID NO: 110, 112, 113, or 115, or residues 22-486 of SEQ ID NO: 58). 
     In one embodiment of the preceding methods, the humanized CAR molecule that binds to CD19 comprises: 
     (i) one or more of (e.g., all three of) heavy chain complementary determining region 1 (HCDR1), HCDR2, and HCDR3 of any CD19 scFv domain amino acid sequence listed in Table 2 and one or more of (e.g., all three of) light chain complementary determining region 1 (LCDR1), LCDR2, and LCDR3 of any CD19 scFv domain amino acid sequence listed in Table 2, 
     (ii) a heavy chain variable region (VH) of any CD19 scFv domain amino acid sequence listed in Table 2 and a light chain variable region (VL) of any CD19 scFv domain amino acid sequence listed in Table 2, 
     (iii) a CD19 scFv domain amino acid sequence listed in Table 2 (e.g., any one of SEQ ID NOs: 1-12), or 
     (iv) a full-length CD19 CAR amino acid sequence listed in Table 2 (e.g., residues 22-486 of any one of SEQ ID NOs: 31-34 or 42, or residues 22-491 of any one of SEQ ID NOs: 35-41). In one embodiment, the CAR molecule comprises an anti-CD19 binding domain that includes one or more (e.g., 2, 3, 4, 5, or 6) LC CDR1, LC CDR2, LC CDR3, HC CDR1, HC CDR2, and HC CDR3 of a construct of Table 4 and 5, e.g., murine_CART19, humanized_CART19 a, humanized_CART19 b, or humanized_CART19 c. 
     In one embodiment, the CAR molecule comprises a leader sequence, e.g., a leader sequence described herein, e.g., a leader sequence of SEQ ID NO: 13, or having 95-99% identity thereof; an anti-CD19 binding domain described herein, e.g., an anti-CD19 binding domain comprising a LC CDR1, a LC CDR2, a LC CDR3, a HC CDR1, a HC CDR2 and a HC CDR3 described herein, e.g., a murine anti-CD19 binding domain described in Table 3, e.g., CTL019, a humanized anti-CD19 binding domain described in Table 2, e.g., CTL119, or a sequence with at least 95%, e.g., 95-99%, identity thereof; a hinge region, e.g., a hinge region described herein, e.g., a hinge region of SEQ ID NO:14 or having at least 95%, e.g., 95-99%, identity thereof; a transmembrane domain, e.g., a transmembrane domain described herein, e.g., a transmembrane domain having a sequence of SEQ ID NO:15 or a sequence having at least 95%, e.g., 95-99%, identity thereof; an intracellular signaling domain, e.g., an intracellular signaling domain described herein (e.g., an intracellular signaling domain comprising a costimulatory domain and/or a primary signaling domain). In one embodiment, the intracellular signaling domain comprises a costimulatory domain, e.g., a costimulatory domain described herein, e.g., a 4-1BB costimulatory domain having a sequence of SEQ ID NO:16 or SEQ ID NO:51, or having at least 95%, e.g., 95-99%, identity thereof, and/or a primary signaling domain, e.g., a primary signaling domain described herein, e.g., a CD3 zeta stimulatory domain having a sequence of SEQ ID NO:17 or SEQ ID NO:43, or having at least 95%, e.g., 95-99%, identity thereof. 
     In one embodiment, the CAR molecule comprises (e.g., consists of) an amino acid sequence of SEQ ID NO:58, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41 or SEQ ID NO:42, or an amino acid sequence having at least one, two, three, four, five, 10, 15, 20 or 30 modifications (e.g., substitutions) but not more than 60, 50 or 40 modifications (e.g., substitutions) of an amino acid sequence of SEQ ID NO:58, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41 or SEQ ID NO:42, or an amino acid sequence having 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to an amino acid sequence of SEQ ID NO:58, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41 or SEQ ID NO:42. 
     In some embodiments, the CD19 inhibitor comprises an antibody molecule having, e.g., an antibody molecule having a CD19-binding sequence as described herein. For instance, the antibody molecule may comprise CDRs or a VH and VL as described in any of Tables 2, 3, 4, and 5, or a sequence with homology thereto, e.g., having at least 95%, e.g., 95-99%, identity thereto. The antibody molecule may comprise a CD19-binding region having a sequence described in this section, e.g., in the context of a CAR. 
     In some embodiments, the CD19 inhibitor, e.g., the CD19 CAR, can be used to treat a hematological malignancy. In embodiments, the CD19 inhibitor, e.g., the CD19 CAR, can be used to treat a disease associated with CD19 expression. 
     In one embodiment, the disease associated with CD19 expression is selected from a proliferative disease such as a cancer or malignancy or a precancerous condition such as a myelodysplasia, a myelodysplastic syndrome or a preleukemia, or is a non-cancer related indication associated with expression of CD19. In one embodiment, the disease is a solid or a liquid tumor. In one embodiment, the cancer is a pancreatic cancer. In one embodiment, the disease is a hematologic cancer. In one embodiment, the hematologic cancer is a leukemia. In one embodiment, the cancer is selected from the group consisting of one or more acute leukemias including but not limited to B-cell acute lymphoid leukemia (BALL), T-cell acute lymphoid leukemia (TALL), small lymphocytic leukemia (SLL), acute lymphoid leukemia (ALL) (e.g., relapsing and refractory ALL); one or more chronic leukemias including but not limited to chronic myelogenous leukemia (CML), and chronic lymphocytic leukemia (CLL). Additional hematologic cancers or conditions include, but are not limited to mantle cell lymphoma (MCL), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt&#39;s lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, Marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin lymphoma, Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and “preleukemia.” Preleukemia encompasses a diverse collection of hematological conditions united by ineffective production (or dysplasia) of myeloid blood cells In embodiments, a disease associated with CD19 expression include, but not limited to atypical and/or non-classical cancers, malignancies, precancerous conditions or proliferative diseases expressing CD19; and any combination thereof. 
     In one embodiment, the disease associated with expression of CD19 is a lymphoma, e.g., MCL or Hodgkin lymphoma. In one embodiment, the disease associated with expression of CD19 is leukemia, e.g., SLL, CLL and/or ALL. 
     In an embodiment, the subject (e.g., a subject to be treated with a CD19 CAR, optionally in combination with a second agent such as a PD1 inhibitor or PD-L1 inhibitor) has, or is identified as having, at least 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cancer cells, e.g., DLBCL cells, which are CD3+/PD1+. 
     In an embodiment, the subject has relapsed or is identified as having relapsed after treatment with the one or more cells that express a CAR molecule that binds CD19, e.g., a CD19 CAR. In an embodiment, the subject has relapsed or is identified as having relapsed based on one or more of reappearance of blasts in the blood, bone marrow (&gt;5%), or any extramedullary site, after a complete response. In an embodiment, the subject has relapsed or is identified as having relapsed based on detection of CD19-blasts above a predetermined threshold, e.g., over 1%, 2%, 3%, 4%, 5%, or 10%. 
     BCMA Inhibitors 
     In embodiments the BCMA CAR comprises an anti-BCMA binding domain (e.g., human or humanized anti-BCMA binding domain), a transmembrane domain, and an intracellular signaling domain, and wherein said anti-BCMA binding domain comprises a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) of any anti-BMCA heavy chain binding domain amino acid sequences listed in Table 4D or 4E. In embodiments, the anti-BCMA binding domain comprises a light chain variable region described herein (e.g., in Table 4D or 4E) and/or a heavy chain variable region described herein (e.g., in Table 4D or 4E). In some embodiments, the CDRs are defined according to the Kabat numbering scheme, the Chothia numbering scheme, or a combination thereof. 
     In one embodiment of the preceding methods, the CAR molecule that binds to BCMA comprises: 
     (i) one or more of (e.g., all three of) heavy chain complementary determining region 1 (HCDR1), HCDR2, and HCDR3 of any CD19 scFv domain amino acid sequence listed in Table 4D or 4E and one or more of (e.g., all three of) light chain complementary determining region 1 (LCDR1), LCDR2, and LCDR3 of any CD19 scFv domain amino acid sequence listed in Table 4D or 4E, 
     (ii) a heavy chain variable region (VH) listed in Table 4D or 4E and a light chain variable region (VL) listed in Table 4D or 4E, 
     (iii) a BCMA scFv domain amino acid sequence listed in Table 4D or 4E (e.g., any one of SEQ ID NOs: 1400, 1406, 1412, 1418, 1424, 1430, 1436, 1442, 1448, 1454, 1460, 1466, 1472, 1478, 1485, 1491, 1497, 1503, 1509, 1515, 1521, 1527, 1533, 1539, 1545, 1551, 1557, 1563, 1569, 1575, 1581, 1587, 1593, 1599, 1605, 1611, 1619, 1623, 1627, or 1631), or 
     (iv) a full-length BCMA CAR amino acid sequence listed in Table 4D or 4E (e.g., residues 22-483 of SEQ ID NO: 1404, residues 22-490 of SEQ ID NO: 1410, residues 22-488 of SEQ ID NO: 1416, residues 22-487 of SEQ ID NO: 1422, residues 22-493 of SEQ ID NO: 1428, residues 22-490 of SEQ ID NO: 1434, residues 22-491 of SEQ ID NO: 1440, residues 22-482 of SEQ ID NO: 1446, residues 22-483 of SEQ ID NO: 1452, residues 22-485 of SEQ ID NO: 1458, residues 22-483 of SEQ ID NO: 1464, residues 22-490 of SEQ ID NO: 1470, residues 22-483 of SEQ ID NO: 1476, residues 22-484 of SEQ ID NO: 1483, residues 22-485 of SEQ ID NO: 1489, residues 22-487 of SEQ ID NO: 1495, residues 23-489 of SEQ ID NO: 1501, residues 22-490 of SEQ ID NO: 1507, residues 22-484 of SEQ ID NO: 1513, residues 22-485 of SEQ ID NO: 1519, residues 22-489 of SEQ ID NO: 1525, residues 22-497 of SEQ ID NO: 1531, residues 22-492 of SEQ ID NO: 1537, residues 22-490 of SEQ ID NO: 1543, residues 22-485 of SEQ ID NO: 1549, residues 22-492 of SEQ ID NO: 1555, residues 22-492 of SEQ ID NO: 1561, residues 22-483 of SEQ ID NO: 1567, residues 22-490 of SEQ ID NO: 1573, residues 22-485 of SEQ ID NO: 1579, residues 22-486 of SEQ ID NO: 1585, residues 22-492 of SEQ ID NO: 1591, residues 22-488 of SEQ ID NO: 1597, residues 22-488 of SEQ ID NO: 1603, residues 22-495 of SEQ ID NO: 1609, residues 22-490 of SEQ ID NO: 1615, SEQ ID NO: 1620, SEQ ID NO: 1624, SEQ ID NO: 1628, or SEQ ID NO: 1632). 
     In one embodiment of the preceding methods, the CAR molecule comprises: 
     (i) an scFv; 
     (ii) a transmembrane domain that comprises a transmembrane domain of a protein selected from the group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154; 
     (iii) a hinge region comprising SEQ ID NO:14, or a sequence with 95-99% identity thereof; 
     (iv) a costimulatory domain that is a functional signaling domain obtained from a protein selected from the group consisting of OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), and 4-1BB (CD137), wherein optionally the costimulatory domain comprises the amino acid sequence of SEQ ID NO:16 or 51; 
     (v) an intracellular signaling domain comprising a functional signaling domain of 4-1BB and/or a functional signaling domain of CD3 zeta; e.g., an intracellular signaling domain comprising the sequence of SEQ ID NO: 16 and/or the sequence of SEQ ID NO:17 or 43; or (vi) a leader sequence, optionally wherein the leader sequence comprises the amino acid sequence of SEQ ID NO: 13. 
     In one embodiment, the BCMA CAR-expressing cell comprises a nucleic acid encoding a CAR molecule, wherein the CAR molecule comprises an anti-BCMA binding domain, a transmembrane domain, and an intracellular signaling domain. 
     In one embodiment, the encoded anti-BCMA binding domain comprises: 
     a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VHCDR1), a VHCDR2, and a VHCDR3 of any anti-BCMA heavy chain binding domain amino acid sequence listed in Tables 4D, 4E, 4G, 4I, and 4F (or a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g., conserved substitutions), and/or a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VLCDR1), a VLCDR2, and a VLCDR3 of any anti-BCMA light chain binding domain amino acid sequence listed in Tables 4D, 4E, 4H 4J, and 4F (or a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g., conserved substitutions). 
     Additional heavy chain variable domain CDR sequences according to the Chothia numbering scheme are described in Table 22 on page 100 of WO/2016/014565, filed 21 Jul. 2015. Additional light chain variable domain CDR sequences according to the Chothia numbering scheme are described in Table 23 on pages 101-102 of WO/2016/014565, filed 21 Jul. 2015. 
     In one embodiment, the encoded anti-BCMA binding domain comprises: 
     a VH comprising a VH of any anti-BCMA heavy chain binding domain amino acid sequence listed in Tables 4D, 4E, and 4F (or a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g., conserved substitutions), and/or 
     a VL comprising a VL of any anti-BCMA light chain binding domain amino acid sequence listed in Tables 4D, 4E, and 4F (or a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g., conserved substitutions). 
     In one embodiment, the encoded anti-BCMA binding domain comprises an scFv comprising an scFv amino acid sequence listed in Tables 4D and 4E (or a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g., conserved substitutions). 
     In one embodiment, the encoded anti-BCMA binding domain comprises an scFv comprising a VH, a VL, and a linker, wherein the linker comprises the amino acid sequence of 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 3200) 
               
               
                   
                 GGGGSGGGGSGGGGSGGGGS. 
               
            
           
         
       
     
     In one embodiment, the encoded anti-BCMA binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1400, 1406, 1412, 1418, 1424, 1430, 1436, 1442, 1448, 1454, 1460, 1466, 1472, 1478, 1485, 1491, 1497, 1503, 1509, 1515, 1521, 1527, 1533, 1539, 1545, 1551, 1557, 1563, 1569, 1575, 1581, 1587, 1593, 1599, 1605, 1611, 1619, 1623, 1627, or 1631 or a sequence with at least 95%, e.g., 95-99%, identity thereof. 
     In one embodiment, the nucleic acid encoding the anti-BCMA binding domain comprises a nucleotide sequence selected from the group consisting of SEQ ID NO: 1407, SEQ ID NO: 1413, SEQ ID NO: 1419, SEQ ID NO: 1425, SEQ ID NO: 1431, SEQ ID NO: 1437, SEQ ID NO: 1443., SEQ ID NO: 1449, SEQ ID NO: 1455, SEQ ID NO: 1461, SEQ ID NO: 1401, SEQ ID NO: 1467, SEQ ID NO: 1473, SEQ ID NO: 1480, SEQ ID NO: 1486, SEQ ID NO: 1492, SEQ ID NO: 1498, SEQ ID NO: 1504, SEQ ID NO: 1510, SEQ ID NO: 1516, SEQ ID NO: 1522, SEQ ID NO: 1528, SEQ ID NO: 1534, SEQ ID NO: 1540, SEQ ID NO: 1546, SEQ ID NO: 1552, SEQ ID NO: 1558, SEQ ID NO: 1564, SEQ ID NO: 1570, SEQ ID NO: 1576, SEQ ID NO: 1582, SEQ ID NO: 1588, SEQ ID NO: 1594, SEQ ID NO: 1600, SEQ ID NO: 1606, SEQ ID NO: 1612, or a sequence with at least 95%, e.g., 95-99%, identity thereof. 
     In one embodiment, the encoded CAR molecule comprises a full CAR amino acid sequence listed in Tables 4D and 4E (or a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g., conserved substitutions). 
     In one embodiment, the encoded CAR molecule comprises an amino acid sequence selected from the group consisting of residues 22-483 of SEQ ID NO: 1404, residues 22-490 of SEQ ID NO: 1410, residues 22-488 of SEQ ID NO: 1416, residues 22-487 of SEQ ID NO: 1422, residues 22-493 of SEQ ID NO: 1428, residues 22-490 of SEQ ID NO: 1434, residues 22-491 of SEQ ID NO: 1440, residues 22-482 of SEQ ID NO: 1446, residues 22-483 of SEQ ID NO: 1452, residues 22-485 of SEQ ID NO: 1458, residues 22-483 of SEQ ID NO: 1464, residues 22-490 of SEQ ID NO: 1470, residues 22-483 of SEQ ID NO: 1476, residues 22-484 of SEQ ID NO: 1483, residues 22-485 of SEQ ID NO: 1489, residues 22-487 of SEQ ID NO: 1495, residues 23-489 of SEQ ID NO: 1501, residues 22-490 of SEQ ID NO: 1507, residues 22-484 of SEQ ID NO: 1513, residues 22-485 of SEQ ID NO: 1519, residues 22-489 of SEQ ID NO: 1525, residues 22-497 of SEQ ID NO: 1531, residues 22-492 of SEQ ID NO: 1537, residues 22-490 of SEQ ID NO: 1543, residues 22-485 of SEQ ID NO: 1549, residues 22-492 of SEQ ID NO: 1555, residues 22-492 of SEQ ID NO: 1561, residues 22-483 of SEQ ID NO: 1567, residues 22-490 of SEQ ID NO: 1573, residues 22-485 of SEQ ID NO: 1579, residues 22-486 of SEQ ID NO: 1585, residues 22-492 of SEQ ID NO: 1591, residues 22-488 of SEQ ID NO: 1597, residues 22-488 of SEQ ID NO: 1603, residues 22-495 of SEQ ID NO: 1609, residues 22-490 of SEQ ID NO: 1615, SEQ ID NO: 1620, SEQ ID NO: 1624, SEQ ID NO: 1628, or SEQ ID NO: 1632, or a sequence with at least 95%, e.g., 95-99%, identity thereof. 
     In one embodiment, the nucleic acid encoding the CAR molecule comprises a nucleotide sequence listed in Table 4D, or a sequence with at least 95%, e.g., 95-99%, identity thereof. 
     In one embodiment, the nucleic acid encoding the CAR molecule comprises a nucleotide sequence selected from the group consisting of SEQ ID NO: 1405, SEQ ID NO: 1411, SEQ ID NO: 1417, SEQ ID NO: 1423, SEQ ID NO: 1429, SEQ ID NO: 1435, SEQ ID NO: 1441, SEQ ID NO: 1447, SEQ ID NO: 1453, SEQ ID NO: 1459, SEQ ID NO: 1465, SEQ ID NO: 1471, SEQ ID NO: 1477, SEQ ID NO: 1484, SEQ ID NO: 1490, SEQ ID NO: 1496, SEQ ID NO: 1502, SEQ ID NO: 1508, SEQ ID NO: 1514, SEQ ID NO: 1520, SEQ ID NO: 1526, SEQ ID NO: 1532, SEQ ID NO: 1538, SEQ ID NO: 1544, SEQ ID NO: 1550, SEQ ID NO: 1556, SEQ ID NO: 1562, SEQ ID NO: 1568, SEQ ID NO: 1574, SEQ ID NO: 1580, SEQ ID NO: 1586, SEQ ID NO: 1592, SEQ ID NO: 1598, SEQ ID NO: 1604, SEQ ID NO: 1610, and SEQ ID NO: 1616, or a sequence with at least 95%, e.g., 95-99%, identity thereof. 
     In one embodiment, the encoded transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of the alpha, beta or zeta chain of a T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154. 
     In one embodiment, the encoded transmembrane domain comprises the amino acid sequence of SEQ ID NO: 15 (or a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g., conserved substitutions). 
     In one embodiment, the nucleic acid encoding the CAR molecule comprises the nucleotide sequence of SEQ ID NO: 56, or a sequence with 95-99% identity thereof. 
     In one embodiment, the encoded anti-BCMA binding domain is connected to the transmembrane domain by a hinge region. 
     In one embodiment, the encoded hinge region comprises the amino acid sequence of SEQ ID NO: 14 or 102 (or a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g., conserved substitutions). 
     In one embodiment, the nucleic acid encoding the CAR molecule comprises the nucleotide sequence of SEQ ID NO: 55 or 103, or a sequence with 95-99% identity thereof. 
     In one embodiment, the encoded intracellular signaling domain is a functional signaling domain obtained from a protein chosen from an MHC class I molecule, a TNF receptor, an immunoglobulin-like protein, a cytokine receptor, integrin, signaling lymphocytic activation molecule (SLAM), an activating NK cell receptor, BTLA, a Toll ligand receptor, CD3, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CD11a/CD18), 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, or a ligand that specifically binds with CD83. 
     In one embodiment, the encoded intracellular signaling domain is a functional signaling domain of a protein chosen from 4-1BB, CD3 zeta, CD28, or ICOS. 
     In one embodiment, the encoded intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 16, 17, 43, 1317, or 1319 (or a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g., conserved substitutions). 
     In one embodiment, the nucleic acid molecule encoding the CAR molecule comprises the nucleotide sequence of SEQ ID NO: 60, 101, 44, 1318, or 1320, or a sequence with 95-99% identity thereof. 
     In one embodiment, the nucleic acid encoding the CAR molecule comprises: 
     (i) a leader sequence encoding the amino acid sequence of SEQ ID NO: 13 (or a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g., conserved substitutions); or 
     (ii) the nucleotide sequence of SEQ ID NO: 54, or a sequence with 95-99% identity thereof. 
     In one embodiment, the nucleic acid encoding the CAR molecule is a DNA molecule, optionally wherein the DNA molecule is transcribed under an EF-1 promoter comprising the sequence of SEQ ID NO: 100. 
     In one embodiment, the cell is an autologous cell or an allogeneic cell. 
     In one embodiment, the cell is a T cell or a natural killer (NK) cell. 
     In some embodiments, the BCMA inhibitor, e.g., the BCMA CAR, can be used to treat a hematological malignancy. In embodiments, the BCMA inhibitor, e.g., the BCMA CAR, can be used to treat a disease associated with BCMA expression. 
     In one embodiment, the disease associated with expression of BCMA is: 
     (i) a cancer or malignancy, or a precancerous condition chosen from one or more of a myelodysplasia, a myelodysplastic syndrome or a preleukemia, or 
     (ii) a non-cancer related indication associated with expression of BCMA. 
     In one embodiment, the disease is chosen from acute leukemia, B-cell acute lymphoid leukemia (BALL), T-cell acute lymphoid leukemia (TALL), acute lymphoid leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt&#39;s lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or large cell-follicular lymphoma, a malignant lymphoproliferative condition, mucosa associated lymphoid tissue (MALT) lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin&#39;s lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, a plasma cell proliferative disorder (e.g., asymptomatic myeloma (smoldering multiple myeloma or indolent myeloma), monoclonal gammapathy of undetermined significance (MGUS), Waldenstrom&#39;s macroglobulinemia, plasmacytomas (e.g., plasma cell dyscrasia, solitary myeloma, solitary plasmacytoma, extramedullary plasmacytoma, and multiple plasmacytoma), systemic amyloid light chain amyloidosis, and POEMS syndrome (also known as Crow-Fukase syndrome, Takatsuki disease, and PEP syndrome)), prostate cancer (e.g., castrate-resistant or therapy-resistant prostate cancer, or metastatic prostate cancer), pancreatic cancer, or lung cancer. 
     In one embodiment, the disease is a hematologic cancer. In one embodiment, the disease is multiple myeloma. In one embodiment, the disease is CD19-negative multiple myeloma. 
     In embodiments, the compositions disclosed herein (e.g., nucleic acids, vectors, or cells) are for use as a medicament. 
     In embodiments, the compositions disclosed herein are used in the treatment of a hematological cancer. 
     In embodiments, the compositions disclosed herein are used in the treatment of a disease associated with expression of a B-cell antigen (e.g., CD19), e.g., a B-cell leukemia or lymphoma (e.g., a CD19-associated disease). 
     In other embodiments, the compositions disclosed herein are used in the treatment of a disease associated with expression of a BCMA antigen (e.g., CD19), e.g., a BCMA-associated disease. 
     Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein (e.g., sequence database reference numbers) are incorporated by reference in their entirety. For example, all GenBank, Unigene, and Entrez sequences referred to herein, e.g., in any Table herein, are incorporated by reference. Unless otherwise specified, the sequence accession numbers specified herein, including in any Table herein, refer to the database entries current as of Apr. 8, 2015. When one gene or protein references a plurality of sequence accession numbers, all of the sequence variants are encompassed. 
     In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. 
     Headings, sub-headings or numbered or lettered elements, e.g., (a), (b), (i) etc, are presented merely for ease of reading. The use of headings or numbered or lettered elements in this document does not require the steps or elements be performed in alphabetical order or that the steps or elements are necessarily discrete from one another. 
     Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIGS. 1A and 1B  are Kaplan-Meier plots showing overall survival ( FIG. 76A ) and relapse-free survival ( FIG. 76B ) of ALL patients treated with CTL019. 
         FIG. 2  is a time course depicting serum IL-6 levels, CSF IL-6 levels, patient temperature, and CART-BCMA frequency in a patient experiencing CRS. 
         FIG. 3  shows levels of sBCMA, BAFF and APRIL in longitudinal serum samples from 6 UPCC14415 patients after CAR-BCMA infusion. 
         FIG. 4  shows levels of serum sBCMA (right Y axis, squares) correlated with CAR-BCMA marking (left Y axis, circles) in peripheral blood DNA from 6 UPCC14415 patients over time after CAR-BCMA infusion. 
         FIGS. 5A-5C  show sBCMA levels in patient samples.  FIG. 5A  shows levels of serum sBCMA (right Y axis, squares) correlated with CAR-19 marking (left Y axis, circles) in peripheral blood DNA from 6 UPCC02413 patients over time after CAR-19 infusion. Dotted line is sBCMA in normal donor sera (see  FIG. 81 ).  FIG. 5B  shows levels of serum sBCMA (right Y axis, squares) correlated with CAR-19 marking (left Y axis, circles) in peripheral blood DNA from 4 UPCC02413 patients over time after CAR-19 infusion.  FIG. 5C  shows levels of serum sBCMA (right Y axis, squares) correlated with CAR-19 marking (left Y axis, circles) in peripheral blood DNA from a UPCC019413 patient (single-patient compassionate-use protocol) over time after CAR-19 infusion. 
         FIG. 6  shows Sox2 antibody levels in patients treated with CTL019. Left panel shows anti-sox2 antibodies in patients 1, 2, 5, 7, 8, 9, 10, and 12. The right panel shows patient 1 samples tested using 1:400, 1:800, or 1:1200 dilutions. 
         FIG. 7  is a set of graphs showing peak expansion, persistence, and in vitro proliferation in the indicated patient populations, and proliferation in vitro vs in vivo expansion. 
         FIG. 8  is a set of graphs showing levels of STAT3 signaling mediators and targets in the indicated patient populations. 
         FIG. 9  shows the response of relapsed refractory Acute Lymphocytic Leukemia (ALL) pediatric patients with CNS involvement to CTL019 therapy. 
         FIGS. 10A-10B  show the absolute count ( FIG. 10A ) and percentages of lymphocytes ( FIG. 10B ) in the peripheral blood from NHL patients whose cells were used for CAR T manufacturing. 
         FIGS. 11A-11C  show the CD45, lymphocyte and monocyte profiles in apheresis samples from for each patient grouped by success or failure of CAR T manufacturing. CD3+CD45+ FACS staining data is shown in  FIG. 11A .  FIG. 11B  shows percent lymphocytes, as determined by a multisizer and  FIG. 11C  shows percent monocytes in the samples, as determined by a multisizer. 
         FIGS. 12A-12D  show growth curves of fresh vs. thawed cells from samples that failed the first CAR T manufacturing attempt. 
         FIGS. 13A-13B  show CD45 vs. CD3 flow cytometry dot plots of fresh and thawed cells from two patient samples.  FIG. 13A  shows data from sample 41 and  FIG. 13B  shows data from sample 26. 
         FIGS. 14A-14B  show CD15 vs. CD14 (top panels) and CXCR2 vs. CD14 (bottom panels) flow cytometry dot plots of fresh and thawed cells from two patient samples.  FIG. 14A  shows data from sample 54 and  FIG. 14B  shows data from sample 58. 
         FIGS. 15A-15B  show dose response logistic regression analyses for patients treated with autologous CTL019. 
     
    
    
     DETAILED DESCRIPTION 
     Definitions 
     Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. 
     The term “a” and “an” refers to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. 
     The term “about” when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or in some instances ±10%, or in some instances ±5%, or in some instances ±1%, or in some instances ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods. 
     The term “apheresis” as used herein refers to the art-recognized extracorporeal process by which the blood of a donor or patient is removed from the donor or patient and passed through an apparatus that separates out selected particular constituent(s) and returns the remainder to the circulation of the donor or patient, e.g., by retransfusion. Thus, “an apheresis sample” refers to a sample obtained using apheresis. 
     The term “bioequivalent” refers to an amount of an agent other than the reference compound (e.g., RAD001), required to produce an effect equivalent to the effect produced by the reference dose or reference amount of the reference compound (e.g., RAD001). In an embodiment the effect is the level of mTOR inhibition, e.g., as measured by P70 S6 kinase inhibition, e.g., as evaluated in an in vivo or in vitro assay, e.g., as measured by an assay described herein, e.g., the Boulay assay, or measurement of phosphorylated S6 levels by western blot. In an embodiment, the effect is alteration of the ratio of PD-1 positive/PD-1 negative T cells, as measured by cell sorting. In an embodiment a bioequivalent amount or dose of an mTOR inhibitor is the amount or dose that achieves the same level of P70 S6 kinase inhibition as does the reference dose or reference amount of a reference compound. In an embodiment, a bioequivalent amount or dose of an mTOR inhibitor is the amount or dose that achieves the same level of alteration in the ratio of PD-1 positive/PD-1 negative T cells as does the reference dose or reference amount of a reference compound. 
     The term “inhibition” or “inhibitor” includes a reduction in a certain parameter, e.g., an activity, of a given molecule, e.g., CD20, CD19, or BCMA. For example, inhibition of an activity, e.g., an activity of CD19, of at least 5%, 10%, 20%, 30%, 40%, or more is included by this term. Thus, inhibition need not be 100%. Activities for the inhibitors can be determined as described herein or by assays known in the art. A “B-cell inhibitor” is a molecule, e.g., a small molecule, antibody, CAR or cell comprising a CAR, which causes the reduction in a certain parameter, e.g., an activity, e.g., growth or proliferation, of a B-cell, or which causes a reduction in a certain parameter, e.g., an activity, of a molecule associated with a B cell. Non-limiting examples of molecules associated with a B cell include proteins expressed on the surface of B cells, e.g., CD19, CD20, CD10, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, CD79a, or BCMA. 
     The term “Chimeric Antigen Receptor” or alternatively a “CAR” refers to a set of polypeptides, typically two in the simplest embodiments, which when in an immune effector cell, provides the cell with specificity for a target cell, typically a cancer cell, and with intracellular signal generation. In some embodiments, a CAR comprises at least an extracellular antigen binding domain, a transmembrane domain and a cytoplasmic signaling domain (also referred to herein as “an intracellular signaling domain”) comprising a functional signaling domain derived from a stimulatory molecule and/or costimulatory molecule as defined below. In some embodiments, the set of polypeptides are in the same polypeptide chain, e.g., comprise a chimeric fusion protein. In some embodiments, the set of polypeptides are not contiguous with each other, e.g., are in different polypeptide chains. In some embodiments, the set of polypeptides include a dimerization switch that, upon the presence of a dimerization molecule, can couple the polypeptides to one another, e.g., can couple an antigen binding domain to an intracellular signaling domain. In one aspect, the stimulatory molecule of the CAR is the zeta chain associated with the T cell receptor complex (e.g., CD3 zeta). In one aspect, the cytoplasmic signaling domain comprises a primary signaling domain (e.g., a primary signaling domain of CD3-zeta). 
     In one aspect, the cytoplasmic signaling domain further comprises one or more functional signaling domains derived from at least one costimulatory molecule as defined below. In one aspect, the costimulatory molecule is chosen from the costimulatory molecules described herein, e.g., 4-1BB (i.e., CD137), CD27, and/or CD28. In one aspect, the CAR comprises a chimeric fusion protein comprising an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain comprising a functional signaling domain derived from a stimulatory molecule. In one aspect, the CAR comprises a chimeric fusion protein comprising an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain comprising a functional signaling domain derived from a costimulatory molecule and a functional signaling domain derived from a stimulatory molecule. In one aspect, the CAR comprises a chimeric fusion protein comprising an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain comprising two functional signaling domains derived from one or more costimulatory molecule(s) and a functional signaling domain derived from a stimulatory molecule. In one aspect, the CAR comprises a chimeric fusion protein comprising an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain comprising at least two functional signaling domains derived from one or more costimulatory molecule(s) and a functional signaling domain derived from a stimulatory molecule. In one aspect the CAR comprises an optional leader sequence at the amino-terminus (N-ter) of the CAR fusion protein. In one aspect, the CAR further comprises a leader sequence at the N-terminus of the extracellular antigen binding domain, wherein the leader sequence is optionally cleaved from the antigen binding domain (e.g., a scFv) during cellular processing and localization of the CAR to the cellular membrane. 
     As used herein, unless otherwise specified, the terms “prevent,” “preventing” and “prevention” refer to an action that occurs before the subject begins to suffer from the condition, or relapse of the condition. Prevention need not result in a complete prevention of the condition; partial prevention or reduction of the condition or a symptom of the condition, or reduction of the risk of developing the condition, is encompassed by this term. 
     Administered “in combination”, as used herein, means that two (or more) different treatments are delivered to the subject during the course of the subject&#39;s affliction with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery”. In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered. In one embodiment, the CAR-expressing cell is administered at a dose and/or dosing schedule described herein, and the B-cell inhibitor, or agent that enhances the activity of the CD19 CAR-expressing cell is administered at a dose and/or dosing schedule described herein. 
     “Derived from” as that term is used herein, indicates a relationship between a first and a second molecule. It generally refers to structural similarity between the first molecule and a second molecule and does not connote or include a process or source limitation on a first molecule that is derived from a second molecule. For example, in the case of an intracellular signaling domain that is derived from a CD3zeta molecule, the intracellular signaling domain retains sufficient CD3zeta structure such that is has the required function, namely, the ability to generate a signal under the appropriate conditions. It does not connote or include a limitation to a particular process of producing the intracellular signaling domain, e.g., it does not mean that, to provide the intracellular signaling domain, one must start with a CD3zeta sequence and delete unwanted sequence, or impose mutations, to arrive at the intracellular signaling domain. 
     The term “signaling domain” refers to the functional portion of a protein which acts by transmitting information within the cell to regulate cellular activity via defined signaling pathways by generating second messengers or functioning as effectors by responding to such messengers. 
     As used herein, the term “BCMA” refers to B-cell maturation antigen. BCMA (also known as TNFRSF17, BCM or CD269) is a member of the tumor necrosis receptor (TNFR) family and is predominantly expressed on terminally differentiated B cells, e.g., memory B cells and plasma cells. Its ligands include B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). The protein BCMA is encoded by the gene TNFRSF17. Exemplary BCMA sequences are available at the Uniprot database under accession number Q02223. 
     As used herein, the term “CD19” refers to the Cluster of Differentiation 19 protein, which is an antigenic determinant detectable on leukemia precursor cells. The human and murine amino acid and nucleic acid sequences can be found in a public database, such as GenBank, UniProt and Swiss-Prot. For example, the amino acid sequence of human CD19 can be found as UniProt/Swiss-Prot Accession No. P15391 and the nucleotide sequence encoding of the human CD19 can be found at Accession No. NM_001178098. As used herein, “CD19” includes proteins comprising mutations, e.g., point mutations, fragments, insertions, deletions and splice variants of full length wild-type CD19. CD19 is expressed on most B lineage cancers, including, e.g., acute lymphoblastic leukemia, chronic lymphocyte leukemia and non-Hodgkin lymphoma. Other cells with express CD19 are provided below in the definition of “disease associated with expression of CD19.” It is also an early marker of B cell progenitors. See, e.g., Nicholson et al. Mol. Immun. 34 (16-17): 1157-1165 (1997). In one aspect the antigen-binding portion of the CART recognizes and binds an antigen within the extracellular domain of the CD19 protein. In one aspect, the CD19 protein is expressed on a cancer cell. 
     The term “antibody,” as used herein, refers to a protein, or polypeptide sequence derived from an immunoglobulin molecule which specifically binds with an antigen. Antibodies can be polyclonal or monoclonal, multiple or single chain, or intact immunoglobulins, and may be derived from natural sources or from recombinant sources. Antibodies can be tetramers of immunoglobulin molecules. 
     The term “antibody fragment” refers to at least one portion of an antibody, that retains the ability to specifically interact with (e.g., by binding, steric hindrance, stabilizing/destabilizing, spatial distribution) an epitope of an antigen. Examples of antibody fragments include, but are not limited to, Fab, Fab′, F(ab′) 2 , Fv fragments, scFv antibody fragments, disulfide-linked Fvs (sdFv), a Fd fragment consisting of the VH and CH1 domains, linear antibodies, single domain antibodies such as sdAb (either VL or VH), camelid VHH domains, multi-specific antibodies formed from antibody fragments such as a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, and an isolated CDR or other epitope binding fragments of an antibody. An antigen binding fragment can also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005). Antigen binding fragments can also be grafted into scaffolds based on polypeptides such as a fibronectin type III (Fn3)(see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide minibodies). 
     The term “scFv” refers to a fusion protein comprising at least one antibody fragment comprising a variable region of a light chain and at least one antibody fragment comprising a variable region of a heavy chain, wherein the light and heavy chain variable regions are contiguously linked, e.g., via a synthetic linker, e.g., a short flexible polypeptide linker, and capable of being expressed as a single chain polypeptide, and wherein the scFv retains the specificity of the intact antibody from which it is derived. Unless specified, as used herein an scFv may have the VL and VH variable regions in either order, e.g., with respect to the N-terminal and C-terminal ends of the polypeptide, the scFv may comprise VL-linker-VH or may comprise VH-linker-VL. 
     The term “complementarity determining region” or “CDR,” as used herein, refers to the sequences of amino acids within antibody variable regions which confer antigen specificity and binding affinity. For example, in general, there are three CDRs in each heavy chain variable region (e.g., HCDR1, HCDR2, and HCDR3) and three CDRs in each light chain variable region (LCDR1, LCDR2, and LCDR3). The precise amino acid sequence boundaries of a given CDR can be determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (“Kabat” numbering scheme), Al-Lazikani et al., (1997) JMB 273, 927-948 (“Chothia” numbering scheme), or a combination thereof. Under the Kabat numbering scheme, in some embodiments, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3). Under the Chothia numbering scheme, in some embodiments, the CDR amino acids in the VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3). In a combined Kabat and Chothia numbering scheme, in some embodiments, the CDRs correspond to the amino acid residues that are part of a Kabat CDR, a Chothia CDR, or both. For instance, in some embodiments, the CDRs correspond to amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in a VH, e.g., a mammalian VH, e.g., a human VH; and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in a VL, e.g., a mammalian VL, e.g., a human VL. 
     As used herein, the term “binding domain” or “antibody molecule” refers to a protein, e.g., an immunoglobulin chain or fragment thereof, comprising at least one immunoglobulin variable domain sequence. The term “binding domain” or “antibody molecule” encompasses antibodies and antibody fragments. In an embodiment, an antibody molecule is a multispecific antibody molecule, e.g., it comprises a plurality of immunoglobulin variable domain sequences, wherein a first immunoglobulin variable domain sequence of the plurality has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality has binding specificity for a second epitope. In an embodiment, a multispecific antibody molecule is a bispecific antibody molecule. A bispecific antibody has specificity for no more than two antigens. A bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence which has binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope. 
     The portion of the CAR of the invention comprising an antibody or antibody fragment thereof may exist in a variety of forms where the antigen binding domain is expressed as part of a contiguous polypeptide chain including, for example, a single domain antibody fragment (sdAb), a single chain antibody (scFv), a humanized antibody, or bispecific antibody (Harlow et al., 1999, In: Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY; Harlow et al., 1989, In: Antibodies: A Laboratory Manual, Cold Spring Harbor, N.Y.; Houston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; Bird et al., 1988, Science 242:423-426). In one aspect, the antigen binding domain of a CAR composition of the invention comprises an antibody fragment. In a further aspect, the CAR comprises an antibody fragment that comprises a scFv. 
     The term “antibody heavy chain,” refers to the larger of the two types of polypeptide chains present in antibody molecules in their naturally occurring conformations, and which normally determines the class to which the antibody belongs. 
     The term “antibody light chain,” refers to the smaller of the two types of polypeptide chains present in antibody molecules in their naturally occurring conformations. Kappa (x) and lambda (k) light chains refer to the two major antibody light chain isotypes. 
     The term “recombinant antibody” refers to an antibody which is generated using recombinant DNA technology, such as, for example, an antibody expressed by a bacteriophage or yeast expression system. The term should also be construed to mean an antibody which has been generated by the synthesis of a DNA molecule encoding the antibody and which DNA molecule expresses an antibody protein, or an amino acid sequence specifying the antibody, wherein the DNA or amino acid sequence has been obtained using recombinant DNA or amino acid sequence technology which is available and well known in the art. 
     The term “antigen” or “Ag” refers to a molecule that provokes an immune response. This immune response may involve either antibody production, or the activation of specific immunologically-competent cells, or both. The skilled artisan will understand that any macromolecule, including virtually all proteins or peptides, can serve as an antigen. Furthermore, antigens can be derived from recombinant or genomic DNA. A skilled artisan will understand that any DNA, which comprises a nucleotide sequences or a partial nucleotide sequence encoding a protein that elicits an immune response therefore encodes an “antigen” as that term is used herein. Furthermore, one skilled in the art will understand that an antigen need not be encoded solely by a full length nucleotide sequence of a gene. It is readily apparent that the present invention includes, but is not limited to, the use of partial nucleotide sequences of more than one gene and that these nucleotide sequences are arranged in various combinations to encode polypeptides that elicit the desired immune response. Moreover, a skilled artisan will understand that an antigen need not be encoded by a “gene” at all. It is readily apparent that an antigen can be generated synthesized or can be derived from a biological sample, or might be macromolecule besides a polypeptide. Such a biological sample can include, but is not limited to a tissue sample, a tumor sample, a cell or a fluid with other biological components. 
     The terms “compete” or “cross-compete” are used interchangeably herein to refer to the ability of an antibody molecule to interfere with binding of an antibody molecule, e.g., an anti-CD19 or BCMA antibody molecule provided herein, to a target, e.g., human CD19 or BCMA. The interference with binding can be direct or indirect (e.g., through an allosteric modulation of the antibody molecule or the target). The extent to which an antibody molecule is able to interfere with the binding of another antibody molecule to the target, and therefore whether it can be said to compete, can be determined using a competition binding assay, e.g., as described herein. In some embodiments, a competition binding assay is a quantitative competition assay. In some embodiments, a first antibody molecule is said to compete for binding to the target with a second antibody molecule when the binding of the first antibody molecule to the target is reduced by 10% or more, e.g., 20% or more, 30% or more, 40% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more in a competition binding assay (e.g., a competition assay described herein). 
     As used herein, the term “epitope” refers to the moieties of an antigen (e.g., human CD19 or BCMA) that specifically interact with an antibody molecule. Such moieties, referred to herein as epitopic determinants, typically comprise, or are part of, elements such as amino acid side chains or sugar side chains. An epitopic determinate can be defined, e.g., by methods known in the art or disclosed herein, e.g., by crystallography or by hydrogen-deuterium exchange. At least one or some of the moieties on the antibody molecule, that specifically interact with an epitopic determinant, are typically located in a CDR(s). Typically an epitope has a specific three dimensional structural characteristics. Typically an epitope has specific charge characteristics. Some epitopes are linear epitopes while others are conformational epitopes. 
     The term “anti-cancer effect” refers to a biological effect which can be manifested by various means, including but not limited to, e.g., a decrease in tumor volume, a decrease in the number of cancer cells, a decrease in the number of metastases, an increase in life expectancy, decrease in cancer cell proliferation, decrease in cancer cell survival, or amelioration of various physiological symptoms associated with the cancerous condition. An “anti-cancer effect” can also be manifested by the ability of the peptides, polynucleotides, cells and antibodies described herein in prevention of the occurrence of cancer in the first place. The term “anti-tumor effect” refers to a biological effect which can be manifested by various means, including but not limited to, e.g., a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in tumor cell proliferation, or a decrease in tumor cell survival. 
     The term “autologous” refers to any material derived from the same individual to whom it is later to be re-introduced into the individual. 
     The term “allogeneic” refers to any material derived from a different animal of the same species as the individual to whom the material is introduced. Two or more individuals are said to be allogeneic to one another when the genes at one or more loci are not identical. In some aspects, allogeneic material from individuals of the same species may be sufficiently unlike genetically to interact antigenically 
     The term “xenogeneic” refers to a graft derived from an animal of a different species. 
     The term “cancer” refers to a disease characterized by the uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein and include but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer and the like. The terms “tumor” and “cancer” are used interchangeably herein, e.g., both terms encompass solid and liquid, e.g., diffuse or circulating, tumors. As used herein, the term “cancer” or “tumor” includes premalignant, as well as malignant cancers and tumors. 
     The terms “cancer associated antigen” or “tumor antigen” or “proliferative disorder antigen” or “antigen associated with a proliferative disorder” interchangeably refers to a molecule (typically protein, carbohydrate or lipid) that is preferentially expressed on the surface of a cancer cell, either entirely or as a fragment (e.g., MHC/peptide), in comparison to a normal cell, and which is useful for the preferential targeting of a pharmacological agent to the cancer cell. In some embodiments, a tumor antigen is a marker expressed by both normal cells and cancer cells, e.g., a lineage marker, e.g., CD19 on B cells. In certain aspects, the tumor antigens of the present invention are derived from, cancers including but not limited to primary or metastatic melanoma, thymoma, lymphoma, sarcoma, lung cancer, liver cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, leukemias, uterine cancer, cervical cancer, bladder cancer, kidney cancer and adenocarcinomas such as breast cancer, prostate cancer, ovarian cancer, pancreatic cancer, and the like. In some embodiments, the tumor antigen is an antigen that is common to a specific proliferative disorder. In some embodiments, a cancer-associated antigen is a cell surface molecule that is overexpressed in a cancer cell in comparison to a normal cell, for instance, 1-fold over expression, 2-fold overexpression, 3-fold overexpression or more in comparison to a normal cell. In some embodiments, a cancer-associated antigen is a cell surface molecule that is inappropriately synthesized in the cancer cell, for instance, a molecule that contains deletions, additions or mutations in comparison to the molecule expressed on a normal cell. In some embodiments, a cancer-associated antigen will be expressed exclusively on the cell surface of a cancer cell, entirely or as a fragment (e.g., MHC/peptide), and not synthesized or expressed on the surface of a normal cell. In some embodiments, the CARs of the present invention includes CARs comprising an antigen binding domain (e.g., antibody or antibody fragment) that binds to a MHC presented peptide. Normally, peptides derived from endogenous proteins fill the pockets of Major histocompatibility complex (MHC) class I molecules, and are recognized by T cell receptors (TCRs) on CD8+T lymphocytes. The MHC class I complexes are constitutively expressed by all nucleated cells. In cancer, virus-specific and/or tumor-specific peptide/MHC complexes represent a unique class of cell surface targets for immunotherapy. TCR-like antibodies targeting peptides derived from viral or tumor antigens in the context of human leukocyte antigen (HLA)-A1 or HLA-A2 have been described (see, e.g., Sastry et al., J Virol. 201185(5):1935-1942; Sergeeva et al., Bood, 2011 117(16):4262-4272; Verma et al., J Immunol 2010 184(4):2156-2165; Willemsen et al., Gene Ther 2001 8(21):1601-1608; Dao et al., Sci Transl Med 2013 5(176):176ra33; Tassev et al., Cancer Gene Ther 2012 19(2):84-100). For example, TCR-like antibody can be identified from screening a library, such as a human scFv phage displayed library. 
     The phrase “disease associated with expression of CD19” includes, but is not limited to, a disease associated with expression of CD19 (e.g., wild-type or mutant CD19) or condition associated with cells which express, or at any time expressed, CD19 (e.g., wild-type or mutant CD19) including, e.g., proliferative diseases such as a cancer or malignancy or a precancerous condition such as a myelodysplasia, a myelodysplastic syndrome or a preleukemia; or a noncancer related indication associated with cells which express CD19. For the avoidance of doubt, a disease associated with expression of CD19 may include a condition associated with cells which do not presently express CD19, e.g., because CD19 expression has been downregulated, e.g., due to treatment with a molecule targeting CD19, e.g., a CD19 CAR, but which at one time expressed CD19. In one aspect, a cancer associated with expression of CD19 is a hematological cancer. In one aspect, the hematological cancer is a leukemia or a lymphoma. In one aspect, a cancer associated with expression of CD19 includes cancers and malignancies including, but not limited to, e.g., one or more acute leukemias including but not limited to, e.g., B-cell acute Lymphoid Leukemia (BALL), T-cell acute Lymphoid Leukemia (TALL), acute lymphoid leukemia (ALL); one or more chronic leukemias including but not limited to, e.g., chronic myelogenous leukemia (CML), Chronic Lymphoid Leukemia (CLL). Additional cancers or hematologic conditions associated with expression of CD19 comprise, but are not limited to, e.g., B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt&#39;s lymphoma, diffuse large B cell lymphoma, Follicular lymphoma, Hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma (MCL), Marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin lymphoma, Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and “preleukemia” which are a diverse collection of hematological conditions united by ineffective production (or dysplasia) of myeloid blood cells, and the like. Further diseases associated with expression of CD19 expression include, but not limited to, e.g., atypical and/or non-classical cancers, malignancies, precancerous conditions or proliferative diseases associated with expression of CD19. Non-cancer related indications associated with expression of CD19 include, but are not limited to, e.g., autoimmune disease, (e.g., lupus), inflammatory disorders (allergy and asthma) and transplantation. In some embodiments, the CD19-expressing cells express, or at any time expressed, CD19 mRNA. In an embodiment, the CD19-expressing cells produce a CD19 protein (e.g., wild-type or mutant), and the CD19 protein may be present at normal levels or reduced levels. In an embodiment, the CD19-expressing cells produced detectable levels of a CD19 protein at one point, and subsequently produced substantially no detectable CD19 protein. 
     The phrase “disease associated with expression of BCMA” includes, but is not limited to, a disease associated with a cell which expresses BCMA (e.g., wild-type or mutant BCMA) or condition associated with a cell which expresses BCMA (e.g., wild-type or mutant BCMA) including, e.g., proliferative diseases such as a cancer or malignancy or a precancerous condition such as a myelodysplasia, a myelodysplastic syndrome or a preleukemia; or a noncancer related indication associated with a cell which expresses BCMA (e.g., wild-type or mutant BCMA). For the avoidance of doubt, a disease associated with expression of BCMA may include a condition associated with a cell which does not presently express BCMA, e.g., because BCMA expression has been downregulated, e.g., due to treatment with a molecule targeting BCMA, e.g., a BCMA inhibitor described herein, but which at one time expressed BCMA. In one aspect, a cancer associated with expression of BCMA (e.g., wild-type or mutant BCMA) is a hematological cancer. In one aspect, the hematological cancer is a leukemia or a lymphoma. In one aspect, a cancer associated with expression of BCMA (e.g., wild-type or mutant BCMA) is a malignancy of differentiated plasma B cells. In one aspect, a cancer associated with expression of BCMA (e.g., wild-type or mutant BCMA) includes cancers and malignancies including, but not limited to, e.g., one or more acute leukemias including but not limited to, e.g., B-cell acute Lymphoid Leukemia (“BALL”), T-cell acute Lymphoid Leukemia (“TALL”), acute lymphoid leukemia (ALL); one or more chronic leukemias including but not limited to, e.g., chronic myelogenous leukemia (CML), Chronic Lymphoid Leukemia (CLL). Additional cancers or hematologic conditions associated with expression of BMCA (e.g., wild-type or mutant BCMA) comprise, but are not limited to, e.g., B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt&#39;s lymphoma, diffuse large B cell lymphoma, Follicular lymphoma, Hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, Marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin&#39;s lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and “preleukemia” which are a diverse collection of hematological conditions united by ineffective production (or dysplasia) of myeloid blood cells, and the like. In some embodiments, the cancer is multiple myeloma, Hodgkin&#39;s lymphoma, non-Hodgkin&#39;s lymphoma, or glioblastoma. In embodiments, a disease associated with expression of BCMA includes a plasma cell proliferative disorder, e.g., asymptomatic myeloma (smoldering multiple myeloma or indolent myeloma), monoclonal gammapathy of undetermined significance (MGUS), Waldenstrom&#39;s macroglobulinemia, plasmacytomas (e.g., plasma cell dyscrasia, solitary myeloma, solitary plasmacytoma, extramedullary plasmacytoma, and multiple plasmacytoma), systemic amyloid light chain amyloidosis, and POEMS syndrome (also known as Crow-Fukase syndrome, Takatsuki disease, and PEP syndrome). Further diseases associated with expression of BCMA (e.g., wild-type or mutant BCMA) expression include, but not limited to, e.g., atypical and/or non-classical cancers, malignancies, precancerous conditions or proliferative diseases associated with expression of BCMA (e.g., wild-type or mutant BCMA), e.g., a cancer described herein, e.g., a prostate cancer (e.g., castrate-resistant or therapy-resistant prostate cancer, or metastatic prostate cancer), pancreatic cancer, or lung cancer. 
     Non-cancer related conditions that are associated with BCMA (e.g., wild-type or mutant BCMA) include viral infections; e.g., HIV, fungal infections, e.g.,  C. neoformans ; autoimmune disease; e.g. rheumatoid arthritis, system lupus erythematosus (SLE or lupus), pemphigus vulgaris, and Sjogren&#39;s syndrome; inflammatory bowel disease, ulcerative colitis; transplant-related allospecific immunity disorders related to mucosal immunity; and unwanted immune responses towards biologics (e.g., Factor VIII) where humoral immunity is important. In embodiments, a non-cancer related indication associated with expression of BCMA includes but is not limited to, e.g., autoimmune disease, (e.g., lupus), inflammatory disorders (allergy and asthma) and transplantation. In some embodiments, the tumor antigen-expressing cell expresses, or at any time expressed, mRNA encoding the tumor antigen. In an embodiment, the tumor antigen-expressing cell produces the tumor antigen protein (e.g., wild-type or mutant), and the tumor antigen protein may be present at normal levels or reduced levels. In an embodiment, the tumor antigen-expressing cell produced detectable levels of a tumor antigen protein at one point, and subsequently produced substantially no detectable tumor antigen protein. 
     The term “conservative sequence modifications” refers to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody or antibody fragment containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into an antibody or antibody fragment of the invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, one or more amino acid residues within a CAR of the invention can be replaced with other amino acid residues from the same side chain family and the altered CAR can be tested using the functional assays described herein. 
     The term “stimulation,” refers to a primary response induced by binding of a stimulatory molecule (e.g., a TCR/CD3 complex or CAR) with its cognate ligand (or tumor antigen in the case of a CAR) thereby mediating a signal transduction event, such as, but not limited to, signal transduction via the TCR/CD3 complex or signal transduction via the appropriate NK receptor or signaling domains of the CAR. Stimulation can mediate altered expression of certain molecules. 
     The term “stimulatory molecule,” refers to a molecule expressed by an immune cell, e.g., T cell, NK cell, or B cell) that provides the cytoplasmic signaling sequence(s) that regulate activation of the immune cell in a stimulatory way for at least some aspect of the immune cell signaling pathway. In one aspect, the signal is a primary signal that is initiated by, for instance, binding of a TCR/CD3 complex with an MHC molecule loaded with peptide, and which leads to mediation of a T cell response, including, but not limited to, proliferation, activation, differentiation, and the like. A primary cytoplasmic signaling sequence (also referred to as a “primary signaling domain”) that acts in a stimulatory manner may contain a signaling motif which is known as immunoreceptor tyrosine-based activation motif or ITAM. Examples of an ITAM containing cytoplasmic signaling sequence that is of particular use in the invention includes, but is not limited to, those derived from CD3 zeta, common FcR gamma (FCER1G), Fc gamma RIIa, FcR beta (Fc Epsilon Rib), CD3 gamma, CD3 delta, CD3 epsilon, CD79a, CD79b, DAP10, and DAP12. In a specific CAR of the invention, the intracellular signaling domain in any one or more CARS of the invention comprises an intracellular signaling sequence, e.g., a primary signaling sequence of CD3-zeta. In a specific CAR of the invention, the primary signaling sequence of CD3-zeta is the sequence provided as SEQ ID NO:17, or the equivalent residues from a non-human species, e.g., mouse, rodent, monkey, ape and the like. In a specific CAR of the invention, the primary signaling sequence of CD3-zeta is the sequence as provided in SEQ ID NO:43, or the equivalent residues from a non-human species, e.g., mouse, rodent, monkey, ape and the like. 
     The term “antigen presenting cell” or “APC” refers to an immune system cell such as an accessory cell (e.g., a B-cell, a dendritic cell, and the like) that displays a foreign antigen complexed with major histocompatibility complexes (MHC&#39;s) on its surface. T-cells may recognize these complexes using their T-cell receptors (TCRs). APCs process antigens and present them to T-cells. 
     “Immune effector cell,” as that term is used herein, refers to a cell that is involved in an immune response, e.g., in the promotion of an immune effector response. Examples of immune effector cells include T cells, e.g., alpha/beta T cells and gamma/delta T cells, B cells, natural killer (NK) cells, natural killer T (NK-T) cells, mast cells, and myeloid-derived phagocytes. 
     “Immune effector function or immune effector response,” as that term is used herein, refers to function or response, e.g., of an immune effector cell, that enhances or promotes an immune attack of a target cell. E.g., an immune effector function or response refers a property of a T or NK cell that promotes killing or the inhibition of growth or proliferation, of a target cell. In the case of a T cell, primary stimulation and co-stimulation are examples of immune effector function or response. 
     The term “effector function” refers to a specialized function of a cell. Effector function of a T cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines. 
     An “intracellular signaling domain,” as the term is used herein, refers to an intracellular portion of a molecule. The intracellular signaling domain can generate a signal that promotes an immune effector function of the CAR containing cell, e.g., a CART cell. Examples of immune effector function, e.g., in a CART cell, include cytolytic activity and helper activity, including the secretion of cytokines. In embodiments, the intracellular signal domain is the portion of the protein which transduces the effector function signal and directs the cell to perform a specialized function. While the entire intracellular signaling domain can be employed, in many cases it is not necessary to use the entire chain. To the extent that a truncated portion of the intracellular signaling domain is used, such truncated portion may be used in place of the intact chain as long as it transduces the effector function signal. The term intracellular signaling domain is thus meant to include any truncated portion of the intracellular signaling domain sufficient to transduce the effector function signal. 
     In an embodiment, the intracellular signaling domain can comprise a primary intracellular signaling domain. Exemplary primary intracellular signaling domains include those derived from the molecules responsible for primary stimulation, or antigen dependent simulation. In an embodiment, the intracellular signaling domain can comprise a costimulatory intracellular domain. Exemplary costimulatory intracellular signaling domains include those derived from molecules responsible for costimulatory signals, or antigen independent stimulation. For example, in the case of a CART, a primary intracellular signaling domain can comprise a cytoplasmic sequence of a T cell receptor, and a costimulatory intracellular signaling domain can comprise cytoplasmic sequence from co-receptor or costimulatory molecule. 
     A primary intracellular signaling domain can comprise a signaling motif which is known as an immunoreceptor tyrosine-based activation motif or ITAM. Examples of ITAM containing primary cytoplasmic signaling sequences include, but are not limited to, those derived from CD3 zeta, FcR gamma, common FcR gamma (FCER1G), Fc gamma RIIa, FcR beta (Fc Epsilon Rib), CD3 gamma, CD3 delta, CD3 epsilon, CD22, CD79a, CD79b, CD278 (“ICOS”), FRI, CD66d, CD32, DAP10 and DAP12. 
     The term “zeta” or alternatively “zeta chain”, “CD3-zeta” or “TCR-zeta” is defined as the protein provided as GenBank Acc. No. BAG36664.1, or the equivalent residues from a non-human species, e.g., mouse, rodent, monkey, ape and the like, and a “zeta stimulatory domain” or alternatively a “CD3-zeta stimulatory domain” or a “TCR-zeta stimulatory domain” is defined as the amino acid residues from the cytoplasmic domain of the zeta chain, or functional derivatives thereof, that are sufficient to functionally transmit an initial signal necessary for T cell activation. In one aspect the cytoplasmic domain of zeta comprises residues 52 through 164 of GenBank Acc. No. BAG36664.1 or the equivalent residues from a non-human species, e.g., mouse, rodent, monkey, ape and the like, that are functional orthologs thereof. In one aspect, the “zeta stimulatory domain” or a “CD3-zeta stimulatory domain” is the sequence provided as SEQ ID NO:17. In one aspect, the “zeta stimulatory domain” or a “CD3-zeta stimulatory domain” is the sequence provided as SEQ ID NO:43. 
     The term “costimulatory molecule” refers to the cognate binding partner on a T cell that specifically binds with a costimulatory ligand, thereby mediating a costimulatory response by the T cell, such as, but not limited to, proliferation. Costimulatory molecules are cell surface molecules other than antigen receptors or their ligands that contribute to an efficient immune response. Costimulatory molecules include, but are not limited to an MHC class I molecule, TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signalling lymphocytic activation molecules (SLAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CD11a/CD18), 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, and a ligand that specifically binds with CD83. 
     A costimulatory intracellular signaling domain refers to the intracellular portion of a costimulatory molecule. The intracellular signaling domain can comprise the entire intracellular portion, or the entire native intracellular signaling domain, of the molecule from which it is derived, or a functional fragment or derivative thereof. 
     The term “4-1BB” refers to a member of the TNFR superfamily with an amino acid sequence provided as GenBank Acc. No. AAA62478.2, or the equivalent residues from a non-human species, e.g., mouse, rodent, monkey, ape and the like; and a “4-1BB costimulatory domain” is defined as amino acid residues 214-255 of GenBank Acc. No. AAA62478.2, or the equivalent residues from a non-human species, e.g., mouse, rodent, monkey, ape and the like. In one aspect, the “4-1BB costimulatory domain” is the sequence provided as SEQ ID NO:16 or the equivalent residues from a non-human species, e.g., mouse, rodent, monkey, ape and the like. 
     The term “encoding” refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (e.g., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene, cDNA, or RNA, encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA. 
     Unless otherwise specified, a “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. The phrase nucleotide sequence that encodes a protein or a RNA may also include introns to the extent that the nucleotide sequence encoding the protein may in some version contain an intron(s). 
     The term “effective amount” or “therapeutically effective amount” are used interchangeably herein, and refer to an amount of a compound, formulation, material, or composition, as described herein effective to achieve a particular biological result. 
     The term “endogenous” refers to any material from or produced inside an organism, cell, tissue or system. 
     The term “exogenous” refers to any material introduced from or produced outside an organism, cell, tissue or system. 
     The term “expression” refers to the transcription and/or translation of a particular nucleotide sequence driven by a promoter. 
     The term “transfer vector” refers to a composition of matter which comprises an isolated nucleic acid and which can be used to deliver the isolated nucleic acid to the interior of a cell. Numerous vectors are known in the art including, but not limited to, linear polynucleotides, polynucleotides associated with ionic or amphiphilic compounds, plasmids, and viruses. Thus, the term “transfer vector” includes an autonomously replicating plasmid or a virus. The term should also be construed to further include non-plasmid and non-viral compounds which facilitate transfer of nucleic acid into cells, such as, for example, a polylysine compound, liposome, and the like. Examples of viral transfer vectors include, but are not limited to, adenoviral vectors, adeno-associated virus vectors, retroviral vectors, lentiviral vectors, and the like. 
     The term “expression vector” refers to a vector comprising a recombinant polynucleotide comprising expression control sequences operatively linked to a nucleotide sequence to be expressed. An expression vector comprises sufficient cis-acting elements for expression; other elements for expression can be supplied by the host cell or in an in vitro expression system. Expression vectors include all those known in the art, including cosmids, plasmids (e.g., naked or contained in liposomes) and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses) that incorporate the recombinant polynucleotide. 
     The term “lentivirus” refers to a genus of the Retroviridae family. Lentiviruses are unique among the retroviruses in being able to infect non-dividing cells; they can deliver a significant amount of genetic information into the DNA of the host cell, so they are one of the most efficient methods of a gene delivery vector. HIV, SIV, and FIV are all examples of lentiviruses. The term “lentiviral vector” refers to a vector derived from at least a portion of a lentivirus genome, including especially a self-inactivating lentiviral vector as provided in Milone et al., Mol. Ther. 17(8): 1453-1464 (2009). Other examples of lentivirus vectors that may be used in the clinic, include but are not limited to, e.g., the LENTIVECTOR® gene delivery technology from Oxford BioMedica, the LENTIMAX™ vector system from Lentigen and the like. Nonclinical types of lentiviral vectors are also available and would be known to one skilled in the art. 
     The term “homologous” or “identity” refers to the subunit sequence identity between two polymeric molecules, e.g., between two nucleic acid molecules, such as, two DNA molecules or two RNA molecules, or between two polypeptide molecules. When a subunit position in both of the two molecules is occupied by the same monomeric subunit; e.g., if a position in each of two DNA molecules is occupied by adenine, then they are homologous or identical at that position. The homology between two sequences is a direct function of the number of matching or homologous positions; e.g., if half (e.g., five positions in a polymer ten subunits in length) of the positions in two sequences are homologous, the two sequences are 50% homologous; if 90% of the positions (e.g., 9 of 10), are matched or homologous, the two sequences are 90% homologous. 
     “Humanized” forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab′, F(ab′)2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies and antibody fragments thereof are human immunoglobulins (recipient antibody or antibody fragment) in which residues from a complementary-determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity, and capacity. In some instances, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, a humanized antibody/antibody fragment can comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. These modifications can further refine and optimize antibody or antibody fragment performance. In general, the humanized antibody or antibody fragment thereof will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or a significant portion of the FR regions are those of a human immunoglobulin sequence. The humanized antibody or antibody fragment can also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature, 321: 522-525, 1986; Reichmann et al., Nature, 332: 323-329, 1988; Presta, Curr. Op. Struct. Biol., 2: 593-596, 1992. 
     “Fully human” refers to an immunoglobulin, such as an antibody or antibody fragment, where the whole molecule is of human origin or consists of an amino acid sequence identical to a human form of the antibody or immunoglobulin. 
     The term “isolated” means altered or removed from the natural state. For example, a nucleic acid or a peptide naturally present in a living animal is not “isolated,” but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is “isolated.” An isolated nucleic acid or protein can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell. 
     In the context of the present invention, the following abbreviations for the commonly occurring nucleic acid bases are used. “A” refers to adenosine, “C” refers to cytosine, “G” refers to guanosine, “T” refers to thymidine, and “U” refers to uridine. 
     The term “operably linked” or “transcriptional control” refers to functional linkage between a regulatory sequence and a heterologous nucleic acid sequence resulting in expression of the latter. For example, a first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Operably linked DNA sequences can be contiguous with each other and, e.g., where necessary to join two protein coding regions, are in the same reading frame. 
     The term “parenteral” administration of an immunogenic composition includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), or intrasternal injection, intratumoral, or infusion techniques. 
     The term “nucleic acid” or “polynucleotide” refers to deoxyribonucleic acids (DNA) or ribonucleic acids (RNA) and polymers thereof in either single- or double-stranded form. The term “nucleic acid” includes a gene, cDNA, or an mRNA. In one embodiment, the nucleic acid molecule is synthetic (e.g., chemically synthesized) or recombinant. Unless specifically limited, the term encompasses nucleic acids containing analogues or derivatives of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608 (1985); and Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)). 
     The terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a protein&#39;s or peptide&#39;s sequence. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. “Polypeptides” include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. A polypeptide includes a natural peptide, a recombinant peptide, or a combination thereof. 
     As used herein, the term “plurality” refers to two or more. 
     The term “promoter” refers to a DNA sequence recognized by the synthetic machinery of the cell, or introduced synthetic machinery, required to initiate the specific transcription of a polynucleotide sequence. 
     The term “promoter/regulatory sequence” refers to a nucleic acid sequence which is required for expression of a gene product operably linked to the promoter/regulatory sequence. In some instances, this sequence may be the core promoter sequence and in other instances, this sequence may also include an enhancer sequence and other regulatory elements which are required for expression of the gene product. The promoter/regulatory sequence may, for example, be one which expresses the gene product in a tissue specific manner. 
     The term “constitutive” promoter refers to a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a cell under most or all physiological conditions of the cell. 
     The term “inducible” promoter refers to a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a cell substantially only when an inducer which corresponds to the promoter is present in the cell. 
     The term “tissue-specific” promoter refers to a nucleotide sequence which, when operably linked with a polynucleotide encodes or specified by a gene, causes the gene product to be produced in a cell substantially only if the cell is a cell of the tissue type corresponding to the promoter. 
     The term “flexible polypeptide linker” or “linker” as used in the context of a scFv refers to a peptide linker that consists of amino acids such as glycine and/or serine residues used alone or in combination, to link variable heavy and variable light chain regions together. In one embodiment, the flexible polypeptide linker is a Gly/Ser linker and comprises the amino acid sequence (Gly-Gly-Gly-Ser)n, where n is a positive integer equal to or greater than 1. For example, n=1, n=2, n=3. n=4, n=5, n=6, n=7, n=8, n=9 and n=10 (SEQ ID NO:105). In one embodiment, the flexible polypeptide linkers include, but are not limited to, (Gly 4  Ser) 4  (SEQ ID NO:106) or (Gly 4  Ser) 3  (SEQ ID NO:107). In another embodiment, the linkers include multiple repeats of (Gly 2 Ser), (GlySer) or (Gly 3 Ser) (SEQ ID NO:108). Also included within the scope of the invention are linkers described in WO2012/138475, incorporated herein by reference. 
     As used herein, a 5′ cap (also termed an RNA cap, an RNA 7-methylguanosine cap or an RNA m 7 G cap) is a modified guanine nucleotide that has been added to the “front” or 5′ end of a eukaryotic messenger RNA shortly after the start of transcription. The 5′ cap consists of a terminal group which is linked to the first transcribed nucleotide. Its presence is important for recognition by the ribosome and protection from RNases. Cap addition is coupled to transcription, and occurs co-transcriptionally, such that each influences the other. Shortly after the start of transcription, the 5′ end of the mRNA being synthesized is bound by a cap-synthesizing complex associated with RNA polymerase. This enzymatic complex catalyzes the chemical reactions that are required for mRNA capping. Synthesis proceeds as a multi-step biochemical reaction. The capping moiety can be modified to modulate functionality of mRNA such as its stability or efficiency of translation. 
     As used herein, “in vitro transcribed RNA” refers to RNA, e.g., mRNA, that has been synthesized in vitro. Generally, the in vitro transcribed RNA is generated from an in vitro transcription vector. The in vitro transcription vector comprises a template that is used to generate the in vitro transcribed RNA. 
     As used herein, a “poly(A)” is a series of adenosines attached by polyadenylation to the mRNA. In some embodiments of a construct for transient expression, the polyA is between 50 and 5000 (SEQ ID NO: 28), e.g., greater than 64, e.g., greater than 100, e.g., than 300 or 400. Poly(A) sequences can be modified chemically or enzymatically to modulate mRNA functionality such as localization, stability or efficiency of translation. 
     As used herein, “polyadenylation” refers to the covalent linkage of a polyadenylyl moiety, or its modified variant, to a messenger RNA molecule. In eukaryotic organisms, most messenger RNA (mRNA) molecules are polyadenylated at the 3′ end. The 3′ poly(A) tail is a long sequence of adenine nucleotides (often several hundred) added to the pre-mRNA through the action of an enzyme, polyadenylate polymerase. In higher eukaryotes, the poly(A) tail is added onto transcripts that contain a specific sequence, the polyadenylation signal. The poly(A) tail and the protein bound to it aid in protecting mRNA from degradation by exonucleases. Polyadenylation is also important for transcription termination, export of the mRNA from the nucleus, and translation. Polyadenylation occurs in the nucleus immediately after transcription of DNA into RNA, but additionally can also occur later in the cytoplasm. After transcription has been terminated, the mRNA chain is cleaved through the action of an endonuclease complex associated with RNA polymerase. The cleavage site is usually characterized by the presence of the base sequence AAUAAA near the cleavage site. After the mRNA has been cleaved, adenosine residues are added to the free 3′ end at the cleavage site. 
     As used herein, “transient” refers to expression of a non-integrated transgene for a period of hours, days or weeks, wherein the period of time of expression is less than the period of time for expression of the gene if integrated into the genome or contained within a stable plasmid replicon in the host cell. 
     The term “signal transduction pathway” refers to the biochemical relationship between a variety of signal transduction molecules that play a role in the transmission of a signal from one portion of a cell to another portion of a cell. The phrase “cell surface receptor” includes molecules and complexes of molecules capable of receiving a signal and transmitting signal across the membrane of a cell. 
     The term “subject” is intended to include living organisms in which an immune response can be elicited (e.g., mammals, human). 
     The term, a “substantially purified” cell refers to a cell that is essentially free of other cell types. A substantially purified cell also refers to a cell which has been separated from other cell types with which it is normally associated in its naturally occurring state. In some instances, a population of substantially purified cells refers to a homogenous population of cells. In other instances, this term refers simply to cell that have been separated from the cells with which they are naturally associated in their natural state. In some aspects, the cells are cultured in vitro. In other aspects, the cells are not cultured in vitro. 
     The term “therapeutic” as used herein means a treatment. A therapeutic effect is obtained by reduction, suppression, remission, or eradication of a disease state. 
     The term “prophylaxis” as used herein means the prevention of or protective treatment for a disease or disease state. 
     In the context of the present invention, “tumor antigen” or “hyperproliferative disorder antigen” or “antigen associated with a hyperproliferative disorder” refers to antigens that are common to specific hyperproliferative disorders. In certain aspects, the hyperproliferative disorder antigens of the present invention are derived from, cancers including but not limited to primary or metastatic melanoma, thymoma, lymphoma, sarcoma, lung cancer, liver cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, leukemias, uterine cancer, cervical cancer, bladder cancer, kidney cancer and adenocarcinomas such as breast cancer, prostate cancer, ovarian cancer, pancreatic cancer, and the like. 
     The term “transfected” or “transformed” or “transduced” refers to a process by which exogenous nucleic acid is transferred or introduced into the host cell. A “transfected” or “transformed” or “transduced” cell is one which has been transfected, transformed or transduced with exogenous nucleic acid. The cell includes the primary subject cell and its progeny. 
     A subject “responds” to treatment if a parameter of a cancer (e.g., a hematological cancer, e.g., cancer cell growth, proliferation and/or survival) in the subject is retarded or reduced by a detectable amount, e.g., about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more as determined by any appropriate measure, e.g., by mass, cell count or volume. In one example, a subject responds to treatment if the subject experiences a life expectancy extended by about 5%, 10%, 20%, 30%, 40%, 50% or more beyond the life expectancy predicted if no treatment is administered. In another example, a subject responds to treatment, if the subject has an increased disease-free survival, overall survival or increased time to progression. Several methods can be used to determine if a patient responds to a treatment including, for example, criteria provided by NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). For example, in the context of B-ALL, a complete response or complete responder, may involve one or more of: &lt;5% BM blast, &gt;1000 neutrophil/ANC (/μL). &gt;100,000 platelets (/μL) with no circulating blasts or extramedullary disease (no lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS involvement), Trilineage hematopoiesis, and no recurrence for 4 weeks. A partial responder may involve one or more of &gt;50% reduction in BM blast, &gt;1000 neutrophil/ANC (/μL). &gt;100,000 platelets (/μL). A non-responder can show disease progression, e.g., &gt;25% in BM blasts. 
     “Refractory” as used herein refers to a disease, e.g., cancer, that does not respond to a treatment. In embodiments, a refractory cancer can be resistant to a treatment before or at the beginning of the treatment. In other embodiments, the refractory cancer can become resistant during a treatment. A refractory cancer is also called a resistant cancer. 
     The term “relapse” as used herein refers to reappearance of a cancer after an initial period of responsiveness (e.g., complete response or partial response). The initial period of responsiveness may involve the level of cancer cells falling below a certain threshold, e.g., below 20%, 1%, 10%, 5%, 4%, 3%, 2%, or 1%. The reappearance may involve the level of cancer cells rising above a certain threshold, e.g., above 20%, 1%, 10%, 5%, 4%, 3%, 2%, or 1%. For example, e.g., in the context of B-ALL, the reappearance may involve, e.g., a reappearance of blasts in the blood, bone marrow (&gt;5%), or any extramedullary site, after a complete response. A complete response, in this context, may involve &lt;5% BM blast. More generally, in an embodiment, a response (e.g., complete response or partial response) can involve the absence of detectable MRD (minimal residual disease). In an embodiment, the initial period of responsiveness lasts at least 1, 2, 3, 4, 5, or 6 days; at least 1, 2, 3, or 4 weeks; at least 1, 2, 3, 4, 6, 8, 10, or 12 months; or at least 1, 2, 3, 4, or 5 years. 
     In some embodiments, a therapy that includes a CD19 inhibitor, e.g., a CD19 CAR therapy, may relapse or be refractory to treatment. The relapse or resistance can be caused by CD19 loss (e.g., an antigen loss mutation) or other CD19 alteration that reduces the level of CD19 (e.g., caused by clonal selection of CD19-negative clones). A cancer that harbors such CD19 loss or alteration is referred to herein as a “CD19-negative cancer” or a “CD19-negative relapsed cancer”). It shall be understood that a CD19-negative cancer need not have 100% loss of CD19, but a sufficient reduction to reduce the effectiveness of a CD19 therapy such that the cancer relapses or becomes refractory. In some embodiments, a CD19-negative cancer results from a CD19 CAR therapy. 
     The term “specifically binds,” refers to an antibody, or a ligand, which recognizes and binds with a binding partner (e.g., a stimulatory tumor antigen) protein present in a sample, but which antibody or ligand does not substantially recognize or bind other molecules in the sample. 
     As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in  J. Pharmaceutical Sciences  (1977) 66:1-19. 
     “Regulatable chimeric antigen receptor (RCAR),” as that term is used herein, refers to a set of polypeptides, typically two in the simplest embodiments, which when in a RCARX cell, provides the RCARX cell with specificity for a target cell, typically a cancer cell, and with regulatable intracellular signal generation or proliferation, which can optimize an immune effector property of the RCARX cell. An RCARX cell relies at least in part, on an antigen binding domain to provide specificity to a target cell that comprises the antigen bound by the antigen binding domain. In an embodiment, an RCAR includes a dimerization switch that, upon the presence of a dimerization molecule, can couple an intracellular signaling domain to the antigen binding domain. 
     “Membrane anchor” or “membrane tethering domain”, as that term is used herein, refers to a polypeptide or moiety, e.g., a myristoyl group, sufficient to anchor an extracellular or intracellular domain to the plasma membrane. 
     “Switch domain,” as that term is used herein, e.g., when referring to an RCAR, refers to an entity, typically a polypeptide-based entity, that, in the presence of a dimerization molecule, associates with another switch domain. The association results in a functional coupling of a first entity linked to, e.g., fused to, a first switch domain, and a second entity linked to, e.g., fused to, a second switch domain. A first and second switch domain are collectively referred to as a dimerization switch. In embodiments, the first and second switch domains are the same as one another, e.g., they are polypeptides having the same primary amino acid sequence, and are referred to collectively as a homodimerization switch. In embodiments, the first and second switch domains are different from one another, e.g., they are polypeptides having different primary amino acid sequences, and are referred to collectively as a heterodimerization switch. In embodiments, the switch is intracellular. In embodiments, the switch is extracellular. In embodiments, the switch domain is a polypeptide-based entity, e.g., FKBP or FRB-based, and the dimerization molecule is small molecule, e.g., a rapalogue. In embodiments, the switch domain is a polypeptide-based entity, e.g., an scFv that binds a myc peptide, and the dimerization molecule is a polypeptide, a fragment thereof, or a multimer of a polypeptide, e.g., a myc ligand or multimers of a myc ligand that bind to one or more myc scFvs. In embodiments, the switch domain is a polypeptide-based entity, e.g., myc receptor, and the dimerization molecule is an antibody or fragments thereof, e.g., myc antibody. 
     “Dimerization molecule,” as that term is used herein, e.g., when referring to an RCAR, refers to a molecule that promotes the association of a first switch domain with a second switch domain. In embodiments, the dimerization molecule does not naturally occur in the subject, or does not occur in concentrations that would result in significant dimerization. In embodiments, the dimerization molecule is a small molecule, e.g., rapamycin or a rapalogue, e.g., RAD001. 
     The term “low, immune enhancing, dose” when used in conjunction with an mTOR inhibitor, e.g., an allosteric mTOR inhibitor, e.g., RAD001 or rapamycin, or a catalytic mTOR inhibitor, refers to a dose of mTOR inhibitor that partially, but not fully, inhibits mTOR activity, e.g., as measured by the inhibition of P70 S6 kinase activity. Methods for evaluating mTOR activity, e.g., by inhibition of P70 S6 kinase, are discussed herein. The dose is insufficient to result in complete immune suppression but is sufficient to enhance the immune response. In an embodiment, the low, immune enhancing, dose of mTOR inhibitor results in a decrease in the number of PD-1 positive T cells and/or an increase in the number of PD-1 negative T cells, or an increase in the ratio of PD-1 negative T cells/PD-1 positive T cells. In an embodiment, the low, immune enhancing, dose of mTOR inhibitor results in an increase in the number of naïve T cells. In an embodiment, the low, immune enhancing, dose of mTOR inhibitor results in one or more of the following: 
     an increase in the expression of one or more of the following markers: CD62L high , CD127 high , CD27 + , and BCL2, e.g., on memory T cells, e.g., memory T cell precursors; 
     a decrease in the expression of KLRG1, e.g., on memory T cells, e.g., memory T cell precursors; and 
     an increase in the number of memory T cell precursors, e.g., cells with any one or combination of the following characteristics: increased CD62L high  increased CD127 high , increased CD27 + , decreased KLRG1, and increased BCL2; 
     wherein any of the changes described above occurs, e.g., at least transiently, e.g., as compared to a non-treated subject. 
     Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. As another example, a range such as 95-99% identity, includes something with 95%, 96%, 97%, 98% or 99% identity, and includes subranges such as 96-99%, 96-98%, 96-97%, 97-99%, 97-98% and 98-99% identity. This applies regardless of the breadth of the range. 
     Description 
     CD19 Inhibitors, Binding Domains and CARs 
     Provided herein are compositions of matter and methods of use for the treatment of a disease such as cancer using CD19 chimeric antigen receptors (CAR). The methods include, inter alia, administering a CD19 CAR described herein in combination with another agent such as B-cell inhibitor. The methods also include, e.g., administering a CD19 CAR described herein to treat a lymphoma such as Hodgkin lymphoma. 
     In one aspect, the invention provides a number of chimeric antigen receptors (CAR) comprising an antibody or antibody fragment engineered for specific binding to a CD19 protein. In one aspect, the invention provides a cell (e.g., T cell) engineered to express a CAR, wherein the CAR T cell (“CART”) exhibits an anticancer property. In one aspect a cell is transformed with the CAR and the CAR is expressed on the cell surface. In some embodiments, the cell (e.g., T cell) is transduced with a viral vector encoding a CAR. In some embodiments, the viral vector is a retroviral vector. In some embodiments, the viral vector is a lentiviral vector. In some such embodiments, the cell may stably express the CAR. In another embodiment, the cell (e.g., T cell) is transfected with a nucleic acid, e.g., mRNA, cDNA, DNA, encoding a CAR. In some such embodiments, the cell may transiently express the CAR. 
     In one aspect, the anti-CD19 protein binding portion of the CAR is a scFv antibody fragment. In one aspect such antibody fragments are functional in that they retain the equivalent binding affinity, e.g., they bind the same antigen with comparable affinity, as the IgG antibody from which it is derived. In one aspect such antibody fragments are functional in that they provide a biological response that can include, but is not limited to, activation of an immune response, inhibition of signal-transduction origination from its target antigen, inhibition of kinase activity, and the like, as will be understood by a skilled artisan. In one aspect, the anti-CD19 antigen binding domain of the CAR is a scFv antibody fragment that is humanized compared to the murine sequence of the scFv from which it is derived. In one aspect, the parental murine scFv sequence is the CAR19 construct provided in PCT publication WO2012/079000 and provided herein as SEQ ID NO:59. In one embodiment, the anti-CD19 binding domain is a scFv described in WO2012/079000 and provided in SEQ ID NO:59, or a sequence at least 95%, e.g., 95-99%, identical thereto. In an embodiment, the anti-CD19 binding domain is part of a CAR construct provided in PCT publication WO2012/079000 and provided herein as SEQ ID NO:58, or a sequence at least 95%, e.g., 95%-99%, identical thereto. In an embodiment, the anti-CD19 binding domain comprises at least one (e.g., 2, 3, 4, 5, or 6) CDRs selected from Table 4 and/or Table 5. 
     In some aspects, the antibodies of the invention are incorporated into a chimeric antigen receptor (CAR). In one aspect, the CAR comprises the polypeptide sequence provided as SEQ ID NO: 12 in PCT publication WO2012/079000, and provided herein as SEQ ID NO: 58, wherein the scFv domain is substituted by one or more sequences selected from SEQ ID NOS: 1-12. In one aspect, the scFv domains of SEQ ID NOS:1-12 are humanized variants of the scFv domain of SEQ ID NO:59, which is an scFv fragment of murine origin that specifically binds to human CD19. Humanization of this mouse scFv may be desired for the clinical setting, where the mouse-specific residues may induce a human-anti-mouse antigen (HAMA) response in patients who receive CART19 treatment, e.g., treatment with T cells transduced with the CAR19 construct. 
     In one embodiment, the CD19 CAR comprises an amino acid sequence provided as SEQ ID NO: 12 in PCT publication WO2012/079000. In embodiment, the amino acid sequence is: 
                    (SEQ ID NO: 58)       MALPVTALLLPLALLLHAARPdiqmtqttsslsaslgdrvtiscrasqd               iskylnwyqqkpdgtvklliyhtsrlhsgvpsrfsgsgsgtdysltisn               leqediatyfcqqgntlpytfgggtkleitggggsggggsggggsevkl               qesgpglvapsqslsvtctvsgvslpdygvswirqpprkglewlgviwg               settyynsalksrltiikdnsksqvflkmnslqtddtaiyycakhyyyg               gsyamdywgqgtsvtvsstttpaprpptpaptiasqplslrpeacrpaa               ggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyif               kqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapaykqgqn               qlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkm               aeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr,            
substantially homologous thereto.
 
     In embodiment, the amino acid sequence is 
                    (SEQ ID NO: 1633)       diqmtqttsslsaslgdrvtiscrasqdiskylnwyqqkpdgtvklliy               htsrlhsgvpsrfsgsgsgtdysltisnleqediatyfcqqgntlpytf               gggtkleitggggsggggsggggsevklqesgpglvapsqslsvtctvs               gvslpdygvswirqpprkglewlgviwgsettyynsalksrltiikdns               ksqvflkmnslqtddtaiyycakhyyyggsyamdywgqgtsvtvssttt               paprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwapl               agtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrf               peeeeggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrr               grdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdg               lyqglstatkdtydalhmqalppr,            
or a sequence substantially homologous thereto.
 
     In one embodiment, the CD19 CAR has the USAN designation TISAGENLECLEUCEL-T. In embodiments, CTL019 is made by a gene modification of T cells is mediated by stable insertion via transduction with a self-inactivating, replication deficient Lentiviral (LV) vector containing the CTL019 transgene under the control of the EF-1 alpha promoter. CTL019 can be a mixture of transgene positive and negative T cells that are delivered to the subject on the basis of percent transgene positive T cells. 
     In one aspect, the humanized CAR19 comprises the scFv portion provided in SEQ ID NO:1. In one aspect, the humanized CAR19 comprises the scFv portion provided in SEQ ID NO:2. In one aspect, the humanized CAR19 comprises the scFv portion provided in SEQ ID NO:3. In one aspect, the humanized CAR19 comprises the scFv portion provided in SEQ ID NO:4. In one aspect, the humanized CAR19 comprises the scFv portion provided in SEQ ID NO:5. In one aspect, the humanized CAR19 comprises the scFv portion provided in SEQ ID NO:6. In one aspect, the humanized CAR19 comprises the scFv portion provided in SEQ ID NO:7. In one aspect, the humanized CAR19 comprises the scFv portion provided in SEQ ID NO:8. In one aspect, the humanized CAR19 comprises the scFv portion provided in SEQ ID NO:9. In one aspect, the humanized CAR19 comprises the scFv portion provided in SEQ ID NO:10. In one aspect, the humanized CAR19 comprises the scFv portion provided in SEQ ID NO:11. In one aspect, the humanized CAR19 comprises the scFv portion provided in SEQ ID NO:12. 
     In one aspect, the CARs of the invention combine an antigen binding domain of a specific antibody with an intracellular signaling molecule. For example, in some aspects, the intracellular signaling molecule includes, but is not limited to, CD3-zeta chain, 4-1BB and CD28 signaling modules and combinations thereof. In one aspect, the CD19 CAR comprises a CAR selected from the sequence provided in one or more of SEQ ID NOS: 31-42. In one aspect, the CD19 CAR comprises the sequence provided in SEQ ID NO:31. In one aspect, the CD19 CAR comprises the sequence provided in SEQ ID NO:32. In one aspect, the CD19 CAR comprises the sequence provided in SEQ ID NO:33. In one aspect, the CD19 CAR comprises the sequence provided in SEQ ID NO:34. In one aspect, the CD19 CAR comprises the sequence provided in SEQ ID NO:35. In one aspect, the CD19 CAR comprises the sequence provided in SEQ ID NO:36. In one aspect, the CD19 CAR comprises the sequence provided in SEQ ID NO:37. In one aspect, the CD19 CAR comprises the sequence provided in SEQ ID NO:38. In one aspect, the CD19 CAR comprises the sequence provided in SEQ ID NO:39. In one aspect, the CD19 CAR comprises the sequence provided in SEQ ID NO:40. In one aspect, the CD19 CAR comprises the sequence provided in SEQ ID NO:41. In one aspect, the CD19 CAR comprises the sequence provided in SEQ ID NO:42. 
     In embodiments, the CAR molecule is a CD19 CAR molecule described herein, e.g., a humanized CAR molecule described herein, e.g., a humanized CD19 CAR molecule of Table 2 or having CDRs as set out in Tables 4 and 5. 
     In embodiments, the CAR molecule is a CD19 CAR molecule described herein, e.g., a murine CAR molecule described herein, e.g., a murine CD19 CAR molecule of Table 3 or having CDRs as set out in Tables 4 and 5. 
     In some embodiments, the CAR molecule comprises one, two, and/or three CDRs from the heavy chain variable region and/or one, two, and/or three CDRs from the light chain variable region of the murine or humanized CD19 CAR of Table 4 and 5. 
     In one embodiment, the antigen binding domain comprises one, two three (e.g., all three) heavy chain CDRs, HC CDR1, HC CDR2 and HC CDR3, from an antibody listed above, and/or one, two, three (e.g., all three) light chain CDRs, LC CDR1, LC CDR2 and LC CDR3, from an antibody listed above. In one embodiment, the antigen binding domain comprises a heavy chain variable region and/or a variable light chain region of an antibody listed or described above. 
     In an embodiment, the antigen binding domain comprises a humanized antibody or an antibody fragment. In one embodiment, the humanized anti-CD19 binding domain comprises one or more (e.g., all three) light chain complementary determining region 1 (LC CDR1), light chain complementary determining region 2 (LC CDR2), and light chain complementary determining region 3 (LC CDR3) of a murine or humanized anti-CD19 binding domain described herein, and/or one or more (e.g., all three) heavy chain complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary determining region 3 (HC CDR3) of a murine or humanized anti-CD19 binding domain described herein, e.g., a humanized anti-CD19 binding domain comprising one or more, e.g., all three, LC CDRs and one or more, e.g., all three, HC CDRs. 
     In one embodiment, an antigen binding domain comprises one, two three (e.g., all three) heavy chain CDRs, HC CDR1, HC CDR2 and HC CDR3, from an antibody listed herein, e.g., in Table 2, 4, or 5 and/or one, two, three (e.g., all three) light chain CDRs, LC CDR1, LC CDR2 and LC CDR3, from an antibody listed herein, e.g., in Table 2, 4, or 5. In one embodiment, the antigen binding domain comprises a heavy chain variable region and/or a variable light chain region of an antibody listed or described above. 
     In an embodiment, the CD19 binding domain (e.g., an scFv) comprises: a light chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a light chain variable region provided in Table 2, or a sequence with 95-99% identity with an amino acid sequence of Table 2; and/or a heavy chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a heavy chain variable region provided in Table 2, or a sequence with 95-99% identity to an amino acid sequence of Table 2. In embodiments, the CD19 binding domain comprises one or more CDRs (e.g., one each of a HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3) of Table 4 or Table 5, or CDRs having one, two, three, four, five, or six modifications (e.g., substitutions) of one or more of the CDRs. 
     Exemplary anti-CD19 antibody molecules (including antibodies or fragments or conjugates thereof) can include a scFv, CDRs, or VH and VL chains described in Tables 2, 4, or 5. In an embodiment, the CD19-binding antibody molecule comprises: alight chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a light chain variable region provided in Table 2, or a sequence with 95-99% identity with an amino acid sequence of Table 2; and/or a heavy chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a heavy chain variable region provided in Table 2, or a sequence with 95-99% identity to an amino acid sequence of Table 2. In embodiments, the CD19-binding antibody molecule comprises one or more CDRs (e.g., one each of a HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3) of Table 4 or Table 5, or CDRs having one, two, three, four, five, or six modifications (e.g., substitutions) of one or more of the CDRs. The antibody molecule may be, e.g., an isolated antibody molecule. 
     In some embodiments, the humanized anti-CD19 binding domain comprises a HC CDR1, a HC CDR2, and a HC CDR3 of any heavy chain binding domain amino acid sequences listed in Table 2. In embodiments, the antigen binding domain further comprises a LC CDR1, a LC CDR2, and a LC CDR3. In embodiments, the antigen binding domain comprises a LC CDR1, a LC CDR2, and a LC CDR3 of any light chain binding domain amino acid sequences listed in Table 2. 
     In some embodiments, the antigen binding domain comprises one, two or all of LC CDR1, LC CDR2, and LC CDR3 of any light chain binding domain amino acid sequences listed in Table 2, and one, two or all of HC CDR1, HC CDR2, and HC CDR3 of any heavy chain binding domain amino acid sequences listed in Table 2. 
     In some embodiments, the CDRs are defined according to the Kabat numbering scheme, the Chothia numbering scheme, or a combination thereof. 
     The sequences of humanized CDR sequences of the scFv domains are shown in Table 4 for the heavy chain variable domains and in Table 5 for the light chain variable domains. “ID” stands for the respective SEQ ID NO for each CDR. 
     In some embodiments, the CD19 binding domain comprises a Kabat HCDR1 having a sequence of DYGVS (SEQ ID NO: 1634), an HCDR2 of Table 4, an HCDR3 of Table 4, an LCDR1 of Table 5, an LCDR2 of Table 5, and an LCDR3 of Table 5. 
     In one embodiment, the humanized anti-CD19 binding domain comprises a sequence selected from a group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, and SEQ ID NO:12, or a sequence with 95-99% identity thereof. In one embodiment, the nucleic acid sequence encoding the humanized anti-CD19 binding domain comprises a sequence selected from a group consisting of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:70, SEQ ID NO:71 and SEQ ID NO:72, or a sequence with 95-99% identity thereof. 
     In one embodiment, the humanized anti-CD19 binding domain is a scFv, and a light chain variable region comprising an amino acid sequence described herein, e.g., in Table 2, is attached to a heavy chain variable region comprising an amino acid sequence described herein, e.g., in Table 2, via a linker, e.g., a linker described herein. In one embodiment, the humanized anti-CD19 binding domain includes a (Gly 4 -Ser)n linker, wherein n is 1, 2, 3, 4, 5, or 6, e.g., 3 or 4 (SEQ ID NO:53). The light chain variable region and heavy chain variable region of a scFv can be, e.g., in any of the following orientations: light chain variable region-linker-heavy chain variable region or heavy chain variable region-linker-light chain variable region. 
     In one aspect, the antigen binding domain portion comprises one or more sequence selected from SEQ ID NOS:1-12. In one aspect the humanized CAR is selected from one or more sequence selected from SEQ ID NOS: 31-42. In some aspects, a non-human antibody is humanized, where specific sequences or regions of the antibody are modified to increase similarity to an antibody naturally produced in a human or fragment thereof. 
     In one embodiment, the anti-CD19 binding domain comprises a murine light chain variable region described herein (e.g., in Table 3) and/or a murine heavy chain variable region described herein (e.g., in Table 3). In one embodiment, the anti-CD19 binding domain is a scFv comprising a murine light chain and a murine heavy chain of an amino acid sequence of Table 3. In an embodiment, the anti-CD19 binding domain (e.g., an scFv) comprises: a light chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a light chain variable region provided in Table 3, or a sequence with 95-99% identity with an amino acid sequence of Table 3; and/or a heavy chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a heavy chain variable region provided in Table 3, or a sequence with 95-99% identity to an amino acid sequence of Table 3. In one embodiment, the anti-CD19 binding domain comprises a sequence of SEQ ID NO:59, or a sequence with 95-99% identity thereof. In one embodiment, the anti-CD19 binding domain is a scFv, and a light chain variable region comprising an amino acid sequence described herein, e.g., in Table 3, is attached to a heavy chain variable region comprising an amino acid sequence described herein, e.g., in Table 3, via a linker, e.g., a linker described herein. In one embodiment, the antigen binding domain includes a (Gly 4 -Ser)n linker, wherein n is 1, 2, 3, 4, 5, or 6, e.g., 3 or 4 (SEQ ID NO: 53). The light chain variable region and heavy chain variable region of a scFv can be, e.g., in any of the following orientations: light chain variable region-linker-heavy chain variable region or heavy chain variable region-linker-light chain variable region. 
     In embodiments, the CAR molecule comprises a CD19 inhibitor comprising an antibody or antibody fragment which includes a CD19 binding domain, a transmembrane domain, and an intracellular signaling domain comprising a stimulatory domain, and wherein said CD19 binding domain comprises one or more of (e.g., all three of) light chain complementary determining region 1 (LC CDR1), light chain complementary determining region 2 (LC CDR2), and light chain complementary determining region 3 (LC CDR3) of any CD19 light chain binding domain amino acid sequence listed in Tables 2 or 3, and one or more of (e.g., all three of) heavy chain complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary determining region 3 (HC CDR3) of any CD19 heavy chain binding domain amino acid sequence listed in Tables 2 or 3. 
     In embodiments, a CD19 CAR comprises light chain variable region listed in Tables 2 or 3 and any heavy chain variable region listed Tables 2 or 3. 
     In embodiments, the CD19 inhibitor comprises a CD19 binding domain which comprises a sequence selected from a group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO: 4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12, or a sequence with 95-99% identity thereof. In embodiments, the CD19 CAR comprises a polypeptide of SEQ ID NO:58. 
     In one embodiment, the CAR molecule comprises an anti-CD19 binding domain comprising one or more (e.g., all three) light chain complementary determining region 1 (LC CDR1), light chain complementary determining region 2 (LC CDR2), and light chain complementary determining region 3 (LC CDR3) of an anti-CD19 binding domain described herein, and one or more (e.g., all three) heavy chain complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary determining region 3 (HC CDR3) of an anti-CD19 binding domain described herein, e.g., an anti-CD19 binding domain comprising one or more, e.g., all three, LC CDRs and one or more, e.g., all three, HC CDRs. In one embodiment, the anti-CD19 binding domain comprises one or more (e.g., all three) heavy chain complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary determining region 3 (HC CDR3) of an anti-CD19 binding domain described herein, e.g., the anti-CD19 binding domain has two variable heavy chain regions, each comprising a HC CDR1, a HC CDR2 and a HC CDR3 described herein. 
     In one aspect, the anti-CD19 binding domain is characterized by particular functional features or properties of an antibody or antibody fragment. For example, in one aspect, the portion of a CAR composition of the invention that comprises an antigen binding domain specifically binds human CD19. In one aspect, the invention relates to an antigen binding domain comprising an antibody or antibody fragment, wherein the antibody binding domain specifically binds to a CD19 protein or fragment thereof, wherein the antibody or antibody fragment comprises a variable light chain and/or a variable heavy chain that includes an amino acid sequence of SEQ ID NO: 1-12 or SEQ ID NO:59. In one aspect, the antigen binding domain comprises an amino acid sequence of an scFv selected from SEQ ID NOs: 1-12 or SEQ ID NO:59. In certain aspects, the scFv is contiguous with and in the same reading frame as a leader sequence. In one aspect the leader sequence is the polypeptide sequence provided as SEQ ID NO:13. 
     In one aspect, the portion of the CAR comprising the antigen binding domain comprises an antigen binding domain that targets CD19. In one aspect, the antigen binding domain targets human CD19. In one aspect, the antigen binding domain of the CAR has the same or a similar binding specificity as, or includes, the FMC63 scFv fragment described in Nicholson et al. Mol. Immun. 34 (16-17): 1157-1165 (1997). In one aspect, the portion of the CAR comprising the antigen binding domain comprises an antigen binding domain that targets a B-cell antigen, e.g., a human B-cell antigen. A CD19 antibody molecule can be, e.g., an antibody molecule (e.g., a humanized anti-CD19 antibody molecule) described in WO2014/153270, which is incorporated herein by reference in its entirety. WO2014/153270 also describes methods of assaying the binding and efficacy of various CART constructs. 
     In some embodiments, the CD19 CAR comprises an antigen binding domain derived from (e.g., comprises an amino acid sequence of) an anti-CD19 antibody (e.g., an anti-CD19 mono- or bispecific antibody) or a fragment or conjugate thereof. In one embodiment, the anti-CD19 antibody is a humanized antigen binding domain as described in WO2014/153270 (e.g., Table 3 of WO2014/153270) incorporated herein by reference, or a conjugate thereof. Other exemplary anti-CD19 antibodies or fragments or conjugates thereof, include but are not limited to, a bispecific T cell engager that targets CD19 (e.g., blinatumomab), SAR3419 (Sanofi), MEDI-551 (MedImmune LLC), Combotox, DT2219ARL (Masonic Cancer Center), MOR-208 (also called XmAb-5574; MorphoSys), XmAb-5871 (Xencor), MDX-1342 (Bristol-Myers Squibb), SGN-CD19A (Seattle Genetics), and AFM11 (Affimed Therapeutics). See, e.g., Hammer. MAbs. 4.5(2012): 571-77. Blinatomomab is a bispecific antibody comprised of two scFvs-one that binds to CD19 and one that binds to CD3. Blinatomomab directs T cells to attack cancer cells. See, e.g., Hammer et al.; Clinical Trial Identifier No. NCT00274742 and NCT01209286. MEDI-551 is a humanized anti-CD19 antibody with a Fc engineered to have enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). See, e.g., Hammer et al.; and Clinical Trial Identifier No. NCT01957579. Combotox is a mixture of immunotoxins that bind to CD19 and CD22. The immunotoxins are made up of scFv antibody fragments fused to a deglycosylated ricin A chain. See, e.g., Hammer et al.; and Herrera et al. J. Pediatr. Hematol. Oncol. 31.12(2009):936-41; Schindler et al. Br. J. Haematol. 154.4(2011):471-6. DT2219ARL is a bispecific immunotoxin targeting CD19 and CD22, comprising two scFvs and a truncated diphtheria toxin. See, e.g., Hammer et al.; and Clinical Trial Identifier No. NCT00889408. SGN-CD19A is an antibody-drug conjugate (ADC) comprised of an anti-CD19 humanized monoclonal antibody linked to a synthetic cytotoxic cell-killing agent, monomethyl auristatin F (MMAF). See, e.g., Hammer et al.; and Clinical Trial Identifier Nos. NCT01786096 and NCT01786135. SAR3419 is an anti-CD19 antibody-drug conjugate (ADC) comprising an anti-CD19 humanized monoclonal antibody conjugated to a maytansine derivative via a cleavable linker. See, e.g., Younes et al. J. Clin. Oncol. 30.2(2012): 2776-82; Hammer et al.; Clinical Trial Identifier No. NCT00549185; and Blanc et al. Clin Cancer Res. 2011; 17:6448-58. XmAb-5871 is an Fc-engineered, humanized anti-CD19 antibody. See, e.g., Hammer et al. MDX-1342 is a human Fc-engineered anti-CD19 antibody with enhanced ADCC. See, e.g., Hammer et al. In embodiments, the antibody molecule is a bispecific anti-CD19 and anti-CD3 molecule. For instance, AFM11 is a bispecific antibody that targets CD19 and CD3. See, e.g., Hammer et al.; and Clinical Trial Identifier No. NCT02106091. In some embodiments, an anti-CD19 antibody described herein is conjugated or otherwise bound to a therapeutic agent, e.g., a chemotherapeutic agent, peptide vaccine (such as that described in Izumoto et al. 2008 J Neurosurg 108:963-971), immunosuppressive agent, or immunoablative agent, e.g., cyclosporin, azathioprine, methotrexate, mycophenolate, FK506, CAMPATH, anti-CD3 antibody, cytoxin, fludarabine, rapamycin, mycophenolic acid, steroid, FR901228, or cytokine. 
     In one embodiment, an antigen binding domain against CD19 is an antigen binding portion, e.g., CDRs, of an antigen binding domain described in a Table herein. In one embodiment, a CD19 antigen binding domain can be from any CD19 CAR, e.g., LG-740; U.S. Pat. Nos. 8,399,645; 7,446,190; Xu et al., Leuk Lymphoma. 2013 54(2):255-260(2012); Cruz et al., Blood 122(17):2965-2973 (2013); Brentjens et al., Blood, 118(18):4817-4828 (2011); Kochenderfer et al., Blood 116(20):4099-102 (2010); Kochenderfer et al., Blood 122 (25):4129-39(2013); and 16th Annu Meet Am Soc Gen Cell Ther (ASGCT) (May 15-18, Salt Lake City) 2013, Abst 10, each of which is herein incorporated by reference in its entirety. 
     In embodiments, the CAR molecule comprises a CD19 CAR molecule described herein, e.g., a CD19 CAR molecule described in US-2015-0283178-A1, e.g., CTL019. In embodiments, the CD19 CAR comprises an amino acid, or has a nucleotide sequence shown in US-2015-0283178-A1, incorporated herein by reference. 
     In one aspect, the invention provides a cell (e.g., T cell) engineered to express a chimeric antigen receptor (CAR), wherein the CAR-expressing cell, e.g., CAR T cell (“CART”) exhibits an anticancer property. A suitable antigen is CD19. In one aspect, the antigen binding domain of the CAR comprises a partially humanized anti-CD19 antibody fragment. In one aspect, the antigen binding domain of the CAR comprises a partially humanized anti-CD19 antibody fragment comprising an scFv. Accordingly, the invention provides (among other things) a CD19-CAR that comprises a humanized anti-CD19 binding domain and is engineered into an immune effector cell, e.g., a T cell or an NK cell, and methods of their use for adoptive therapy. 
     In one aspect, the CAR, e.g., CD19-CAR comprises at least one intracellular domain selected from the group of a CD137 (4-1BB) signaling domain, a CD28 signaling domain, a CD3zeta signal domain, and any combination thereof. In one aspect, the CAR, e.g., CD19-CAR comprises at least one intracellular signaling domain is from one or more co-stimulatory molecule(s) other than a CD137 (4-1BB) or CD28. 
     Exemplary CD19 CAR Constructs 
     Of the CD19 CAR constructs described in International Application WO2014/153270, certain sequences are reproduced herein. It is understood that the sequences in this section can also be used in the context of other CARs, e.g., BCMA CARs. 
     The sequences of the murine scFv fragments (SEQ ID NOS: 98, 109, 111 and 114) are provided below in Table 3. Full CAR constructs were generated using SEQ ID NOs: 98, 109, 111 and 114 with additional sequences, SEQ ID NOs: 13-17, shown below, to generate full CAR constructs with SEQ ID NOs: 58, 110, 112, 113 and 115. 
     The sequences of the humanized scFv fragments (SEQ ID NOS: 1-12) are provided below in Table 2. Full CAR constructs were generated using SEQ ID NOs: 1-12 with additional sequences, SEQ ID NOs: 13-17, shown below, to generate full CAR constructs with SEQ ID NOs: 31-42. 
     
       
         
           
               
            
               
                 leader (amino acid sequence) 
               
               
                 (SEQ ID NO: 13) 
               
               
                 MALPVTALLLPLALLLHAARP 
               
               
                   
               
               
                 leader (nucleic acid sequence) 
               
               
                 (SEQ ID NO: 54) 
               
               
                 ATGGCCCTGCCTGTGACAGCCCTGCTGCTGCCTCTGGCTCTGCTGCTGCA 
               
               
                   
               
               
                 TGCCGCTAGACCC 
               
               
                   
               
               
                 CD8 hinge (amino acid sequence) 
               
               
                 (SEQ ID NO: 14) 
               
               
                 TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD 
               
               
                   
               
               
                 CD8 hinge (nucleic acid sequence) 
               
               
                 (SEQ ID NO: 55) 
               
               
                 ACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTC 
               
               
                   
               
               
                 GCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCG 
               
               
                   
               
               
                 CAGTGCACACGAGGGGGCTGGACTTCGCCTGTGAT 
               
               
                   
               
               
                 CD8 transmembrane (amino acid sequence) 
               
               
                 (SEQ ID NO: 15) 
               
               
                 IYIWAPLAGTCGVLLLSLVITLYC 
               
               
                   
               
               
                 transmembrane (nucleic acid sequence) 
               
               
                 (SEQ ID NO: 56) 
               
               
                 ATCTACATCTGGGCGCCCTTGGCCGGGACTTGTGGGGTCCTTCTCCTGTC 
               
               
                   
               
               
                 ACTGGTTATCACCCTTTACTGC 
               
               
                   
               
               
                 4-1BB Intracellular domain (amino acid sequence) 
               
               
                 (SEQ ID NO: 16) 
               
               
                 KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL 
               
               
                   
               
               
                 4-1BB Intracellular domain (nucleic acid sequence) 
               
               
                 (SEQ ID NO: 60) 
               
               
                 AAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAG 
               
               
                   
               
               
                 ACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAG 
               
               
                   
               
               
                 AAGAAGAAGAAGGAGGATGTGAACTG 
               
               
                   
               
               
                 CD3 zeta domain (amino acid sequence) 
               
               
                 (SEQ ID NO: 17) 
               
               
                 RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPR 
               
               
                   
               
               
                 RKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDT 
               
               
                   
               
               
                 YDALHMQALPPR 
               
               
                   
               
               
                 CD3 zeta (nucleic acid sequence) 
               
               
                 (SEQ ID NO: 101) 
               
               
                 AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACAAGCAGGGCCA 
               
               
                   
               
               
                 GAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATG 
               
               
                   
               
               
                 TTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGA 
               
               
                   
               
               
                 AGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGAT 
               
               
                   
               
               
                 GGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCA 
               
               
                   
               
               
                 AGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACC 
               
               
                   
               
               
                 TACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC 
               
               
                   
               
               
                 CD3 zeta domain (amino acid sequence; NCBI 
               
               
                 Reference Sequence NM_000734.3) 
               
               
                 (SEQ ID NO: 43) 
               
               
                 RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPR 
               
               
                   
               
               
                 RKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDT 
               
               
                   
               
               
                 YDALHMQALPPR 
               
               
                   
               
               
                 CD3 zeta (nucleic acid sequence; NCBI Reference 
               
               
                 Sequence NM_000734.3); 
               
               
                 (SEQ ID NO: 44) 
               
               
                 AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCA 
               
               
                   
               
               
                 GAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATG 
               
               
                   
               
               
                 TTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGA 
               
               
                   
               
               
                 AGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGAT 
               
               
                   
               
               
                 GGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCA 
               
               
                   
               
               
                 AGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACC 
               
               
                   
               
               
                 TACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC 
               
               
                   
               
               
                 CD28 domain 
               
               
                 (amino acid sequence, SEQ ID NO: 1317) 
               
               
                 RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS 
               
               
                   
               
               
                 CD28 domain 
               
               
                 (nucleotide sequence, SEQ ID NO: 1318) 
               
               
                 AGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCC 
               
               
                   
               
               
                 CCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCAC 
               
               
                   
               
               
                 GCGACTTCGCAGCCTATCGCTCC 
               
               
                   
               
               
                 Wild-type ICOS domain 
               
               
                 (amino acid sequence, SEQ ID NO: 1319) 
               
               
                 TKKKYSSSVHDPNGEYMFMRAVNTAKKSRLTDVTL 
               
               
                   
               
               
                 Wild-type ICOS domain 
               
               
                 (nucleotide sequence, SEQ ID NO: 1320) 
               
               
                 ACAAAAAAGAAGTATTCATCCAGTGTGCACGACCCTAACGGTGAATACAT 
               
               
                   
               
               
                 GTTCATGAGAGCAGTGAACACAGCCAAAAAATCCAGACTCACAGATGTGA 
               
               
                   
               
               
                 CCCTA 
               
               
                   
               
               
                 Y to F mutant ICOS domain 
               
               
                 (amino acid sequence, SEQ ID NO: 1321) 
               
               
                 TKKKYSSSVHDPNGEFMFMRAVNTAKKSRLTDVTL 
               
               
                   
               
               
                 IgG4 Hinge (amino acid sequence) 
               
               
                 (SEQ ID NO: 102) 
               
               
                 ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ 
               
               
                   
               
               
                 EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKE 
               
               
                   
               
               
                 YKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCL 
               
               
                   
               
               
                 VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ 
               
               
                   
               
               
                 EGNVFSCSVMHEALHNHYTQKSLSLSLGKM 
               
               
                   
               
               
                 IgG4 Hinge (nucleotide sequence) 
               
               
                 (SEQ ID NO: 103) 
               
               
                 GAGAGCAAGTACGGCCCTCCCTGCCCCCCTTGCCCTGCCCCCGAGTTCCT 
               
               
                   
               
               
                 GGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGA 
               
               
                   
               
               
                 TGATCAGCCGGACCCCCGAGGTGACCTGTGTGGTGGTGGACGTGTCCCAG 
               
               
                   
               
               
                 GAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCA 
               
               
                   
               
               
                 CAACGCCAAGACCAAGCCCCGGGAGGAGCAGTTCAATAGCACCTACCGGG 
               
               
                   
               
               
                 TGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAA 
               
               
                   
               
               
                 TACAAGTGTAAGGTGTCCAACAAGGGCCTGCCCAGCAGCATCGAGAAAAC 
               
               
                   
               
               
                 CATCAGCAAGGCCAAGGGCCAGCCTCGGGAGCCCCAGGTGTACACCCTGC 
               
               
                   
               
               
                 CCCCTAGCCAAGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGCCTG 
               
               
                   
               
               
                 GTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGG 
               
               
                   
               
               
                 CCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGACG 
               
               
                   
               
               
                 GCAGCTTCTTCCTGTACAGCCGGCTGACCGTGGACAAGAGCCGGTGGCAG 
               
               
                   
               
               
                 GAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCA 
               
               
                   
               
               
                 CTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGCAAGATG 
               
            
           
         
       
     
     The CAR scFv fragments were then cloned into lentiviral vectors to create a full length CAR construct in a single coding frame, and using the EF1 alpha promoter for expression (SEQ ID NO: 100). 
     
       
         
           
               
            
               
                 EF-1 alpha promoter 
               
               
                 (SEQ ID NO: 100) 
               
               
                 CGTGAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTC 
               
               
                   
               
               
                 CCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAG 
               
               
                   
               
               
                 GTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTT 
               
               
                   
               
               
                 TTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAAC 
               
               
                   
               
               
                 GTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTG 
               
               
                   
               
               
                 TGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTT 
               
               
                   
               
               
                 GAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGG 
               
               
                   
               
               
                 GTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTC 
               
               
                   
               
               
                 GCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGC 
               
               
                   
               
               
                 GAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTA 
               
               
                   
               
               
                 GCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGA 
               
               
                   
               
               
                 TAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTG 
               
               
                   
               
               
                 GGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCG 
               
               
                   
               
               
                 AGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCA 
               
               
                   
               
               
                 AGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCC 
               
               
                   
               
               
                 CGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAA 
               
               
                   
               
               
                 AGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCG 
               
               
                   
               
               
                 GCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCT 
               
               
                   
               
               
                 TTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCG 
               
               
                   
               
               
                 TCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGG 
               
               
                   
               
               
                 TTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGG 
               
               
                   
               
               
                 AGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTT 
               
               
                   
               
               
                 GCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGT 
               
               
                   
               
               
                 TCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGA. 
               
            
           
         
       
     
     In embodiments, these clones contain a Q/K residue change in the signal domain of the co-stimulatory domain derived from 4-1BB. 
     In one aspect, the anti-CD19 binding domain, e.g., humanized scFv, portion of a CAR of the invention is encoded by a transgene whose sequence has been codon optimized for expression in a mammalian cell. In one aspect, entire CAR construct of the invention is encoded by a transgene whose entire sequence has been codon optimized for expression in a mammalian cell. Codon optimization refers to the discovery that the frequency of occurrence of synonymous codons (i.e., codons that code for the same amino acid) in coding DNA is biased in different species. Such codon degeneracy allows an identical polypeptide to be encoded by a variety of nucleotide sequences. A variety of codon optimization methods is known in the art, and include, e.g., methods disclosed in at least U.S. Pat. Nos. 5,786,464 and 6,114,148. 
     The present disclosure encompasses, but is not limited to, a recombinant DNA construct comprising sequences encoding a CAR, wherein the CAR comprises an antibody or antibody fragment that binds specifically to CD19, wherein the sequence of the antibody fragment is contiguous with and in the same reading frame as a nucleic acid sequence encoding an intracellular signaling domain. The intracellular signaling domain can comprise a costimulatory signaling domain and/or a primary signaling domain, e.g., a zeta chain. The costimulatory signaling domain refers to a portion of the CAR comprising at least a portion of the intracellular domain of a costimulatory molecule. In one embodiment, the antigen binding domain is a murine antibody or antibody fragment described herein. In one embodiment, the antigen binding domain is a humanized antibody or antibody fragment. 
     In specific aspects, a CAR construct of the invention comprises a scFv domain selected from the group consisting of SEQ ID NOS:1-12 or an scFV domain of SEQ ID NO:59, wherein the scFv may be preceded by an optional leader sequence such as provided in SEQ ID NO: 13, and followed by an optional hinge sequence such as provided in SEQ ID NO:14 or SEQ ID NO:45 or SEQ ID NO:47 or SEQ ID NO:49, a transmembrane region such as provided in SEQ ID NO:15, an intracellular signalling domain that includes SEQ ID NO:16 or SEQ ID NO:51 and a CD3 zeta sequence that includes SEQ ID NO:17 or SEQ ID NO:43, wherein the domains are contiguous with and in the same reading frame to form a single fusion protein. 
     Also included in the invention (among other things) is a nucleotide sequence that encodes the polypeptide of each of the scFv fragments selected from the group consisting of SEQ IS NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ IS NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:59. Also included in the invention (among other things) is a nucleotide sequence that encodes the polypeptide of each of the scFv fragments selected from the group consisting of SEQ IS NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:59, and each of the domains of SEQ ID NOS: 13-17, plus an encoded CD19 CAR fusion protein of the invention. In one aspect an exemplary CD19 CAR constructs comprise an optional leader sequence, an extracellular antigen binding domain, a hinge, a transmembrane domain, and an intracellular stimulatory domain. In one aspect an exemplary CD19 CAR construct comprises an optional leader sequence, an extracellular antigen binding domain, a hinge, a transmembrane domain, an intracellular costimulatory domain and an intracellular stimulatory domain. In some embodiments, specific CD19 CAR constructs containing humanized scFv domains of the invention are provided as SEQ ID NOS: 31-42, or a murine scFv domain as provided as SEQ ID NO:59. 
     In one aspect the nucleic acid sequence of a CAR construct of the invention is selected from one or more of SEQ ID NOS:85-96. In one aspect the nucleic acid sequence of a CAR construct is SEQ ID NO:85. In one aspect the nucleic acid sequence of a CAR construct is SEQ ID NO:86. In one aspect the nucleic acid sequence of a CAR construct is SEQ ID NO:87. In one aspect the nucleic acid sequence of a CAR construct is SEQ ID NO:88. In one aspect the nucleic acid sequence of a CAR construct is SEQ ID NO:89. In one aspect the nucleic acid sequence of a CAR construct is SEQ ID NO:90. In one aspect the nucleic acid sequence of a CAR construct is SEQ ID NO:91. In one aspect the nucleic acid sequence of a CAR construct is SEQ ID NO:92. In one aspect the nucleic acid sequence of a CAR construct is SEQ ID NO:93. In one aspect the nucleic acid sequence of a CAR construct is SEQ ID NO:94. In one aspect the nucleic acid sequence of a CAR construct is SEQ ID NO:95. In one aspect the nucleic acid sequence of a CAR construct is SEQ ID NO:96. In one aspect the nucleic acid sequence of a CAR construct is SEQ ID NO:97. In one aspect the nucleic acid sequence of a CAR construct is SEQ ID NO:98. In one aspect the nucleic acid sequence of a CAR construct is SEQ ID NO:99. 
     Full-length CAR sequences are also provided herein as SEQ ID NOS: 31-42 and 58, as shown in Table 2 (e.g., CTL119) and Table 3 (e.g., CTL019). 
     An exemplary leader sequence is provided as SEQ ID NO: 13. An exemplary hinge/spacer sequence is provided as SEQ ID NO: 14 or SEQ ID NO:45 or SEQ ID NO:47 or SEQ ID NO:49. An exemplary transmembrane domain sequence is provided as SEQ ID NO:15. An exemplary sequence of the intracellular signaling domain of the 4-1BB protein is provided as SEQ ID NO: 16. An exemplary sequence of the intracellular signaling domain of CD27 is provided as SEQ ID NO:51. An exemplary CD3zeta domain sequence is provided as SEQ ID NO: 17 or SEQ ID NO:43. These sequences may be used, e.g., in combination with an scFv that recognizes one or more of CD19, CD10, CD20, CD22, CD34, CD123, FLT-3, or ROR1. 
     Exemplary sequences of various scFv fragments and other CAR components are provided herein. It is noted that these CAR components (e.g., of SEQ ID NO: 121, or a sequence of Table 2, 3, 6, 11A, 11B, 16, or 25) without a leader sequence (e.g., without the amino acid sequence of SEQ ID NO: 13 or a nucleotide sequence of SEQ ID NO: 54), are also provided herein. 
     In embodiments, the CAR sequences described herein contain a Q/K residue change in the signal domain of the co-stimulatory domain derived from CD3zeta chain. 
     In one aspect, the present invention encompasses a recombinant nucleic acid construct comprising a nucleic acid molecule encoding a CAR, wherein the nucleic acid molecule comprises the nucleic acid sequence encoding an anti-CD19 binding domain, e.g., described herein, that is contiguous with and in the same reading frame as a nucleic acid sequence encoding an intracellular signaling domain. In one aspect, the anti-CD19 binding domain is selected from one or more of SEQ ID NOS:1-12 and 58. In one aspect, the anti-CD19 binding domain is encoded by a nucleotide residues 64 to 813 of the sequence provided in one or more of SEQ ID NOS:61-72 and 97. In one aspect, the anti-CD19 binding domain is encoded by a nucleotide residues 64 to 813 of SEQ ID NO:61. In one aspect, the anti-CD19 binding domain is encoded by a nucleotide residues 64 to 813 of SEQ ID NO:62. In one aspect, the anti-CD19 binding domain is encoded by a nucleotide residues 64 to 813 of SEQ ID NO:63. In one aspect, the anti-CD19 binding domain is encoded by a nucleotide residues 64 to 813 of SEQ ID NO:64. In one aspect, the anti-CD19 binding domain is encoded by a nucleotide residues 64 to 813 of SEQ ID NO:65. In one aspect, the anti-CD19 binding domain is encoded by a nucleotide residues 64 to 813 of SEQ ID NO:66. In one aspect, the anti-CD19 binding domain is encoded by a nucleotide residues 64 to 813 of SEQ ID NO:67. In one aspect, the anti-CD19 binding domain is encoded by a nucleotide residues 64 to 813 of SEQ ID NO:68. In one aspect, the anti-CD19 binding domain is encoded by a nucleotide residues 64 to 813 of SEQ ID NO:69. In one aspect, the anti-CD19 binding domain is encoded by a nucleotide residues 64 to 813 of SEQ ID NO:70. In one aspect, the anti-CD19 binding domain is encoded by a nucleotide residues 64 to 813 of SEQ ID NO:71. In one aspect, the anti-CD19 binding domain is encoded by a nucleotide residues 64 to 813 of SEQ ID NO:72. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Humanized CD19 CAR Constructs 
               
            
           
           
               
               
               
            
               
                 Name 
                 SEQ ID 
                 Sequence 
               
               
                   
               
            
           
           
               
            
               
                 CAR 1 
               
            
           
           
               
               
               
            
               
                 CAR1 scFv 
                 1 
                 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHT 
               
               
                 domain 
                   
                 SRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGT 
               
               
                   
                   
                 KLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPD 
               
               
                   
                   
                 YGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKL 
               
               
                   
                   
                 SSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSS 
               
               
                   
               
               
                 103101 
                 61 
                 atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgc 
               
               
                 CAR1 
                   
                 tcggcccgaaattgtgatgacccagtcacccgccactcttagcctttcacccggtg 
               
               
                 Soluble 
                   
                 agcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattgg 
               
               
                 scFv - nt 
                   
                 tatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggct 
               
               
                   
                   
                 ccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccc 
               
               
                   
                   
                 tcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaaggg 
               
               
                   
                   
                 aacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggagg 
               
               
                   
                   
                 tggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaa 
               
               
                   
                   
                 gcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagc 
               
               
                   
                   
                 ggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaaggg 
               
               
                   
                   
                 tctggaatggattggagtgatttggggctctgagactacttactactcttcatccc 
               
               
                   
                   
                 tcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaa 
               
               
                   
                   
                 ctgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattacta 
               
               
                   
                   
                 ttatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgt 
               
               
                   
                   
                 ccagccaccaccatcatcaccatcaccat 
               
               
                   
               
               
                 103101 
                 73 
                     MALPVTALLLPLALLLHAARP   eivmtqspatlslspgeratlscrasqdiskylnw 
               
               
                 CAR1 
                   
                 yqqkpgqaprlliyhtsrlhsgiparfsgsgsgtdytltisslqpedfavyfcqqg 
               
               
                 Soluble 
                   
                 ntlpytfgqgtkleikggggsggggsggggsqvqlqesgpglvkpsetlsltctvs 
               
               
                 scFv - aa 
                   
                 gvslpdygvswirqppgkglewigviwgsettyyssslksrvtiskdnsknqvslk 
               
               
                   
                   
                 lssvtaadtavyycakhyyyggsyamdywgqgtlvtvss   hhhhhhhh     
               
               
                   
               
               
                 104875 
                 85 
                 atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgc 
               
               
                 CAR 1  
                   
                 tcggcccgaaattgtgatgacccagtcacccgccactcttagcctttcacccggtg 
               
               
                 Full - nt 
                   
                 agcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattgg 
               
               
                   
                   
                 tatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggct 
               
               
                   
                   
                 ccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccc 
               
               
                   
                   
                 tcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaaggg 
               
               
                   
                   
                 aacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggagg 
               
               
                   
                   
                 tggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaa 
               
               
                   
                   
                 gcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagc 
               
               
                   
                   
                 ggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaaggg 
               
               
                   
                   
                 tctggaatggattggagtgatttggggctctgagactacttactactcttcatccc 
               
               
                   
                   
                 tcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaa 
               
               
                   
                   
                 ctgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattacta 
               
               
                   
                   
                 ttatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgt 
               
               
                   
                   
                 ccagcaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcc 
               
               
                   
                   
                 cagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgca 
               
               
                   
                   
                 tacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggta 
               
               
                   
                   
                 cttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcgg 
               
               
                   
                   
                 aagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactca 
               
               
                   
                   
                 agaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaac 
               
               
                   
                   
                 tgcgcgtgaaattcagccgcagcgcagatgctccagcctacaagcaggggcagaac 
               
               
                   
                   
                 cagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaa 
               
               
                   
                   
                 gcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaag 
               
               
                   
                   
                 agggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagatt 
               
               
                   
                   
                 ggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggact 
               
               
                   
                   
                 cagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctc 
               
               
                   
                   
                 gg 
               
               
                   
               
               
                 104875 
                 31 
                 MALPVTALLLPLALLLHAARPeivmtqspatlslspgeratlsc   rasqdiskyln   w 
               
               
                 CAR 1  
                   
                 yqqkpgqaprlliy   htsrlhs   giparfsgsgsgtdytltisslqpedfavyfc   qqg     
               
               
                 Full - aa 
                   
                     ntlpyt   fgqgtkleikggggsggggsggggsqvqlqesgpglvkpsetlsltctvs 
               
               
                   
                   
                 gvslp   dygvs   wirqppgkglewig   viwgsettyyssslks   rvtiskdnsknqvslk 
               
               
                   
                   
                 lssvtaadtavyycak   hyyyggsyamdy   wgqgtlvtvsstttpaprpptpaptias 
               
               
                   
                   
                 qplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgr 
               
               
                   
                   
                 kkllyifkqpfmrpvqttgeedgcscrfpeeeeggcelrvkfsrsadapaykqgqn 
               
               
                   
                   
                 qlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeaysei 
               
               
                   
                   
                 gmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
            
           
           
               
            
               
                 CAR2 
               
            
           
           
               
               
               
            
               
                 CAR2 scFv 
                 2 
                 eivmtqspatlslspgeratlscrasqdiskylnwyqqkpgqaprlliyhtsrlhs 
               
               
                 domain 
                   
                 giparfsgsgsgtdytltisslqpedfavyfcqqgntlpytfgqgtkleikggggs 
               
               
                   
                   
                 ggggsggggsqvqlqesgpglvkpsetlsltctvsgvslpdygvswirqppgkgle 
               
               
                   
                   
                 wigviwgsettyyqsslksrvtiskdnsknqvslklssvtaadtavyycakhyyyg 
               
               
                   
                   
                 gsyamdywgqgtlvtvss 
               
               
                   
               
               
                 103102 
                 62 
                 atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgc 
               
               
                 CAR2 - 
                   
                 tcggcccgaaattgtgatgacccagtcacccgccactcttagcctttcacccggtg 
               
               
                 Soluble 
                   
                 agcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattgg 
               
               
                 scFv - nt 
                   
                 tatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggct 
               
               
                   
                   
                 ccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccc 
               
               
                   
                   
                 tcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaaggg 
               
               
                   
                   
                 aacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggagg 
               
               
                   
                   
                 tggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaa 
               
               
                   
                   
                 gcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagc 
               
               
                   
                   
                 ggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaaggg 
               
               
                   
                   
                 tctggaatggattggagtgatttggggctctgagactacttactaccaatcatccc 
               
               
                   
                   
                 tcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaa 
               
               
                   
                   
                 ctgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattacta 
               
               
                   
                   
                 ttatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgt 
               
               
                   
                   
                 ccagccaccaccatcatcaccatcaccat 
               
               
                   
               
               
                 103102 
                 74 
                     MALPVTALLLPLALLLHAARP   eivmtqspatlslspgeratlscrasqdiskylnw 
               
               
                 CAR2 - 
                   
                 yqqkpgqaprlliyhtsrlhsgiparfsgsgsgtdytltisslqpedfavyfcqqg 
               
               
                 Soluble 
                   
                 ntlpytfgqgtkleikggggsggggsggggsqvqlqesgpglvkpsetlsltctvs 
               
               
                 scFv - aa 
                   
                 gvslpdygvswirqppgkglewigviwgsettyyqsslksrvtiskdnsknqvslk 
               
               
                   
                   
                 lssvtaadtavyycakhyyyggsyamdywgqgtlvtvss   hhhhhhhh     
               
               
                   
               
               
                 104876 
                 86 
                 atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgc 
               
               
                 CAR 2 - 
                   
                 tcggcccgaaattgtgatgacccagtcacccgccactcttagcctttcacccggtg 
               
               
                 Full - nt 
                   
                 agcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattgg 
               
               
                 (also 
                   
                 tatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggct 
               
               
                 referred to 
                   
                 ccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccc 
               
               
                 herein as 
                   
                 tcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaaggg 
               
               
                 CTL119 
                   
                 aacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggagg 
               
               
                 nucleotide 
                   
                 tggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaa 
               
               
                 sequence) 
                   
                 gcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagc 
               
               
                   
                   
                 ggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaaggg 
               
               
                   
                   
                 tctggaatggattggagtgatttggggctctgagactacttactaccaatcatccc 
               
               
                   
                   
                 tcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaa 
               
               
                   
                   
                 ctgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattacta 
               
               
                   
                   
                 ttatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgt 
               
               
                   
                   
                 ccagcaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcc 
               
               
                   
                   
                 cagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgca 
               
               
                   
                   
                 tacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggta 
               
               
                   
                   
                 cttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcgg 
               
               
                   
                   
                 aagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactca 
               
               
                   
                   
                 agaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaac 
               
               
                   
                   
                 tgcgcgtgaaattcagccgcagcgcagatgctccagcctacaagcaggggcagaac 
               
               
                   
                   
                 cagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaa 
               
               
                   
                   
                 gcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaag 
               
               
                   
                   
                 agggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagatt 
               
               
                   
                   
                 ggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggact 
               
               
                   
                   
                 cagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctc 
               
               
                   
                   
                 gg 
               
               
                   
               
               
                 104876 
                 32 
                 MALPVTALLLPLALLLHAARPeivmtqspatlslspgeratlsc   rasqdiskyln   w 
               
               
                 CAR 2 
                 - 
                 yqqkpgqaprlliy   htsrlhs   giparfsgsgsgtdytltisslqpedfavyfc   qqg     
               
               
                 Full - aa 
                   
                     ntlpyt   fgqgtkleikggggsggggsggggsqvqlqesgpglvkpsetlsltctvs 
               
               
                 (also 
                   
                 gvslp   dygvs   wirqppgkglewig   viwgsettyyqsslks   rvtiskdnsknqvslk 
               
               
                 referred to 
                   
                 lssvtaadtavyycak   hyyyggsyamdy   wgqgtlvtvsstttpaprpptpaptias 
               
               
                 herein as 
                   
                 qplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgr 
               
               
                 CTL119 
                   
                 kkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrckfsrsadapaykqgqn 
               
               
                 amino acid 
                   
                 qlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeaysei 
               
               
                 sequence) 
                   
                 gmkgerrrgkghdglyqqlstatkdtydalhmqalppr 
               
               
                   
               
            
           
           
               
            
               
                 CAR 3 
               
            
           
           
               
               
               
            
               
                 CAR3 scFv 
                 3 
                 qvqlqesgpglvkpsetlsltctvsgvslpdygvswirqppgkglewigviwgset 
               
               
                 domain 
                   
                 tyyssslksrvtiskdnsknqvslklssvtaadtavyycakhyyyggsyamdywgq 
               
               
                   
                   
                 gtlvtvssggggsggggsggggseivmtqspatlslspgeratlscrasqdiskyl 
               
               
                   
                   
                 nwyqqkpgqaprlliyhtsrlhsgiparfsgsgsgtdytltisslqpedfavyfcq 
               
               
                   
                   
                 qgntlpytfgqgtkleik 
               
               
                   
               
               
                 103104 
                 63 
                 atggctctgcccgtgaccgcactcctcctgccactggctctgctgcttcacgccgc 
               
               
                 CAR 3 - 
                   
                 tcgcccacaagtccagcttcaagaatcagggcctggtctggtgaagccatctgaga 
               
               
                 Soluble 
                   
                 ctctgtccctcacttgcaccgtgagcggagtgtccctcccagactacggagtgagc 
               
               
                 scFv - nt 
                   
                 tggattagacagcctcccggaaagggactggagtggatcggagtgatttggggtag 
               
               
                   
                   
                 cgaaaccacttactattcatcttccctgaagtcacgggtcaccatttcaaaggata 
               
               
                   
                   
                 actcaaagaatcaagtgagcctcaagctctcatcagtcaccgccgctgacaccgcc 
               
               
                   
                   
                 gtgtattactgtgccaagcattactactatggagggtcctacgccatggactactg 
               
               
                   
                   
                 gggccagggaactctggtcactgtgtcatctggtggaggaggtagcggaggaggcg 
               
               
                   
                   
                 ggagcggtggaggtggctccgaaatcgtgatgacccagagccctgcaaccctgtcc 
               
               
                   
                   
                 ctttctcccggggaacgggctaccctttcttgtcgggcatcacaagatatctcaaa 
               
               
                   
                   
                 atacctcaattggtatcaacagaagccgggacaggcccctaggcttcttatctacc 
               
               
                   
                   
                 acacctctcgcctgcatagcgggattcccgcacgctttagcgggtctggaagcggg 
               
               
                   
                   
                 accgactacactctgaccatctcatctctccagcccgaggacttcgccgtctactt 
               
               
                   
                   
                 ctgccagcagggtaacaccctgccgtacaccttcggccagggcaccaagcttgaga 
               
               
                   
                   
                 tcaaacatcaccaccatcatcaccatcac 
               
               
                   
               
               
                 103104 
                 75 
                     MALPVTALLLPLALLLHAARP   qvqlqesgpglvkpsetlsltctvsgvslpdygvs 
               
               
                 CAR 3 - 
                   
                 wirqppgkglewigviwgsettyyssslksrvtiskdnsknqvslklssvtaadta 
               
               
                 Soluble 
                   
                 vyycakhyyyggsyamdywgqgtlvtvssggggsggggsggggseivmtqspatls 
               
               
                 scFv - aa 
                   
                 lspgeratlscrasqdiskylnwyqqkpgqaprlliyhtsrlhsgiparfsgsgsg 
               
               
                   
                   
                 tdytltisslqpedfavyfcqqgntlpytfgqgtkleik   hhhhhhhh     
               
               
                   
               
               
                 104877 
                 87 
                 atggctctgcccgtgaccgcactcctcctgccactggctctgctgcttcacgccgc 
               
               
                 CAR 3 - 
                   
                 tcgcccacaagtccagcttcaagaatcagggcctggtctggtgaagccatctgaga 
               
               
                 Full - nt 
                   
                 ctctgtccctcacttgcaccgtgagcggagtgtccctcccagactacggagtgagc 
               
               
                   
                   
                 tggattagacagcctcccggaaagggactggagtggatcggagtgatttggggtag 
               
               
                   
                   
                 cgaaaccacttactattcatcttccctgaagtcacgggtcaccatttcaaaggata 
               
               
                   
                   
                 actcaaagaatcaagtgagcctcaagctctcatcagtcaccgccgctgacaccgcc 
               
               
                   
                   
                 gtgtattactgtgccaagcattactactatggagggtcctacgccatggactactg 
               
               
                   
                   
                 gggccagggaactctggtcactgtgtcatctggtggaggaggtagcggaggaggcg 
               
               
                   
                   
                 ggagcggtggaggtggctccgaaatcgtgatgacccagagccctgcaaccctgtcc 
               
               
                   
                   
                 ctttctcccggggaacgggctaccctttcttgtcgggcatcacaagatatctcaaa 
               
               
                   
                   
                 atacctcaattggtatcaacagaagccgggacaggcccctaggcttcttatctacc 
               
               
                   
                   
                 acacctctcgcctgcatagcgggattcccgcacgctttagcgggtctggaagcggg 
               
               
                   
                   
                 accgactacactctgaccatctcatctctccagcccgaggacttcgccgtctactt 
               
               
                   
                   
                 ctgccagcagggtaacaccctgccgtacaccttcggccagggcaccaagcttgaga 
               
               
                   
                   
                 tcaaaaccactactcccgctccaaggccacccacccctgccccgaccatcgcctct 
               
               
                   
                   
                 cagccgctttccctgcgtccggaggcatgtagacccgcagctggtggggccgtgca 
               
               
                   
                   
                 tacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggta 
               
               
                   
                   
                 cttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcgg 
               
               
                   
                   
                 aagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactca 
               
               
                   
                   
                 agaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaac 
               
               
                   
                   
                 tgcgcgtgaaattcagccgcagcgcagatgctccagcctacaagcaggggcagaac 
               
               
                   
                   
                 cagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaa 
               
               
                   
                   
                 gcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaag 
               
               
                   
                   
                 agggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagatt 
               
               
                   
                   
                 ggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggact 
               
               
                   
                   
                 cagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctc 
               
               
                   
                   
                 gg 
               
               
                   
               
               
                 104877 
                 33 
                 MALPVTALLLPLALLLHAARPqvqlqesgpglvkpsetlsltctvsgvslp   dygvs     
               
               
                 CAR 3 - 
                   
                 wirqppgkglewig   viwgsettyyssslks   rvtiskdnsknqvslklssvtaadta 
               
               
                 Full - aa 
                   
                 vyycak   hyyyggsyamdy   wgqgtlvtvssggggsggggsggggseivmtqspatls 
               
               
                   
                   
                 lspgeratlsc   rasqdiskyln   wyqqkpgqaprlliy   htsrlhs   giparfsgsgsg 
               
               
                   
                   
                 tdytltisslqpedfavyfc   qq   g   ntlpyt   fgqgtkleiktttpaprpptpaptias 
               
               
                   
                   
                 qplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgr 
               
               
                   
                   
                 kkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapaykqgqn 
               
               
                   
                   
                 qlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeaysei 
               
               
                   
                   
                 gmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
            
           
           
               
            
               
                 CAR 4 
               
            
           
           
               
               
               
            
               
                 CAR4 scFv 
                 4 
                 qvqlqesgpglvkpsetlsltctvsgvslpdygvswirqppgkglewigviwgset 
               
               
                 domain 
                   
                 tyyqsslksrvtiskdnsknqvslklssvtaadtavyycakhyyyggsyamdywgq 
               
               
                   
                   
                 gtlvtvssggggsggggsggggseivmtqspatlslspgeratlscrasqdiskyl 
               
               
                   
                   
                 nwyqqkpgqaprlliyhtsrlhsgiparfsgsgsgtdytltisslqpedfavyfcq 
               
               
                   
                   
                 qgntlpytfgqgtkleik 
               
               
                   
               
               
                 103106 
                 64 
                 atggctctgcccgtgaccgcactcctcctgccactggctctgctgcttcacgccgc 
               
               
                 CAR4 - 
                   
                 tcgcccacaagtccagcttcaagaatcagggcctggtctggtgaagccatctgaga 
               
               
                 Soluble 
                   
                 ctctgtccctcacttgcaccgtgagcggagtgtccctcccagactacggagtgagc 
               
               
                 scFv - nt 
                   
                 tggattagacagcctcccggaaagggactggagtggatcggagtgatttggggtag 
               
               
                   
                   
                 cgaaaccacttactatcaatcttccctgaagtcacgggtcaccatttcaaaggata 
               
               
                   
                   
                 actcaaagaatcaagtgagcctcaagctctcatcagtcaccgccgctgacaccgcc 
               
               
                   
                   
                 gtgtattactgtgccaagcattactactatggagggtcctacgccatggactactg 
               
               
                   
                   
                 gggccagggaactctggtcactgtgtcatctggtggaggaggtagcggaggaggcg 
               
               
                   
                   
                 ggagcggtggaggtggctccgaaatcgtgatgacccagagccctgcaaccctgtcc 
               
               
                   
                   
                 ctttctcccggggaacgggctaccctttcttgtcgggcatcacaagatatctcaaa 
               
               
                   
                   
                 atacctcaattggtatcaacagaagccgggacaggcccctaggcttcttatctacc 
               
               
                   
                   
                 acacctctcgcctgcatagcgggattcccgcacgctttagcgggtctggaagcggg 
               
               
                   
                   
                 accgactacactctgaccatctcatctctccagcccgaggacttcgccgtctactt 
               
               
                   
                   
                 ctgccagcagggtaacaccctgccgtacaccttcggccagggcaccaagcttgaga 
               
               
                   
                   
                 tcaaacatcaccaccatcatcaccatcac 
               
               
                   
               
               
                 103106 
                 76 
                     MALPVTALLLPLALLLHAARP   qvqlqesgpglvkpsetlsltctvsgvslpdygvs 
               
               
                 CAR4 - 
                   
                 wirqppgkglewigviwgsettyyqsslksrvtiskdnsknqvslklssvtaadta 
               
               
                 Soluble 
                   
                 vyycakhyyyggsyamdywgqgtlvtvssggggsggggsggggseivmtqspatls 
               
               
                 scFv -aa 
                   
                 lspgeratlscrasqdiskylnwyqqkpgqaprlliyhtsrlhsgiparfsgsgsg 
               
               
                   
                   
                 tdytltisslqpedfavyfcqqgntlpytfgqgtkleik   hhhhhhhh     
               
               
                   
               
               
                 104878 
                 88 
                 atggctctgcccgtgaccgcactcctcctgccactggctctgctgcttcacgccgc 
               
               
                 CAR 4 - 
                   
                 tcgcccacaagtccagcttcaagaatcagggcctggtctggtgaagccatctgaga 
               
               
                 Full - nt 
                   
                 ctctgtccctcacttgcaccgtgagcggagtgtccctcccagactacggagtgagc 
               
               
                   
                   
                 tggattagacagcctcccggaaagggactggagtggatcggagtgatttggggtag 
               
               
                   
                   
                 cgaaaccacttactatcaatcttccctgaagtcacgggtcaccatttcaaaggata 
               
               
                   
                   
                 actcaaagaatcaagtgagcctcaagctctcatcagtcaccgccgctgacaccgcc 
               
               
                   
                   
                 gtgtattactgtgccaagcattactactatggagggtcctacgccatggactactg 
               
               
                   
                   
                 gggccagggaactctggtcactgtgtcatctggtggaggaggtagcggaggaggcg 
               
               
                   
                   
                 ggagcggtggaggtggctccgaaatcgtgatgacccagagccctgcaaccctgtcc 
               
               
                   
                   
                 ctttctcccggggaacgggctaccctttcttgtcgggcatcacaagatatctcaaa 
               
               
                   
                   
                 atacctcaattggtatcaacagaagccgggacaggcccctaggcttcttatctacc 
               
               
                   
                   
                 acacctctcgcctgcatagcgggattcccgcacgctttagcgggtctggaagcggg 
               
               
                   
                   
                 accgactacactctgaccatctcatctctccagcccgaggacttcgccgtctactt 
               
               
                   
                   
                 ctgccagcagggtaacaccctgccgtacaccttcggccagggcaccaagcttgaga 
               
               
                   
                   
                 tcaaaaccactactcccgctccaaggccacccacccctgccccgaccatcgcctct 
               
               
                   
                   
                 cagccgctttccctgcgtccggaggcatgtagacccgcagctggtggggccgtgca 
               
               
                   
                   
                 tacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggta 
               
               
                   
                   
                 cttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcgg 
               
               
                   
                   
                 aagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactca 
               
               
                   
                   
                 agaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaac 
               
               
                   
                   
                 tgcgcgtgaaattcagccgcagcgcagatgctccagcctacaagcaggggcagaac 
               
               
                   
                   
                 cagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaa 
               
               
                   
                   
                 gcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaag 
               
               
                   
                   
                 agggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagatt 
               
               
                   
                   
                 ggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggact 
               
               
                   
                   
                 cagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctc 
               
               
                   
                   
                 gg 
               
               
                   
               
               
                 104878 
                 34 
                 MALPVTALLLPLALLLHAARPqvqlqesgpglvkpsetlsltctvsgvslp   dygvs     
               
               
                 CAR 4 - 
                   
                 wirqppgkglewig   viwgsettyyqsslks   rvtiskdnsknqvslklssvtaadta 
               
               
                 Full - aa 
                   
                 vyycak   hyyyggsyamdy   wgqgtlvtvssggggsggggsggggseivmtqspatls 
               
               
                   
                   
                 lspgeratlsc   rasqdiskyln   wyqqkpgqaprlliy   htsrlhs   giparfsgsgsg 
               
               
                   
                   
                 tdytltisslqpedfavyfc   qqgntlpyt   fgqgtkleiktttpaprpptpaptias 
               
               
                   
                   
                 qplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgr 
               
               
                   
                   
                 kkllyifkqpfmrpvqttgeedgcscrfpeeeeggcelrvkfsrsadapaykqgqn 
               
               
                   
                   
                 qlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeaysei 
               
               
                   
                   
                 gmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
            
           
           
               
            
               
                 CAR 5 
               
            
           
           
               
               
               
            
               
                 CAR5 scFv 
                 5 
                 eivmtqspatlslspgeratlscrasqdiskylnwyqqkpgqaprlliyhtsrlhs 
               
               
                 domain 
                   
                 giparfsgsgsgtdytltisslqpedfavyfcqqgntlpytfgqgtkleikggggs 
               
               
                   
                   
                 ggggsggggsggggsqvqlqesgpglvkpsetlsltctvsgvslpdygvswirqpp 
               
               
                   
                   
                 gkglewigviwgsettyyssslksrvtiskdnsknqvslklssvtaadtavyycak 
               
               
                   
                   
                 hyyyggsyamdywgqgtlvtvss 
               
               
                   
               
               
                 99789 
                 65 
                 atggccctcccagtgaccgctctgctgctgcctctcgcacttcttctccatgccgc 
               
               
                 CAR5 - 
                   
                 tcggcctgagatcgtcatgacccaaagccccgctaccctgtccctgtcacccggcg 
               
               
                 Soluble 
                   
                 agagggcaaccctttcatgcagggccagccaggacatttctaagtacctcaactgg 
               
               
                 scFv - nt 
                   
                 tatcagcagaagccagggcaggctcctcgcctgctgatctaccacaccagccgcct 
               
               
                   
                   
                 ccacagcggtatccccgccagattttccgggagcgggtctggaaccgactacaccc 
               
               
                   
                   
                 tcaccatctcttctctgcagcccgaggatttcgccgtctatttctgccagcagggg 
               
               
                   
                   
                 aatactctgccgtacaccttcggtcaaggtaccaagctggaaatcaagggaggcgg 
               
               
                   
                   
                 aggatcaggcggtggcggaagcggaggaggtggctccggaggaggaggttcccaag 
               
               
                   
                   
                 tgcagcttcaagaatcaggacccggacttgtgaagccatcagaaaccctctccctg 
               
               
                   
                   
                 acttgtaccgtgtccggtgtgagcctccccgactacggagtctcttggattcgcca 
               
               
                   
                   
                 gcctccggggaagggtcttgaatggattggggtgatttggggatcagagactactt 
               
               
                   
                   
                 actactcttcatcacttaagtcacgggtcaccatcagcaaagataatagcaagaac 
               
               
                   
                   
                 caagtgtcacttaagctgtcatctgtgaccgccgctgacaccgccgtgtactattg 
               
               
                   
                   
                 tgccaaacattactattacggagggtcttatgctatggactactggggacagggga 
               
               
                   
                   
                 ccctggtgactgtctctagccatcaccatcaccaccatcatcac 
               
               
                   
               
               
                 99789 
                 77 
                     MALPVTALLLPLALLLHAARP   eivmtqspatlslspgeratlscrasqdiskylnw 
               
               
                 CAR5 - 
                   
                 yqqkpgqaprlliyhtsrlhsgiparfsgsgsgtdytltisslqpedfavyfcqqg 
               
               
                 Soluble 
                   
                 ntlpytfgqgtkleikggggsggggsggggsggggsqvqlqesgpglvkpsetlsl 
               
               
                 scFv -aa 
                   
                 tctvsgvslpdygvswirqppgkglewigviwgsettyyssslksrvtiskdnskn 
               
               
                   
                   
                 qvslklssvtaadtavyycakhyyyggsyamdywgqgtlvtvss   hhhhhhhh     
               
               
                   
               
               
                 104879 
                 89 
                 atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgc 
               
               
                 CAR5 - 
                   
                 tcggcccgaaattgtgatgacccagtcacccgccactcttagcctttcacccggtg 
               
               
                 Full - nt 
                   
                 agcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattgg 
               
               
                   
                   
                 tatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggct 
               
               
                   
                   
                 ccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccc 
               
               
                   
                   
                 tcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaaggg 
               
               
                   
                   
                 aacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggagg 
               
               
                   
                   
                 tggcagcggaggaggtgggtccggcggtggaggaagcggcggaggcgggagccagg 
               
               
                   
                   
                 tccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactg 
               
               
                   
                   
                 acttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagaca 
               
               
                   
                   
                 gccaccggggaagggtctggaatggattggagtgatttggggctctgagactactt 
               
               
                   
                   
                 actactcttcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaat 
               
               
                   
                   
                 caggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattg 
               
               
                   
                   
                 cgctaagcattactattatggcgggagctacgcaatggattactggggacagggta 
               
               
                   
                   
                 ctctggtcaccgtgtccagcaccactaccccagcaccgaggccacccaccccggct 
               
               
                   
                   
                 cctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagc 
               
               
                   
                   
                 tggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttggg 
               
               
                   
                   
                 cccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttac 
               
               
                   
                   
                 tgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcc 
               
               
                   
                   
                 tgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggagg 
               
               
                   
                   
                 aaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctac 
               
               
                   
                   
                 aagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagta 
               
               
                   
                   
                 cgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgca 
               
               
                   
                   
                 gaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaa 
               
               
                   
                   
                 gcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacgg 
               
               
                   
                   
                 actgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgc 
               
               
                   
                   
                 aggccctgccgcctcgg 
               
               
                   
               
               
                 104879 
                 35 
                 MALPVTALLLPLALLLHAARPeivmtqspatlslspgeratlsc   rasgdiskyln   w 
               
               
                 CAR 5 - 
                   
                 yqqkpgqaprlliy   htsrlhs   giparfsgsgsgtdytltisslqpedfavyfc   qqg     
               
               
                 Full - aa 
                   
                     ntlpyt   fgqgtkleikggggsggggsggggsggggsqvqlqesgpglvkpsetlsl 
               
               
                   
                   
                 tctvsgvslp   dygvs   wirqppgkglewig   viwgsettyyssslks   rvtiskdnskn 
               
               
                   
                   
                 qvslklssvtaadtavyycak   hyyyggsyamdy   wgqgtlvtvsstttpaprpptpa 
               
               
                   
                   
                 ptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitly 
               
               
                   
                   
                 ckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapay 
               
               
                   
                   
                 kqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmae 
               
               
                   
                   
                 ayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
            
           
           
               
            
               
                 CAR 6 
               
            
           
           
               
               
               
            
               
                 CAR6 
                 6 
                 eivmtqspatlslspgeratlscrasqdiskylnwyqqkpgqaprlliyhtsrlhs 
               
               
                 scFv 
                   
                 giparfsgsgsgtdytltisslqpedfavyfcqqgntlpytfgqgtkleikggggs 
               
               
                 domain 
                   
                 ggggsggggsggggsqvqlqesgpglvkpsetlsltctvsgvslpdygvswirqpp 
               
               
                   
                   
                 gkglewigviwgsettyyqsslksrvtiskdnsknqvslklssvtaadtavyycak 
               
               
                   
                   
                 hyyyggsyamdywgqgtlvtvss 
               
               
                   
               
               
                 99790 
                 66 
                 atggccctcccagtgaccgctctgctgctgcctctcgcacttcttctccatgccgc 
               
               
                 CAR6 - 
                   
                 tcggcctgagatcgtcatgacccaaagccccgctaccctgtccctgtcacccggcg 
               
               
                 Soluble 
                   
                 agagggcaaccctttcatgcagggccagccaggacatttctaagtacctcaactgg 
               
               
                 scFv - nt 
                   
                 tatcagcagaagccagggcaggctcctcgcctgctgatctaccacaccagccgcct 
               
               
                   
                   
                 ccacagcggtatccccgccagattttccgggagcgggtctggaaccgactacaccc 
               
               
                   
                   
                 tcaccatctcttctctgcagcccgaggatttcgccgtctatttctgccagcagggg 
               
               
                   
                   
                 aatactctgccgtacaccttcggtcaaggtaccaagctggaaatcaagggaggcgg 
               
               
                   
                   
                 aggatcaggcggtggcggaagcggaggaggtggctccggaggaggaggttcccaag 
               
               
                   
                   
                 tgcagcttcaagaatcaggacccggacttgtgaagccatcagaaaccctctccctg 
               
               
                   
                   
                 acttgtaccgtgtccggtgtgagcctccccgactacggagtctcttggattcgcca 
               
               
                   
                   
                 gcctccggggaagggtcttgaatggattggggtgatttggggatcagagactactt 
               
               
                   
                   
                 actaccagtcatcacttaagtcacgggtcaccatcagcaaagataatagcaagaac 
               
               
                   
                   
                 caagtgtcacttaagctgtcatctgtgaccgccgctgacaccgccgtgtactattg 
               
               
                   
                   
                 tgccaaacattactattacggagggtcttatgctatggactactggggacagggga 
               
               
                   
                   
                 ccctggtgactgtctctagccatcaccatcaccaccatcatcac 
               
               
                   
               
               
                 99790 
                 78 
                     MALPVTALLLPLALLLHAARP   eivmtqspatlslspgeratlscrasqdiskylnw 
               
               
                 CAR6 - 
                   
                 yqqkpgqaprlliyhtsrlhsgiparfsgsgsgtdytltisslqpedfavyfcqqg 
               
               
                 Soluble 
                   
                 ntlpytfgqgtkleikggggsggggsggggsggggsqvqlqesgpglvkpsetlsl 
               
               
                 scFv - aa 
                   
                 tctvsgvslpdygvswirqppgkglewigviwgsettyyqsslksrvtiskdnskn 
               
               
                   
                   
                 qvslklssvtaadtavyycakhyyyggsyamdywgqgtlvtvss   hhhhhhhh     
               
               
                   
               
               
                 104880 
                 90 
                 atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgc 
               
               
                 CAR6 - 
                   
                 tcggcccgaaattgtgatgacccagtcacccgccactcttagcctttcacccggtg 
               
               
                 Full - nt 
                   
                 agcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattgg 
               
               
                   
                   
                 tatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggct 
               
               
                   
                   
                 ccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccc 
               
               
                   
                   
                 tcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaaggg 
               
               
                   
                   
                 aacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggagg 
               
               
                   
                   
                 tggcagcggaggaggtgggtccggcggtggaggaagcggaggcggagggagccagg 
               
               
                   
                   
                 tccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactg 
               
               
                   
                   
                 acttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagaca 
               
               
                   
                   
                 gccaccggggaagggtctggaatggattggagtgatttggggctctgagactactt 
               
               
                   
                   
                 actaccaatcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaat 
               
               
                   
                   
                 caggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattg 
               
               
                   
                   
                 cgctaagcattactattatggcgggagctacgcaatggattactggggacagggta 
               
               
                   
                   
                 ctctggtcaccgtgtccagcaccactaccccagcaccgaggccacccaccccggct 
               
               
                   
                   
                 cctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagc 
               
               
                   
                   
                 tggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttggg 
               
               
                   
                   
                 cccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttac 
               
               
                   
                   
                 tgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcc 
               
               
                   
                   
                 tgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggagg 
               
               
                   
                   
                 aaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctac 
               
               
                   
                   
                 aagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagta 
               
               
                   
                   
                 cgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgca 
               
               
                   
                   
                 gaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaa 
               
               
                   
                   
                 gcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacgg 
               
               
                   
                   
                 actgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgc 
               
               
                   
                   
                 aggccctgccgcctcgg 
               
               
                   
               
               
                 104880 
                 36 
                 MALPVTALLLPLALLLHAARPeivmtqspatlslspgeratlsc   rasqdiskyln   w 
               
               
                 CAR6 - 
                   
                 yqqkpgqaprlliy   htsrlhs   giparfsgsgsgtdytltisslqpedfavyfc   qqg     
               
               
                 Full - aa 
                   
                     ntlpyt   fgqgtkleikggggsggggsggggsggggsqvqlqesgpglvkpsetlsl 
               
               
                   
                   
                 tctvsgvslp   dygvs   wirqppgkglewig   viwgsettyygsslks   rvtiskdnskn 
               
               
                   
                   
                 qvslklssvtaadtavyycak   hyyyggsyamdy   wgqgtlvtvsstttpaprpptpa 
               
               
                   
                   
                 ptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitly 
               
               
                   
                   
                 ckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapay 
               
               
                   
                   
                 kqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmae 
               
               
                   
                   
                 ayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
            
           
           
               
            
               
                 CAR7 
               
            
           
           
               
               
               
            
               
                 CAR7 scFv 
                 7 
                 qvqlqesgpglvkpsetlsltctvsgvslpdygvswirqppgkglewigviwgset 
               
               
                 domain 
                   
                 tyyssslksrvtiskdnsknqvslklssvtaadtavyycakhyyyggsyamdywgq 
               
               
                   
                   
                 gtlvtvssggggsggggsggggsggggseivmtqspatlslspgeratlscrasqd 
               
               
                   
                   
                 iskylnwyqqkpgqaprlliyhtsrlhsgiparfsgsgsgtdytltisslqpedfa 
               
               
                   
                   
                 vyfcqqgntlpytfgqgtkleik 
               
               
                   
               
               
                 100796 
                 67 
                 atggcactgcctgtcactgccctcctgctgcctctggccctccttctgcatgccgc 
               
               
                 CAR7 - 
                   
                 caggccccaagtccagctgcaagagtcaggacccggactggtgaagccgtctgaga 
               
               
                 Soluble 
                   
                 ctctctcactgacttgtaccgtcagcggcgtgtccctccccgactacggagtgtca 
               
               
                 scFv - nt 
                   
                 tggatccgccaacctcccgggaaagggcttgaatggattggtgtcatctggggttc 
               
               
                   
                   
                 tgaaaccacctactactcatcttccctgaagtccagggtgaccatcagcaaggata 
               
               
                   
                   
                 attccaagaaccaggtcagccttaagctgtcatctgtgaccgctgctgacaccgcc 
               
               
                   
                   
                 gtgtattactgcgccaagcactactattacggaggaagctacgctatggactattg 
               
               
                   
                   
                 gggacagggcactctcgtgactgtgagcagcggcggtggagggtctggaggtggag 
               
               
                   
                   
                 gatccggtggtggtgggtcaggcggaggagggagcgagattgtgatgactcagtca 
               
               
                   
                   
                 ccagccaccctttctctttcacccggcgagagagcaaccctgagctgtagagccag 
               
               
                   
                   
                 ccaggacatttctaagtacctcaactggtatcagcaaaaaccggggcaggcccctc 
               
               
                   
                   
                 gcctcctgatctaccatacctcacgccttcactctggtatccccgctcggtttagc 
               
               
                   
                   
                 ggatcaggatctggtaccgactacactctgaccatttccagcctgcagccagaaga 
               
               
                   
                   
                 tttcgcagtgtatttctgccagcagggcaatacccttccttacaccttcggtcagg 
               
               
                   
                   
                 gaaccaagctcgaaatcaagcaccatcaccatcatcaccaccat 
               
               
                   
               
               
                 100796 
                 79 
                     MALPVTALLLPLALLLHAARP   qvqlqesgpglvkpsetlsltctvsgvslpdygvs 
               
               
                 CAR7 - 
                   
                 wirqppgkglewigviwgsettyyssslksrvtiskdnsknqvslklssvtaadta 
               
               
                 Soluble 
                   
                 vyycakhyyyggsyamdywgqgtlvtvssggggsggggsggggsggggseivmtqs 
               
               
                 scFv - aa 
                   
                 patlslspgeratlscrasqdiskylnwyqqkpgqaprlliyhtsrlhsgiparfs 
               
               
                   
                   
                 gsgsgtdytltisslqpedfavyfcqqgntlpytfgqgtkleik   hhhhhhhh     
               
               
                   
               
               
                 104881 
                 91 
                 atggctctgcccgtgaccgcactcctcctgccactggctctgctgcttcacgccgc 
               
               
                 CAR 7 
                   
                 tcgcccacaagtccagcttcaagaatcagggcctggtctggtgaagccatctgaga 
               
               
                 Full - nt 
                   
                 ctctgtccctcacttgcaccgtgagcggagtgtccctcccagactacggagtgagc 
               
               
                   
                   
                 tggattagacagcctcccggaaagggactggagtggatcggagtgatttggggtag 
               
               
                   
                   
                 cgaaaccacttactattcatcttccctgaagtcacgggtcaccatttcaaaggata 
               
               
                   
                   
                 actcaaagaatcaagtgagcctcaagctctcatcagtcaccgccgctgacaccgcc 
               
               
                   
                   
                 gtgtattactgtgccaagcattactactatggagggtcctacgccatggactactg 
               
               
                   
                   
                 gggccagggaactctggtcactgtgtcatctggtggaggaggtagcggaggaggcg 
               
               
                   
                   
                 ggagcggtggaggtggctccggaggtggcggaagcgaaatcgtgatgacccagagc 
               
               
                   
                   
                 cctgcaaccctgtccctttctcccggggaacgggctaccctttcttgtcgggcatc 
               
               
                   
                   
                 acaagatatctcaaaatacctcaattggtatcaacagaagccgggacaggccccta 
               
               
                   
                   
                 ggcttcttatctaccacacctctcgcctgcatagcgggattcccgcacgctttagc 
               
               
                   
                   
                 gggtctggaagcgggaccgactacactctgaccatctcatctctccagcccgagga 
               
               
                   
                   
                 cttcgccgtctacttctgccagcagggtaacaccctgccgtacaccttcggccagg 
               
               
                   
                   
                 gcaccaagcttgagatcaaaaccactactcccgctccaaggccacccacccctgcc 
               
               
                   
                   
                 ccgaccatcgcctctcagccgctttccctgcgtccggaggcatgtagacccgcagc 
               
               
                   
                   
                 tggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttggg 
               
               
                   
                   
                 cccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttac 
               
               
                   
                   
                 tgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcc 
               
               
                   
                   
                 tgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggagg 
               
               
                   
                   
                 aaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctac 
               
               
                   
                   
                 aagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagta 
               
               
                   
                   
                 cgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgca 
               
               
                   
                   
                 gaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaa 
               
               
                   
                   
                 gcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacgg 
               
               
                   
                   
                 actgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgc 
               
               
                   
                   
                 aggccctgccgcctcgg 
               
               
                   
               
               
                 104881 
                 37 
                 MALPVTALLLPLALLLHAARPqvqlqesgpglvkpsetlsltctvsgvslp   dygvs     
               
               
                 CAR 7 
                   
                 wirqppgkglewig   viwgsettyyssslks   rvtiskdnsknqvslklssvtaadta 
               
               
                 Full - aa 
                   
                 vyycak   hyyyggsyamdy   wgqgtlvtvssggggsggggsggggsggggseivmtqs 
               
               
                   
                   
                 patlslspgeratlsc   rasgdiskyln   wyqqkpgqaprlliy   htsrlhs   giparfs 
               
               
                   
                   
                 gsgsgtdytltisslqpedfavyfc   qqgntlpyt   fgqgtkleiktttpaprpptpa 
               
               
                   
                   
                 ptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitly 
               
               
                   
                   
                 ckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapay 
               
               
                   
                   
                 kqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmae 
               
               
                   
                   
                 ayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
            
           
           
               
            
               
                 CAR8 
               
            
           
           
               
               
               
            
               
                 CAR8 scFv 
                 8 
                 qvqlqesgpglvkpsetlsltctvsgvslpdygvswirqppgkglewigviwgset 
               
               
                 domain 
                   
                 tyyqsslksrvtiskdnsknqvslklssvtaadtavyycakhyyyggsyamdywgq 
               
               
                   
                   
                 gtlvtvssggggsggggsggggsggggseivmtqspatlslspgeratlscrasqd 
               
               
                   
                   
                 iskylnwyqqkpgqaprlliyhtsrlhsgiparfsgsgsgtdytltisslqpedfa 
               
               
                   
                   
                 vyfcqqgntlpytfgqgtkleik 
               
               
                   
               
               
                 100798 
                 68 
                 atggcactgcctgtcactgccctcctgctgcctctggccctccttctgcatgccgc 
               
               
                 CAR8 - 
                   
                 caggccccaagtccagctgcaagagtcaggacccggactggtgaagccgtctgaga 
               
               
                 Soluble 
                   
                 ctctctcactgacttgtaccgtcagcggcgtgtccctccccgactacggagtgtca 
               
               
                 scFv - nt 
                   
                 tggatccgccaacctcccgggaaagggcttgaatggattggtgtcatctggggttc 
               
               
                   
                   
                 tgaaaccacctactaccagtcttccctgaagtccagggtgaccatcagcaaggata 
               
               
                   
                   
                 attccaagaaccaggtcagccttaagctgtcatctgtgaccgctgctgacaccgcc 
               
               
                   
                   
                 gtgtattactgcgccaagcactactattacggaggaagctacgctatggactattg 
               
               
                   
                   
                 gggacagggcactctcgtgactgtgagcagcggcggtggagggtctggaggtggag 
               
               
                   
                   
                 gatccggtggtggtgggtcaggcggaggagggagcgagattgtgatgactcagtca 
               
               
                   
                   
                 ccagccaccctttctctttcacccggcgagagagcaaccctgagctgtagagccag 
               
               
                   
                   
                 ccaggacatttctaagtacctcaactggtatcagcaaaaaccggggcaggcccctc 
               
               
                   
                   
                 gcctcctgatctaccatacctcacgccttcactctggtatccccgctcggtttagc 
               
               
                   
                   
                 ggatcaggatctggtaccgactacactctgaccatttccagcctgcagccagaaga 
               
               
                   
                   
                 tttcgcagtgtatttctgccagcagggcaatacccttccttacaccttcggtcagg 
               
               
                   
                   
                 gaaccaagctcgaaatcaagcaccatcaccatcatcatcaccac 
               
               
                   
               
               
                 100798 
                 80 
                     MALPVTALLLPLALLLHAARP   qvqlqesgpglvkpsetlsltctvsgvslpdygvs 
               
               
                 CAR8 - 
                   
                 wirqppgkglewigviwgsettyyqsslksrvtiskdnsknqvslklssvtaadta 
               
               
                 Soluble 
                   
                 vyycakhyyyggsyamdywgqgtlvtvssggggsggggsggggsggggseivmtqs 
               
               
                 scFv - aa 
                   
                 patlslspgeratlscrasqdiskylnwyqqkpgqaprlliyhtsrlhsgiparfs 
               
               
                   
                   
                 gsgsgtdytltisslqpedfavyfcqqgntlpytfgqgtkleik   hhhhhhhh     
               
               
                   
               
               
                 104882 
                 92 
                 atggctctgcccgtgaccgcactcctcctgccactggctctgctgcttcacgccgc 
               
               
                 CAR 8 - 
                   
                 tcgcccacaagtccagcttcaagaatcagggcctggtctggtgaagccatctgaga 
               
               
                 Full - nt 
                   
                 ctctgtccctcacttgcaccgtgagcggagtgtccctcccagactacggagtgagc 
               
               
                   
                   
                 tggattagacagcctcccggaaagggactggagtggatcggagtgatttggggtag 
               
               
                   
                   
                 cgaaaccacttactatcaatcttccctgaagtcacgggtcaccatttcaaaggata 
               
               
                   
                   
                 actcaaagaatcaagtgagcctcaagctctcatcagtcaccgccgctgacaccgcc 
               
               
                   
                   
                 gtgtattactgtgccaagcattactactatggagggtcctacgccatggactactg 
               
               
                   
                   
                 gggccagggaactctggtcactgtgtcatctggtggaggaggtagcggaggaggcg 
               
               
                   
                   
                 ggagcggtggaggtggctccggaggcggtgggtcagaaatcgtgatgacccagagc 
               
               
                   
                   
                 cctgcaaccctgtccctttctcccggggaacgggctaccctttcttgtcgggcatc 
               
               
                   
                   
                 acaagatatctcaaaatacctcaattggtatcaacagaagccgggacaggccccta 
               
               
                   
                   
                 ggcttcttatctaccacacctctcgcctgcatagcgggattcccgcacgctttagc 
               
               
                   
                   
                 gggtctggaagcgggaccgactacactctgaccatctcatctctccagcccgagga 
               
               
                   
                   
                 cttcgccgtctacttctgccagcagggtaacaccctgccgtacaccttcggccagg 
               
               
                   
                   
                 gcaccaagcttgagatcaaaaccactactcccgctccaaggccacccacccctgcc 
               
               
                   
                   
                 ccgaccatcgcctctcagccgctttccctgcgtccggaggcatgtagacccgcagc 
               
               
                   
                   
                 tggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttggg 
               
               
                   
                   
                 cccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttac 
               
               
                   
                   
                 tgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcc 
               
               
                   
                   
                 tgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggagg 
               
               
                   
                   
                 aaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctac 
               
               
                   
                   
                 aagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagta 
               
               
                   
                   
                 cgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgca 
               
               
                   
                   
                 gaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaa 
               
               
                   
                   
                 gcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacgg 
               
               
                   
                   
                 actgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgc 
               
               
                   
                   
                 aggccctgccgcctcgg 
               
               
                   
               
               
                 104882 
                 38 
                 MALPVTALLLPLALLLHAARPqvqlqesgpglvkpsetlsltctvsgvslp   dygvs     
               
               
                 CAR 8 - 
                   
                 wirqppgkglewig   viwgsettyyqsslks   rvtiskdnsknqvslklssvtaadta 
               
               
                 Full - aa 
                   
                 vyycak   hyyyggsyamdy   wgqgtlvtvssggggsggggsggggsggggseivmtqs 
               
               
                   
                   
                 patlslspgeratlsc   rasqdiskyln   wyqqkpgqaprlliy   htsrlhs   giparfs 
               
               
                   
                   
                 gsgsgtdytltisslqpedfavyfc   qqgntlpyt   fgqgtkleiktttpaprpptpa 
               
               
                   
                   
                 ptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitly 
               
               
                   
                   
                 ckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapay 
               
               
                   
                   
                 kqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmae 
               
               
                   
                   
                 ayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
            
           
           
               
            
               
                 CAR9 
               
            
           
           
               
               
               
            
               
                 CAR9 scFv 
                 9 
                 eivmtqspatlslspgeratlscrasqdiskylnwyqqkpgqaprlliyhtsrlhs 
               
               
                 domain 
                   
                 giparfsgsgsgtdytltisslqpedfavyfcqqgntlpytfgqgtkleikggggs 
               
               
                   
                   
                 ggggsggggsggggsqvqlqesgpglvkpsetlsltctvsgvslpdygvswirqpp 
               
               
                   
                   
                 gkglewigviwgsettyynsslksrvtiskdnsknqvslklssvtaadtavyycak 
               
               
                   
                   
                 hyyyggsyamdywgqgtlvtvss 
               
               
                   
               
               
                 99789 
                 69 
                 atggccctcccagtgaccgctctgctgctgcctctcgcacttcttctccatgccgc 
               
               
                 CAR9 - 
                   
                 tcggcctgagatcgtcatgacccaaagccccgctaccctgtccctgtcacccggcg 
               
               
                 Soluble 
                   
                 agagggcaaccctttcatgcagggccagccaggacatttctaagtacctcaactgg 
               
               
                 scFv - nt 
                   
                 tatcagcagaagccagggcaggctcctcgcctgctgatctaccacaccagccgcct 
               
               
                   
                   
                 ccacagcggtatccccgccagattttccgggagcgggtctggaaccgactacaccc 
               
               
                   
                   
                 tcaccatctcttctctgcagcccgaggatttcgccgtctatttctgccagcagggg 
               
               
                   
                   
                 aatactctgccgtacaccttcggtcaaggtaccaagctggaaatcaagggaggcgg 
               
               
                   
                   
                 aggatcaggcggtggcggaagcggaggaggtggctccggaggaggaggttcccaag 
               
               
                   
                   
                 tgcagcttcaagaatcaggacccggacttgtgaagccatcagaaaccctctccctg 
               
               
                   
                   
                 acttgtaccgtgtccggtgtgagcctccccgactacggagtctcttggattcgcca 
               
               
                   
                   
                 gcctccggggaagggtcttgaatggattggggtgatttggggatcagagactactt 
               
               
                   
                   
                 actacaattcatcacttaagtcacgggtcaccatcagcaaagataatagcaagaac 
               
               
                   
                   
                 caagtgtcacttaagctgtcatctgtgaccgccgctgacaccgccgtgtactattg 
               
               
                   
                   
                 tgccaaacattactattacggagggtcttatgctatggactactggggacagggga 
               
               
                   
                   
                 ccctggtgactgtctctagccatcaccatcaccaccatcatcac 
               
               
                   
               
               
                 99789 
                 81 
                     MALPVTALLLPLALLLHAARP   eivmtqspatlslspgeratlscrasqdiskylnw 
               
               
                 CAR9 - 
                   
                 yqqkpgqaprlliyhtsrlhsgiparfsgsgsgtdytltisslqpedfavyfcqqg 
               
               
                 Soluble 
                   
                 ntlpytfgqgtkleikggggsggggsggggsggggsqvqlqesgpglvkpsetlsl 
               
               
                 scFv - aa 
                   
                 tctvsgvslpdygvswirqppgkglewigviwgsettyynsslksrvtiskdnskn 
               
               
                   
                   
                 qvslklssvtaadtavyycakhyyyggsyamdywgqgtlvtvss   hhhhhhhh     
               
               
                   
               
               
                 105974 
                 93 
                 atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgc 
               
               
                 CAR 9 - 
                   
                 tcggcccgaaattgtgatgacccagtcacccgccactcttagcctttcacccggtg 
               
               
                 Full - nt 
                   
                 agcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattgg 
               
               
                   
                   
                 tatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggct 
               
               
                   
                   
                 ccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccc 
               
               
                   
                   
                 tcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaaggg 
               
               
                   
                   
                 aacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggagg 
               
               
                   
                   
                 tggcagcggaggaggtgggtccggcggtggaggaagcggaggcggtgggagccagg 
               
               
                   
                   
                 tccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactg 
               
               
                   
                   
                 acttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagaca 
               
               
                   
                   
                 gccaccggggaagggtctggaatggattggagtgatttggggctctgagactactt 
               
               
                   
                   
                 actacaactcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaat 
               
               
                   
                   
                 caggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattg 
               
               
                   
                   
                 cgctaagcattactattatggcgggagctacgcaatggattactggggacagggta 
               
               
                   
                   
                 ctctggtcaccgtgtccagcaccactaccccagcaccgaggccacccaccccggct 
               
               
                   
                   
                 cctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagc 
               
               
                   
                   
                 tggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttggg 
               
               
                   
                   
                 cccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttac 
               
               
                   
                   
                 tgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcc 
               
               
                   
                   
                 tgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggagg 
               
               
                   
                   
                 aaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctac 
               
               
                   
                   
                 aagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagta 
               
               
                   
                   
                 cgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgca 
               
               
                   
                   
                 gaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaa 
               
               
                   
                   
                 gcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacgg 
               
               
                   
                   
                 actgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgc 
               
               
                   
                   
                 aggccctgccgcctcgg 
               
               
                   
               
               
                 105974 
                 39 
                 MALPVTALLLPLALLLHAARPeivmtqspatlslspgeratlscrasgdiskylnw 
               
               
                 CAR 9 - 
                   
                 yqqkpgqaprlliyhtsrlhsgiparfsgsgsgtdytltisslqpedfavyfcqqg 
               
               
                 Full - aa 
                   
                 ntlpytfgqgtkleikggggsggggsggggsggggsqvqlqesgpglvkpsetlsl 
               
               
                   
                   
                 tctvsgvslpdygvswirqppgkglewigviwgsettyynsslksrvtiskdnskn 
               
               
                   
                   
                 qvslklssvtaadtavyycakhyyyggsyamdywgqgtlvtvsstttpaprpptpa 
               
               
                   
                   
                 ptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitly 
               
               
                   
                   
                 ckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapay 
               
               
                   
                   
                 kqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmae 
               
               
                   
                   
                 ayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
            
           
           
               
            
               
                 CAR10 
               
            
           
           
               
               
               
            
               
                 CAR10 
                 10 
                 qvqlqesgpglvkpsetlsltctvsgvslpdygvswirqppgkglewigviwgset 
               
               
                 scFv 
                   
                 tyynsslksrvtiskdnsknqvslklssvtaadtavyycakhyyyggsyamdywgq 
               
               
                 domain 
                   
                 gtlvtvssggggsggggsggggsggggseivmtqspatlslspgeratlscrasqd 
               
               
                   
                   
                 iskylnwyqqkpgqaprlliyhtsrlhsgiparfsgsgsgtdytltisslqpedfa 
               
               
                   
                   
                 vyfcqqgntlpytfgqgtkleik 
               
               
                   
               
               
                 100796 
                 70 
                 atggcactgcctgtcactgccctcctgctgcctctggccctccttctgcatgccgc 
               
               
                 CAR10 - 
                   
                 caggccccaagtccagctgcaagagtcaggacccggactggtgaagccgtctgaga 
               
               
                 Soluble 
                   
                 ctctctcactgacttgtaccgtcagcggcgtgtccctccccgactacggagtgtca 
               
               
                 scFv - nt 
                   
                 tggatccgccaacctcccgggaaagggcttgaatggattggtgtcatctggggttc 
               
               
                   
                   
                 tgaaaccacctactacaactcttccctgaagtccagggtgaccatcagcaaggata 
               
               
                   
                   
                 attccaagaaccaggtcagccttaagctgtcatctgtgaccgctgctgacaccgcc 
               
               
                   
                   
                 gtgtattactgcgccaagcactactattacggaggaagctacgctatggactattg 
               
               
                   
                   
                 gggacagggcactctcgtgactgtgagcagcggcggtggagggtctggaggtggag 
               
               
                   
                   
                 gatccggtggtggtgggtcaggcggaggagggagcgagattgtgatgactcagtca 
               
               
                   
                   
                 ccagccaccctttctctttcacccggcgagagagcaaccctgagctgtagagccag 
               
               
                   
                   
                 ccaggacatttctaagtacctcaactggtatcagcaaaaaccggggcaggcccctc 
               
               
                   
                   
                 gcctcctgatctaccatacctcacgccttcactctggtatccccgctcggtttagc 
               
               
                   
                   
                 ggatcaggatctggtaccgactacactctgaccatttccagcctgcagccagaaga 
               
               
                   
                   
                 tttcgcagtgtatttctgccagcagggcaatacccttccttacaccttcggtcagg 
               
               
                   
                   
                 gaaccaagctcgaaatcaagcaccatcaccatcatcaccaccat 
               
               
                   
               
               
                 100796 
                 82 
                     MALPVTALLLPLALLLHAARP   qvqlqesgpglvkpsetlsltctvsgvslpdygvs 
               
               
                 CAR10 - 
                   
                 wirqppgkglewigviwgsettyynsslksrvtiskdnsknqvslklssvtaadta 
               
               
                 Soluble 
                   
                 vyycakhyyyggsyamdywgqgtlvtvssggggsggggsggggsggggseivmtqs 
               
               
                 scFv-aa 
                   
                 patlslspgeratlscrasqdiskylnwyqqkpgqaprlliyhtsrlhsgiparfs 
               
               
                   
                   
                 gsgsgtdytltisslqpedfavyfcqqgntlpytfgqgtkleik   hhhhhhhh     
               
               
                   
               
               
                 105975 
                 94 
                 atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgc 
               
               
                 CAR 10 
                   
                 tcggcccgaaattgtgatgacccagtcacccgccactcttagcctttcacccggtg 
               
               
                 Full - nt 
                   
                 agcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattgg 
               
               
                   
                   
                 tatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggct 
               
               
                   
                   
                 ccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccc 
               
               
                   
                   
                 tcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaaggg 
               
               
                   
                   
                 aacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggagg 
               
               
                   
                   
                 tggcagcggaggaggtgggtccggcggtggaggaagcggaggcggtgggagccagg 
               
               
                   
                   
                 tccaactccaagaaagcggaccgggtcttgtgaagccatcagaaactctttcactg 
               
               
                   
                   
                 acttgtactgtgagcggagtgtctctccccgattacggggtgtcttggatcagaca 
               
               
                   
                   
                 gccaccggggaagggtctggaatggattggagtgatttggggctctgagactactt 
               
               
                   
                   
                 actacaactcatccctcaagtcacgcgtcaccatctcaaaggacaactctaagaat 
               
               
                   
                   
                 caggtgtcactgaaactgtcatctgtgaccgcagccgacaccgccgtgtactattg 
               
               
                   
                   
                 cgctaagcattactattatggcgggagctacgcaatggattactggggacagggta 
               
               
                   
                   
                 ctctggtcaccgtgtccagcaccactaccccagcaccgaggccacccaccccggct 
               
               
                   
                   
                 cctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagacccgcagc 
               
               
                   
                   
                 tggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttggg 
               
               
                   
                   
                 cccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttac 
               
               
                   
                   
                 tgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcc 
               
               
                   
                   
                 tgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggagg 
               
               
                   
                   
                 aaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctac 
               
               
                   
                   
                 aagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagta 
               
               
                   
                   
                 cgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgca 
               
               
                   
                   
                 gaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaa 
               
               
                   
                   
                 gcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacgg 
               
               
                   
                   
                 actgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgc 
               
               
                   
                   
                 aggccctgccgcctcgg 
               
               
                   
               
               
                 105975 
                 40 
                 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYLNW 
               
               
                 CAR 10 
                   
                 YQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQG 
               
               
                 Full - aa 
                   
                 NTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSL 
               
               
                   
                   
                 TCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKN 
               
               
                   
                   
                 QVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPA 
               
               
                   
                   
                 PTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLY 
               
               
                   
                   
                 CKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAY 
               
               
                   
                   
                 KQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAE 
               
               
                   
                   
                 AYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
            
           
           
               
            
               
                 CAR11 
               
            
           
           
               
               
               
            
               
                 CAR11 
                 11 
                 eivmtqspatlslspgeratlscrasqdiskylnwyqqkpgqaprlliyhtsrlhs 
               
               
                 scFv 
                   
                 giparfsgsgsgtdytltisslqpedfavyfcqqgntlpytfgqgtkleikggggs 
               
               
                 domain 
                   
                 ggggsggggsqvqlqesgpglvkpsetlsltctvsgvslpdygvswirqppgkgle 
               
               
                   
                   
                 wigviwgsettyynsslksrvtiskdnsknqvslklssvtaadtavyycakhyyyg 
               
               
                   
                   
                 gsyamdywgqgtlvtvss 
               
               
                   
               
               
                 103101 
                 71 
                 Atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgc 
               
               
                 CAR11 - 
                   
                 tcggcccgaaattgtgatgacccagtcacccgccactcttagcctttcacccggtg 
               
               
                 Soluble 
                   
                 agcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattgg 
               
               
                 scFv - nt 
                   
                 tatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggct 
               
               
                   
                   
                 ccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccc 
               
               
                   
                   
                 tcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaaggg 
               
               
                   
                   
                 aacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggagg 
               
               
                   
                   
                 tggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaa 
               
               
                   
                   
                 gcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagc 
               
               
                   
                   
                 ggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaaggg 
               
               
                   
                   
                 tctggaatggattggagtgatttggggctctgagactacttactacaattcatccc 
               
               
                   
                   
                 tcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaa 
               
               
                   
                   
                 ctgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattacta 
               
               
                   
                   
                 ttatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgt 
               
               
                   
                   
                 ccagccaccaccatcatcaccatcaccat 
               
               
                   
               
               
                 103101 
                 83 
                     MALPVTALLLPLALLLHAARP   eivmtqspatlslspgeratlscrasqdiskylnw 
               
               
                 CAR11 - 
                   
                 yqqkpgqaprlliyhtsrlhsgiparfsgsgsgtdytltisslqpedfavyfcqqg 
               
               
                 Soluble 
                   
                 ntlpytfgqgtkleikggggsggggsggggsqvqlqesgpglvkpsetlsltctvs 
               
               
                 scFv - aa 
                   
                 gvslpdygvswirqppgkglewigviwgsettyynsslksrvtiskdnsknqvslk 
               
               
                   
                   
                 lssvtaadtavyycakhyyyggsyamdywgqgtlvtvss   hhhhhhhh     
               
               
                   
               
               
                 105976 
                 95 
                 atggctctgcccgtgaccgcactcctcctgccactggctctgctgcttcacgccgc 
               
               
                 CAR 11 
                   
                 tcgcccacaagtccagcttcaagaatcagggcctggtctggtgaagccatctgaga 
               
               
                 Full - nt 
                   
                 ctctgtccctcacttgcaccgtgagcggagtgtccctcccagactacggagtgagc 
               
               
                   
                   
                 tggattagacagcctcccggaaagggactggagtggatcggagtgatttggggtag 
               
               
                   
                   
                 cgaaaccacttactataactcttccctgaagtcacgggtcaccatttcaaaggata 
               
               
                   
                   
                 actcaaagaatcaagtgagcctcaagctctcatcagtcaccgccgctgacaccgcc 
               
               
                   
                   
                 gtgtattactgtgccaagcattactactatggagggtcctacgccatggactactg 
               
               
                   
                   
                 gggccagggaactctggtcactgtgtcatctggtggaggaggtagcggaggaggcg 
               
               
                   
                   
                 ggagcggtggaggtggctccggaggtggcggaagcgaaatcgtgatgacccagagc 
               
               
                   
                   
                 cctgcaaccctgtccctttctcccggggaacgggctaccctttcttgtcgggcatc 
               
               
                   
                   
                 acaagatatctcaaaatacctcaattggtatcaacagaagccgggacaggccccta 
               
               
                   
                   
                 ggcttcttatctaccacacctctcgcctgcatagcgggattcccgcacgctttagc 
               
               
                   
                   
                 gggtctggaagcgggaccgactacactctgaccatctcatctctccagcccgagga 
               
               
                   
                   
                 cttcgccgtctacttctgccagcagggtaacaccctgccgtacaccttcggccagg 
               
               
                   
                   
                 gcaccaagcttgagatcaaaaccactactcccgctccaaggccacccacccctgcc 
               
               
                   
                   
                 ccgaccatcgcctctcagccgctttccctgcgtccggaggcatgtagacccgcagc 
               
               
                   
                   
                 tggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttggg 
               
               
                   
                   
                 cccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttac 
               
               
                   
                   
                 tgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcc 
               
               
                   
                   
                 tgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggagg 
               
               
                   
                   
                 aaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctac 
               
               
                   
                   
                 aagcaggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagta 
               
               
                   
                   
                 cgacgtgctggacaagcggagaggacgggacccagaaatgggcgggaagccgcgca 
               
               
                   
                   
                 gaaagaatccccaagagggcctgtacaacgagctccaaaaggataagatggcagaa 
               
               
                   
                   
                 gcctatagcgagattggtatgaaaggggaacgcagaagaggcaaaggccacgacgg 
               
               
                   
                   
                 actgtaccagggactcagcaccgccaccaaggacacctatgacgctcttcacatgc 
               
               
                   
                   
                 aggccctgccgcctcgg 
               
               
                   
               
               
                 105976 
                 41 
                 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGVSLP   DYGVS     
               
               
                 CAR 11 
                   
                 WIRQPPGKGLEWIG   VIWGSETTYYNSSLKS   RVTISKDNSKNQVSLKLSSVTAADTA 
               
               
                 Full - aa 
                   
                 VYYCAK   HYYYGGSYAMDY   WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQS 
               
               
                   
                   
                 PATLSLSPGERATLSC   RASQDISKYLN   WYQQKPGQAPRLLIY   HTSRLHS   GIPARFS 
               
               
                   
                   
                 GSGSGTDYTLTISSLQPEDFAVYFC   QQGNTLPYT   FGQGTKLEIKTTTPAPRPPTPA 
               
               
                   
                   
                 PTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLY 
               
               
                   
                   
                 CKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAY 
               
               
                   
                   
                 KQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAE 
               
               
                   
                   
                 AYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
            
           
           
               
            
               
                 CAR12 
               
            
           
           
               
               
               
            
               
                 CAR12 
                 12 
                 qvqlqesgpglvkpsetlsltctvsgvslpdygvswirqppgkglewigviwgset 
               
               
                 scFv 
                   
                 tyynsslksrvtiskdnsknqvslklssvtaadtavyycakhyyyggsyamdywgq 
               
               
                 domain 
                   
                 gtlvtvssggggsggggsggggseivmtqspatlslspgeratlscrasqdiskyl 
               
               
                   
                   
                 nwyqqkpgqaprlliyhtsrlhsgiparfsgsgsgtdytltisslqpedfavyfcq 
               
               
                   
                   
                 qgntlpytfgqgtkleik 
               
               
                   
               
               
                 103104 
                 72 
                 atggctctgcccgtgaccgcactcctcctgccactggctctgctgcttcacgccgc 
               
               
                 CAR12 - 
                   
                 tcgcccacaagtccagcttcaagaatcagggcctggtctggtgaagccatctgaga 
               
               
                 Soluble 
                   
                 ctctgtccctcacttgcaccgtgagcggagtgtccctcccagactacggagtgagc 
               
               
                 scFv - nt 
                   
                 tggattagacagcctcccggaaagggactggagtggatcggagtgatttggggtag 
               
               
                   
                   
                 cgaaaccacttactataactcttccctgaagtcacgggtcaccatttcaaaggata 
               
               
                   
                   
                 actcaaagaatcaagtgagcctcaagctctcatcagtcaccgccgctgacaccgcc 
               
               
                   
                   
                 gtgtattactgtgccaagcattactactatggagggtcctacgccatggactactg 
               
               
                   
                   
                 gggccagggaactctggtcactgtgtcatctggtggaggaggtagcggaggaggcg 
               
               
                   
                   
                 ggagcggtggaggtggctccgaaatcgtgatgacccagagccctgcaaccctgtcc 
               
               
                   
                   
                 ctttctcccggggaacgggctaccctttcttgtcgggcatcacaagatatctcaaa 
               
               
                   
                   
                 atacctcaattggtatcaacagaagccgggacaggcccctaggcttcttatctacc 
               
               
                   
                   
                 acacctctcgcctgcatagcgggattcccgcacgctttagcgggtctggaagcggg 
               
               
                   
                   
                 accgactacactctgaccatctcatctctccagcccgaggacttcgccgtctactt 
               
               
                   
                   
                 ctgccagcagggtaacaccctgccgtacaccttcggccagggcaccaagcttgaga 
               
               
                   
                   
                 tcaaacatcaccaccatcatcaccatcac 
               
               
                   
               
               
                 103104 
                 84 
                     MALPVTALLLPLALLLHAARP   qvqlqesgpglvkpsetlsltctvsgvslpdygvs 
               
               
                 CAR12 - 
                   
                 wirqppgkglewigviwgsettyynsslksrvtiskdnsknqvslklssvtaadta 
               
               
                 Soluble 
                   
                 vyycakhyyyggsyamdywgqgtlvtvssggggsggggsggggseivmtqspatls 
               
               
                 scFv -aa 
                   
                 lspgeratlscrasqdiskylnwyqqkpgqaprlliyhtsrlhsgiparfsgsgsg 
               
               
                   
                   
                 tdytltisslqpedfavyfcqqgntlpytfgqgtkleik   hhhhhhhh     
               
               
                   
               
               
                 105977 
                 96 
                 atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgc 
               
               
                 CAR 12 - 
                   
                 tcggcccgaaattgtgatgacccagtcacccgccactcttagcctttcacccggtg 
               
               
                 Full - nt 
                   
                 agcgcgcaaccctgtcttgcagagcctcccaagacatctcaaaataccttaattgg 
               
               
                   
                   
                 tatcaacagaagcccggacaggctcctcgccttctgatctaccacaccagccggct 
               
               
                   
                   
                 ccattctggaatccctgccaggttcagcggtagcggatctgggaccgactacaccc 
               
               
                   
                   
                 tcactatcagctcactgcagccagaggacttcgctgtctatttctgtcagcaaggg 
               
               
                   
                   
                 aacaccctgccctacacctttggacagggcaccaagctcgagattaaaggtggagg 
               
               
                   
                   
                 tggcagcggaggaggtgggtccggcggtggaggaagccaggtccaactccaagaaa 
               
               
                   
                   
                 gcggaccgggtcttgtgaagccatcagaaactctttcactgacttgtactgtgagc 
               
               
                   
                   
                 ggagtgtctctccccgattacggggtgtcttggatcagacagccaccggggaaggg 
               
               
                   
                   
                 tctggaatggattggagtgatttggggctctgagactacttactacaactcatccc 
               
               
                   
                   
                 tcaagtcacgcgtcaccatctcaaaggacaactctaagaatcaggtgtcactgaaa 
               
               
                   
                   
                 ctgtcatctgtgaccgcagccgacaccgccgtgtactattgcgctaagcattacta 
               
               
                   
                   
                 ttatggcgggagctacgcaatggattactggggacagggtactctggtcaccgtgt 
               
               
                   
                   
                 ccagcaccactaccccagcaccgaggccacccaccccggctcctaccatcgcctcc 
               
               
                   
                   
                 cagcctctgtccctgcgtccggaggcatgtagacccgcagctggtggggccgtgca 
               
               
                   
                   
                 tacccggggtcttgacttcgcctgcgatatctacatttgggcccctctggctggta 
               
               
                   
                   
                 cttgcggggtcctgctgctttcactcgtgatcactctttactgtaagcgcggtcgg 
               
               
                   
                   
                 aagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagactactca 
               
               
                   
                   
                 agaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaac 
               
               
                   
                   
                 tgcgcgtgaaattcagccgcagcgcagatgctccagcctacaagcaggggcagaac 
               
               
                   
                   
                 cagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaa 
               
               
                   
                   
                 gcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaag 
               
               
                   
                   
                 agggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagatt 
               
               
                   
                   
                 ggtatgaaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggact 
               
               
                   
                   
                 cagcaccgccaccaaggacacctatgacgctcttcacatgcaggccctgccgcctc 
               
               
                   
                   
                 gg 
               
               
                   
               
               
                 105977 
                 42 
                 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSC   RASQDISKYLN   W 
               
               
                 CAR 12 - 
                   
                 YQQKPGQAPRLLIY   HTSRLHS   GIPARFSGSGSGTDYTLTISSLQPEDFAVYFC   QQG     
               
               
                 Full - aa 
                   
                     NTLPYT   FGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVS 
               
               
                   
                   
                 GVSLP   DYGVS   WIRQPPGKGLEWIG   VIWGSETTYYNSSLKS   RVTISKDMSKMQVSLK 
               
               
                   
                   
                 LSSVTAADTAVYYCAK   HYYYGGSYAMDY   WGQGTLVTVSSTTTPAPRPPTPAPTIAS 
               
               
                   
                   
                 QPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGR 
               
               
                   
                   
                 KKLLYIFKQPFMRPVQTTQEEDGCSCREPEEEEGGCELRVKFSRSADAPAYKQGQN 
               
               
                   
                   
                 QLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKMPQEGLYNELQKDKMAEAYSEI 
               
               
                   
                   
                 GMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
               
                   
               
               
                 Murine CD19 CAR Constructs 
               
               
                   
               
             
            
               
                 CTL019 
               
            
           
           
               
               
               
            
               
                 CTL019- 
                  97 
                 Atggccctgcccgtcaccgctctgctgctgccccttgctctgcttcttcatgcagc 
               
               
                 Soluble 
                   
                 aaggccggacatccagatgacccaaaccacctcatccctctctgcctctcttggag 
               
               
                 scFv-Histag- 
                   
                 acagggtgaccatttcttgtcgcgccagccaggacatcagcaagtatctgaactgg 
               
               
                 nt 
                   
                 tatcagcagaagccggacggaaccgtgaagctcctgatctaccatacctctcgcct 
               
               
                   
                   
                 gcatagcggcgtgccctcacgcttctctggaagcggatcaggaaccgattattctc 
               
               
                   
                   
                 tcactatttcaaatcttgagcaggaagatattgccacctatttctgccagcagggt 
               
               
                   
                   
                 aataccctgccctacaccttcggaggagggaccaagctcgaaatcaccggtggagg 
               
               
                   
                   
                 aggcagcggcggtggagggtctggtggaggtggttctgaggtgaagctgcaagaat 
               
               
                   
                   
                 caggccctggacttgtggccccttcacagtccctgagcgtgacttgcaccgtgtcc 
               
               
                   
                   
                 ggagtctccctgcccgactacggagtgtcatggatcagacaacctccacggaaagg 
               
               
                   
                   
                 actggaatggctcggtgtcatctggggtagcgaaactacttactacaattcagccc 
               
               
                   
                   
                 tcaaaagcaggctgactattatcaaggacaacagcaagtcccaagtctttcttaag 
               
               
                   
                   
                 atgaactcactccagactgacgacaccgcaatctactattgtgctaagcactacta 
               
               
                   
                   
                 ctacggaggatcctacgctatggattactggggacaaggtacttccgtcactgtct 
               
               
                   
                   
                 cttcacaccatcatcaccatcaccatcac 
               
               
                   
               
               
                 CTL019- 
                  98 
                     MALPVTALLLPLALLLHAARP   diqmtqttsslsaslgdrvtiscrasqdiskylnw 
               
               
                 Soluble 
                   
                 yqqkpdgtvklliyhtsrlhsgvpsrfsgsgsgtdysltisnleqediatyfcqqg 
               
               
                 scFv-Histag- 
                   
                 ntlpytfgggtkleitggggsggggsggggsevklqesgpglvapsqslsvtctvs 
               
               
                 aa 
                   
                 gvslpdygvswirqpprkglewlgviwgsettyynsalksrltiikdnsksqvflk 
               
               
                   
                   
                 mnslqtddtaiyycakhyyyggsyamdywgqgtsvtvss   hhhhhhhh     
               
               
                   
               
               
                 CTL019 
                  99 
                 atggccttaccagtgaccgccttgctcctgccgctggccttgctgctccacgccgc 
               
               
                 Full-nt 
                   
                 caggccggacatccagatgacacagactacatcctccctgtctgcctctctgggag 
               
               
                   
                   
                 acagagtcaccatcagttgcagggcaagtcaggacattagtaaatatttaaattgg 
               
               
                   
                   
                 tatcagcagaaaccagatggaactgttaaactcctgatctaccatacatcaagatt 
               
               
                   
                   
                 acactcaggagtcccatcaaggttcagtggcagtgggtctggaacagattattctc 
               
               
                   
                   
                 tcaccattagcaacctggagcaagaagatattgccacttacttttgccaacagggt 
               
               
                   
                   
                 aatacgcttccgtacacgttcggaggggggaccaagctggagatcacaggtggcgg 
               
               
                   
                   
                 tggctcgggcggtggtgggtcgggtggcggcggatctgaggtgaaactgcaggagt 
               
               
                   
                   
                 caggacctggcctggtggcgccctcacagagcctgtccgtcacatgcactgtctca 
               
               
                   
                   
                 ggggtctcattacccgactatggtgtaagctggattcgccagcctccacgaaaggg 
               
               
                   
                   
                 tctggagtggctgggagtaatatggggtagtgaaaccacatactataattcagctc 
               
               
                   
                   
                 tcaaatccagactgaccatcatcaaggacaactccaagagccaagttttcttaaaa 
               
               
                   
                   
                 atgaacagtctgcaaactgatgacacagccatttactactgtgccaaacattatta 
               
               
                   
                   
                 ctacggtggtagctatgctatggactactggggccaaggaacctcagtcaccgtct 
               
               
                   
                   
                 cctcaaccacgacgccagcgccgcgaccaccaacaccggcgcccaccatcgcgtcg 
               
               
                   
                   
                 cagcccctgtccctgcgcccagaggcgtgccggccagcggcggggggcgcagtgca 
               
               
                   
                   
                 cacgagggggctggacttcgcctgtgatatctacatctgggcgcccttggccggga 
               
               
                   
                   
                 cttgtggggtccttctcctgtcactggttatcaccctttactgcaaacggggcaga 
               
               
                   
                   
                 aagaaactcctgtatatattcaaacaaccatttatgagaccagtacaaactactca 
               
               
                   
                   
                 agaggaagatggctgtagctgccgatttccagaagaagaagaaggaggatgtgaac 
               
               
                   
                   
                 tgagagtgaagttcagcaggagcgcagacgcccccgcgtacaagcagggccagaac 
               
               
                   
                   
                 cagctctataacgagctcaatctaggacgaagagaggagtacgatgttttggacaa 
               
               
                   
                   
                 gagacgtggccgggaccctgagatggggggaaagccgagaaggaagaaccctcagg 
               
               
                   
                   
                 aaggcctgtacaatgaactgcagaaagataagatggcggaggcctacagtgagatt 
               
               
                   
                   
                 gggatgaaaggcgagcgccggaggggcaaggggcacgatggcctttaccagggtct 
               
               
                   
                   
                 cagtacagccaccaaggacacctacgacgcccttcacatgcaggccctgccccctc 
               
               
                   
                   
                 gc 
               
               
                   
               
               
                 CTL019 
                  58 
                 MALPVTALLLPLALLLHAARPdiqmtqttsslsaslgdrvtiscrasqdiskylnw 
               
               
                 Full-aa 
                   
                 yqqkpdgtvklliyhtsrlhsgvpsrfsgsgsgtdysltisnleqediatyfcqqg 
               
               
                   
                   
                 ntlpytfgggtkleitggggsggggsggggsevklqesgpglvapsqslsvtctvs 
               
               
                   
                   
                 gvslpdygvswirqpprkglewlgviwgsettyynsalksrltiikdnsksqvflk 
               
               
                   
                   
                 mnslqtddtaiyycakhyyyggsyamdywgqgtsvtvsstttpaprpptpaptias 
               
               
                   
                   
                 qplslrpeacrpaaggavhtrgldfacdiyiwaplagtogvlllslvitlyckrgr 
               
               
                   
                   
                 kkllyifkqpfmrpvqttgeedgcscrfpeeeeggcelrvkfsrsadapaykqgqn 
               
               
                   
                   
                 qlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeaysei 
               
               
                   
                   
                 gmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
               
                 CTL019 
                  59 
                 Diqmtqttsslsaslgdrvtiscrasqdiskylnwyqqkpdgtvklliyhtsrlhs 
               
               
                 scFv 
                   
                 gvpsrfsgsgsgtdysltisnleqediatyfcqqgntlpytfgggtkleitggggs 
               
               
                 domain 
                   
                 ggggsggggsevklqesgpglvapsqslsvtctvsgvslpdygvswirqpprkgle 
               
               
                   
                   
                 wlgviwgsettyynsalksrltiikdnsksqvflkmnslqtddtaiyycakhyyyg 
               
               
                   
                   
                 gsyamdywgqgtsvtvss 
               
               
                   
               
               
                 mCAR1 
                 109 
                 QVQLLESGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIYPGDG 
               
               
                 scFv 
                   
                 DTNYNGKFKGQATLTADKSSSTAYMQLSGLTSEDSAVYSCARKTISSVVDFYFDYW 
               
               
                   
                   
                 GQGTTVTGGGSGGGSGGGSGGGSELVLTQSPKFMSTSVGDRVSVTCKASQNVGTNV 
               
               
                   
                   
                 AWYQQKPGQSPKPLIYSATYRNSGVPDRFTGSGSGTDFTLTITNVQSKDLADYFCQ 
               
               
                   
                   
                 YNRYPYTSFFFTKLEIKRRS 
               
               
                   
               
               
                 mCAR1 
                 110 
                 QVQLLESGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIYPGDG 
               
               
                 Full-aa 
                   
                 DTNYNGKFKGQATLTADKSSSTAYMQLSGLTSEDSAVYSCARKTISSVVDFYFDYW 
               
               
                   
                   
                 GQGTTVTGGGSGGGSGGGSGGGSELVLTQSPKFMSTSVGDRVSVTCKASQNVGTNV 
               
               
                   
                   
                 AWYQQKPGQSPKPLIYSATYRNSGVPDRFTGSGSGTDFTLTITNVQSKDLADYFCQ 
               
               
                   
                   
                 YNRYPYTSFFFTKLEIKRRSKIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPG 
               
               
                   
                   
                 PSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRK 
               
               
                   
                   
                 HYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRG 
               
               
                   
                   
                 RDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTA 
               
               
                   
                   
                 TKDTYDALHMQALPPR 
               
               
                   
               
               
                 mCAR2 
                 111 
                 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHS 
               
               
                 scFv 
                   
                 GVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSG 
               
               
                   
                   
                 SGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRK 
               
               
                   
                   
                 GLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHY 
               
               
                   
                   
                 YYGGSYAMDYWGQGTSVTVSSE 
               
               
                   
               
               
                 mCAR2 
                 112 
                 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHS 
               
               
                 CAR-aa 
                   
                 GVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSG 
               
               
                   
                   
                 SGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRK 
               
               
                   
                   
                 GLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIY 
               
               
                   
                   
                 YCAKHYYYGGSYAMDYWGQGTSVTVSSESKYGPPCPPCPMFWVLVVVGGVLACYSL 
               
               
                   
                   
                 LVTVAFIIFWVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFEEEEGGCELRVKF 
               
               
                   
                   
                 SRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYN 
               
               
                   
                   
                 ELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRL 
               
               
                   
               
               
                 mCAR2 
                 113 
                 DIQMTQTT SSLSASLGDR VTISCRASQD ISKYLNWYQQ KPDGTVKLLI 
               
               
                 Full-aa 
                   
                 YHTSRLHSGV PSRFSGSGSG TDYSLTISNL EQEDIATYFC QQGNTLPYTF 
               
               
                   
                   
                 GGGTKLEITG STSGSGKPGS GEGSTKGEVK LQESGPGLVA PSQSLSVTCT 
               
               
                   
                   
                 VSGVSLPDYG VSWIRQPPRK GLEWLGVIWG SETTYYNSAL KSRLTIIKDN 
               
               
                   
                   
                 SKSQVFLKMN SLQTDDTAIY YCAKHYYYGG SYAMDYWGQG TSVTVSSESK 
               
               
                   
                   
                 YGPPCPPCPM FWVLVVVGGV LACYSLLVTV 
               
               
                   
                   
                 AFIIFWVKRG RKKLLYIFKQ PFMRPVQTTQ EEDGCSCRFE EEEGGCELRV 
               
               
                   
                   
                 KFSRSADAPA YQQGQNQLYN ELNLGRREEY DVLDKRRGRD PEMGGKPRRK 
               
               
                   
                   
                 NPQEGLYNEL QKDKMAEAYS EIGMKGERRR GKGHDGLYQG LSTATKDTYD 
               
               
                   
                   
                 ALHMQALPPR LEGGGEGRGS LLTCGDVEEN PGPRMLLLVT SLLLCELPHP 
               
               
                   
                   
                 AFLLIPRKVC NGIGIGEFKD SLSINATNIK HFKNCTSISG DLHILPVAFR 
               
               
                   
                   
                 GDSFTHTPPL DPQELDILKT VKEITGFLLI QAWPENRTDL HAFENLEIIR 
               
               
                   
                   
                 GRTKQHGQFS LAVVSLNITS LGLRSLKEIS DGDVIISGNK NLCYANTINW 
               
               
                   
                   
                 KKLFGTSGQK TKIISNRGEN SCKATGQVCH ALCSPEGCWG PEPRDCVSCR 
               
               
                   
                   
                 NVSRGRECVD KCNLLEGEPR EFVENSECIQ CHPECLPQAM NITCTGRGPD 
               
               
                   
                   
                 NCIQCAHYID GPHCVKTCPA GVMGENNTLV WKYADAGHVC HLCHPNCTYG 
               
               
                   
                   
                 CTGPGLEGCP TNGPKIPSIA TGMVGALLLL LVVALGIGLF M 
               
               
                   
               
               
                 mCAR3 
                 114 
                 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHS 
               
               
                 scFv 
                   
                 GVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSG 
               
               
                   
                   
                 SGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRK 
               
               
                   
                   
                 GLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHY 
               
               
                   
                   
                 YYGGSYAMDYWGQGTSVTVSS 
               
               
                   
               
               
                 mCAR3 
                 115 
                 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHS 
               
               
                 Full-aa 
                   
                 GVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSG 
               
               
                   
                   
                 SGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRK 
               
               
                   
                   
                 GLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHY 
               
               
                   
                   
                 YYGGSYAMDYWGQGTSVTVSSAAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPL 
               
               
                   
                   
                 FPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGP 
               
               
                   
                   
                 TRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDK 
               
               
                   
                   
                 RRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGL 
               
               
                   
                   
                 STATKDTYDALHMQALPPR 
               
               
                   
               
               
                 SSJ25-C1 
                   
                 QVQLLESGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIYPGDG 
               
               
                 VH 
                   
                 DTNYNGKFKGQATLTADKSSSTAYMQLSGLTSEDSAVYSCARKTISSVVDFYFDYW 
               
               
                 sequence 
                   
                 GQGTTVT 
               
               
                   
               
               
                 SSJ25-C1 
                   
                 ELVLTQSPKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKPLIYSATYRNS 
               
               
                 VL 
                   
                 GVPDRFTGSGSGTDFTLTITNVQSKDLADYFYFCQYNRYPYTSGGGTKLEIKRRS 
               
               
                 sequence 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Heavy Chain Variable Domain CDRs 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Candidate 
                 FW 
                 HCDR1 
                 ID 
                 HCDR2 
                 ID 
                 HCDR3 
                 ID 
               
               
                   
               
               
                 murine_CART19 
                   
                 GVSLPDYGVS 
                 19 
                 VIWGSETTYYNSALKS 
                 20 
                 HYYYGGSYAMDY 
                 24 
               
               
                   
               
               
                 humanized_CART19 a 
                 VH4 
                 GVSLPDYGVS 
                 19 
                 VIWGSETTYYSSSLKS 
                 21 
                 HYYYGGSYAMDY 
                 24 
               
               
                   
               
               
                 humanized_CART19 b 
                 VH4 
                 GVSLPDYGVS 
                 19 
                 VIWGSETTYYQSSLKS 
                 22 
                 HYYYGGSYAMDY 
                 24 
               
               
                   
               
               
                 humanized_CART19 c 
                 VH4 
                 GVSLPDYGVS 
                 19 
                 VIWGSETTYYNSSLKS 
                 23 
                 HYYYGGSYAMDY 
                 24 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Light Chain Variable Domain CDRs 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Candidate 
                 FW 
                 LCDR1 
                 ID 
                 LCDR2 
                 ID 
                 LCDR3 
                 ID 
               
               
                   
               
               
                 murine_CART19 
                   
                 RASQDISKYLN 
                 25 
                 HTSRLHS 
                 26 
                 QQGNTLPYT 
                 27 
               
               
                   
               
               
                 humanized_CART19 a 
                 VK3 
                 RASQDISKYLN 
                 25 
                 HTSRLHS 
                 26 
                 QQGNTLPYT 
                 27 
               
               
                   
               
               
                 humanized_CART19 b 
                 VK3 
                 RASQDISKYLN 
                 25 
                 HTSRLHS 
                 26 
                 QQGNTLPYT 
                 27 
               
               
                   
               
               
                 humanized_CART19 c 
                 VK3 
                 RASQDISKYLN 
                 25 
                 HTSRLHS 
                 26 
                 QQGNTLPYT 
                 27 
               
               
                   
               
            
           
         
       
     
     Provided herein are CD19 inhibitors and combination therapies. In some embodiments, the CD19 inhibitor (e.g., a cell therapy, e.g., a CD19-expressing CAR, or an antibody) is administered in combination with a B cell inhibitor, e.g., one or more inhibitors of CD10, CD19, CD20, CD22, CD34, CD123, FLT-3, or ROR1. A CD19 inhibitor includes but is not limited to a CD19 CAR-expressing cell, e.g., a CD19 CART cell, or an anti-CD19 antibody (e.g., an anti-CD19 mono- or bispecific antibody) or a fragment or conjugate thereof. In an embodiment, the CD19 inhibitor is administered in combination with a B-cell inhibitor, e.g., a CAR-expressing cell described herein. 
     In some other embodiments, the CD19 inhibitor is administered in combination with a B-cell inhibitor, and their use in medicaments or methods for treating, among other diseases, cancer or any malignancy or autoimmune diseases involving cells or tissues which express CD19. 
     Numerous CD19 CAR-expressing cells are described in this disclosure. For instance, in some embodiments, a CD19 inhibitor includes an anti-CD19 CAR-expressing cell, e.g., CART, e.g., a cell expressing an anti-CD19 CAR construct described in Table 2, e.g., CTL119, or encoded by a CD19 binding CAR comprising a scFv, CDRs, or VH and VL chains described in Tables 2, 4, or 5. For example, an anti-CD19 CAR-expressing cell, e.g., CART, is a generated by engineering a CD19-CAR (that comprises a CD19 binding domain) into a cell (e.g., a T cell or NK cell), e.g., for administration in combination with a CAR-expressing cell described herein. Also provided herein are methods of use of the CAR-expressing cells described herein for adoptive therapy. 
     BCMA Binding Domains and CARs 
     In embodiments the BCMA CAR comprises an anti-BCMA binding domain (e.g., human or humanized anti-BCMA binding domain), a transmembrane domain, and an intracellular signaling domain, and wherein said anti-BCMA binding domain comprises a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) of any anti-BMCA heavy chain binding domain amino acid sequences listed in Table 4D or 4E. 
     In one embodiment, the anti-BCMA binding domain comprises a light chain variable region described herein (e.g., in Table 4D or 4E) and/or a heavy chain variable region described herein (e.g., in Table 4D or 4E). 
     In one embodiment, the encoded anti-BCMA binding domain is a scFv comprising a light chain and a heavy chain of an amino acid sequence of Table 4D or 4E. 
     In an embodiment, the human or humanized anti-BCMA binding domain (e.g., an scFv) comprises: a light chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of a light chain variable region provided in Table 4D or 4E, or a sequence with at least 95% (e.g., 95-99%) identity thereof; and/or a heavy chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of a heavy chain variable region provided in Table 4D or 4E, or a sequence with at least 95% (e.g., 95-99%) identity thereof. 
     
       
         
           
               
             
               
                 TABLE 4D 
               
             
            
               
                   
               
               
                 Amino Acid and Nucleic Acid Sequences of exemplary anti-BCMA scFv 
               
               
                 domains and BCMA CAR molecules 
               
            
           
           
               
               
               
            
               
                 Name/ 
                 SEQ 
                   
               
               
                 Description 
                 ID NO: 
                 Sequence 
               
               
                   
               
            
           
           
               
            
               
                 139109 
               
            
           
           
               
               
               
            
               
                 139109-aa 
                 1400 
                 EVQLVESGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGLEWV 
               
               
                 ScFv 
                   
                 SGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDTAIYYCS 
               
               
                 domain 
                   
                 AHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGSDIQLTQSPSSLS 
               
               
                   
                   
                 ASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPS 
               
               
                   
                   
                 RFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPYTFGQGTKVEIK 
               
               
                   
               
               
                 139109-nt 
                 1401 
                 GAAGTGCAATTGGTGGAATCAGGGGGAGGACTTGTGCAGCCTGGAGGA 
               
               
                 ScFv 
                   
                 TCGCTGAGACTGTCATGTGCCGTGTCCGGCTTTGCCCTGTCCAACCAC 
               
               
                 domain 
                   
                 GGGATGTCCTGGGTCCGCCGCGCGCCTGGAAAGGGCCTCGAATGGGTG 
               
               
                   
                   
                 TCGGGTATTGTGTACAGCGGTAGCACCTACTATGCCGCATCCGTGAAG 
               
               
                   
                   
                 GGGAGATTCACCATCAGCCGGGACAACTCCAGGAACACTCTGTACCTC 
               
               
                   
                   
                 CAAATGAATTCGCTGAGGCCAGAGGACACTGCCATCTACTACTGCTCC 
               
               
                   
                   
                 GCGCATGGCGGAGAGTCCGACGTCTGGGGACAGGGGACCACCGTGACC 
               
               
                   
                   
                 GTGTCTAGCGCGTCCGGCGGAGGCGGCAGCGGGGGTCGGGCATCAGGG 
               
               
                   
                   
                 GGCGGCGGATCGGACATCCAGCTCACCCAGTCCCCGAGCTCGCTGTCC 
               
               
                   
                   
                 GCCTCCGTGGGAGATCGGGTCACCATCACGTGCCGCGCCAGCCAGTCG 
               
               
                   
                   
                 ATTTCCTCCTACCTGAACTGGTACCAACAGAAGCCCGGAAAAGCCCCG 
               
               
                   
                   
                 AAGCTTCTCATCTACGCCGCCTCGAGCCTGCAGTCAGGAGTGCCCTCA 
               
               
                   
                   
                 CGGTTCTCCGGCTCCGGTTCCGGTACTGATTTCACCCTGACCATTTCC 
               
               
                   
                   
                 TCCCTGCAACCGGAGGACTTCGCTACTTACTACTGCCAGCAGTCGTAC 
               
               
                   
                   
                 TCCACCCCCTACACTTTCGGACAAGGCACCAAGGTCGAAATCAAG 
               
               
                   
               
               
                 139109-aa 
                 1402 
                 EVQLVESGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGLEWV 
               
               
                 VH 
                   
                 SGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDTAIYYCS 
               
               
                   
                   
                 AHGGESDVWGQGTTVTVSS 
               
               
                   
               
               
                 139109-aa 
                 1403 
                 DIQLTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLI 
               
               
                 VL 
                   
                 YAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPY 
               
               
                   
                   
                 TFGQGTKVEIK 
               
               
                   
               
               
                 139109-aa 
                 1404 
                 MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAVSGF 
               
               
                 Full CAR 
                   
                 ALSNHGMSWVRRAPGKGLEWVSGIVYSGSTYYAASVKGRFTISRDNSR 
               
               
                   
                   
                 NTLYLQMNSLRPEDTAIYYCSAHGGESDVWGQGTTVTVSSASGGGGSG 
               
               
                   
                   
                 GRASGGGGSDIQLTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQK 
               
               
                   
                   
                 PGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
               
               
                   
                   
                 CQQSYSTPYTFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACR 
               
               
                   
                   
                 PAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKL 
               
               
                   
                   
                 LYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAY 
               
               
                   
                   
                 KQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNE 
               
               
                   
                   
                 LQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQAL 
               
               
                   
                   
                 PPR 
               
               
                   
               
               
                 139109-nt 
                 1405 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCGAAGTGCAATTGGTGGAATCAGGGGGAGGACTT 
               
               
                   
                   
                 GTGCAGCCTGGAGGATCGCTGAGACTGTCATGTGCCGTGTCCGGCTTT 
               
               
                   
                   
                 GCCCTGTCCAACCACGGGATGTCCTGGGTCCGCCGCGCGCCTGGAAAG 
               
               
                   
                   
                 GGCCTCGAATGGGTGTCGGGTATTGTGTACAGCGGTAGCACCTACTAT 
               
               
                   
                   
                 GCCGCATCCGTGAAGGGGAGATTCACCATCAGCCGGGACAACTCCAGG 
               
               
                   
                   
                 AACACTCTGTACCTCCAAATGAATTCGCTGAGGCCAGAGGACACTGCC 
               
               
                   
                   
                 ATCTACTACTGCTCCGCGCATGGCGGAGAGTCCGACGTCTGGGGACAG 
               
               
                   
                   
                 GGGACCACCGTGACCGTGTCTAGCGCGTCCGGCGGAGGCGGCAGCGGG 
               
               
                   
                   
                 GGTCGGGCATCAGGGGGCGGCGGATCGGACATCCAGCTCACCCAGTCC 
               
               
                   
                   
                 CCGAGCTCGCTGTCCGCCTCCGTGGGAGATCGGGTCACCATCACGTGC 
               
               
                   
                   
                 CGCGCCAGCCAGTCGATTTCCTCCTACCTGAACTGGTACCAACAGAAG 
               
               
                   
                   
                 CCCGGAAAAGCCCCGAAGCTTCTCATCTACGCCGCCTCGAGCCTGCAG 
               
               
                   
                   
                 TCAGGAGTGCCCTCACGGTTCTCCGGCTCCGGTTCCGGTACTGATTTC 
               
               
                   
                   
                 ACCCTGACCATTTCCTCCCTGCAACCGGAGGACTTCGCTACTTACTAC 
               
               
                   
                   
                 TGCCAGCAGTCGTACTCCACCCCCTACACTTTCGGACAAGGCACCAAG 
               
               
                   
                   
                 GTCGAAATCAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCT 
               
               
                   
                   
                 CCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGA 
               
               
                   
                   
                 CCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGC 
               
               
                   
                   
                 GATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTG 
               
               
                   
                   
                 CTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTG 
               
               
                   
                   
                 CTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAA 
               
               
                   
                   
                 GAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGC 
               
               
                   
                   
                 TGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTAC 
               
               
                   
                   
                 AAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGA 
               
               
                   
                   
                 GAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATG 
               
               
                   
                   
                 GGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAG 
               
               
                   
                   
                 CTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAA 
               
               
                   
                   
                 GGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTC 
               
               
                   
                   
                 AGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTG 
               
               
                   
                   
                 CCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139103 
               
            
           
           
               
               
               
            
               
                 139103-aa 
                 1406 
                 QVQLVESGGGLVQPGRSLRLSCAASGFTFSNYAMSWVRQAPGKGLGWV 
               
               
                 ScFv 
                   
                 SGISRSGENTYYADSVKGRFTISRDNSKNTLYLQMNSLRDEDTAVYYC 
               
               
                 domain 
                   
                 ARSPAHYYGGMDVWGQGTTVTVSSASGGGGSGGRASGGGGSDIVLTQS 
               
               
                   
                   
                 PGTLSLSPGERATLSCRASQSISSSFLAWYQQKPGQAPRLLIYGASRR 
               
               
                   
                   
                 ATGIPDRFSGSGSGTDFTLTISRLEPEDSAVYYCQQYHSSPSWTFGQG 
               
               
                   
                   
                 TKLEIK 
               
               
                   
               
               
                 139103-nt 
                 1407 
                 CAAGTGCAACTCGTGGAATCTGGTGGAGGACTCGTGCAACCCGGAAGA 
               
               
                 ScFv 
                   
                 TCGCTTAGACTGTCGTGTGCCGCCAGCGGGTTCACTTTCTCGAACTAC 
               
               
                 domain 
                   
                 GCGATGTCCTGGGTCCGCCAGGCACCCGGAAAGGGACTCGGTTGGGTG 
               
               
                   
                   
                 TCCGGCATTTCCCGGTCCGGCGAAAATACCTACTACGCCGACTCCGTG 
               
               
                   
                   
                 AAGGGCCGCTTCACCATCTCAAGGGACAACAGCAAAAACACCCTGTAC 
               
               
                   
                   
                 TTGCAAATGAACTCCCTGCGGGATGAAGATACAGCCGTGTACTATTGC 
               
               
                   
                   
                 GCCCGGTCGCCTGCCCATTACTACGGCGGAATGGACGTCTGGGGACAG 
               
               
                   
                   
                 GGAACCACTGTGACTGTCAGCAGCGCGTCGGGTGGCGGCGGCTCAGGG 
               
               
                   
                   
                 GGTCGGGCCTCCGGGGGGGGAGGGTCCGACATCGTGCTGACCCAGTCC 
               
               
                   
                   
                 CCGGGAACCCTGAGCCTGAGCCCGGGAGAGCGCGCGACCCTGTCATGC 
               
               
                   
                   
                 CGGGCATCCCAGAGCATTAGCTCCTCCTTTCTCGCCTGGTATCAGCAG 
               
               
                   
                   
                 AAGCCCGGACAGGCCCCGAGGCTGCTGATCTACGGCGCTAGCAGAAGG 
               
               
                   
                   
                 GCTACCGGAATCCCAGACCGGTTCTCCGGCTCCGGTTCCGGGACCGAT 
               
               
                   
                   
                 TTCACCCTTACTATCTCGCGCCTGGAACCTGAGGACTCCGCCGTCTAC 
               
               
                   
                   
                 TACTGCCAGCAGTACCACTCATCCCCGTCGTGGACGTTCGGACAGGGC 
               
               
                   
                   
                 ACCAAGCTGGAGATTAAG 
               
               
                   
               
               
                 139103-aa 
                 1408 
                 QVQLVESGGGLVQPGRSLRLSCAASGFTFSNYAMSWVRQAPGKGLGWV 
               
               
                 VH 
                   
                 SGISRSGENTYYADSVKGRFTISRDNSKNTLYLQMNSLRDEDTAVYYC 
               
               
                   
                   
                 ARSPAHYYGGMDVWGQGTTVTVSS 
               
               
                   
               
               
                 139103-aa 
                 1409 
                 DIVLTQSPGTLSLSPGERATLSCRASQSISSSFLAWYQQKPGQAPRLL 
               
               
                 VL 
                   
                 IYGASRRATGIPDRFSGSGSGTDFTLTISRLEPEDSAVYYCQQYHSSP 
               
               
                   
                   
                 SWTFGQGTKLEIK 
               
               
                   
               
               
                 139103-aa 
                 1410 
                 MALPVTALLLPLALLLHAARPQVQLVESGGGLVQPGRSLRLSCAASGF 
               
               
                 Full CAR 
                   
                 TFSNYAMSWVRQAPGKGLGWVSGISRSGENTYYADSVKGRFTISRDNS 
               
               
                   
                   
                 KNTLYLQMNSLRDEDTAVYYCARSPAHYYGGMDVWGQGTTVTVSSASG 
               
               
                   
                   
                 GGGSGGRASGGGGSDIVLTQSPGTLSLSPGERATLSCRASQSISSSFL 
               
               
                   
                   
                 AWYQQKPGQAPRLLIYGASRRATGIPDRFSGSGSGTDFTLTISRLEPE 
               
               
                   
                   
                 DSAVYYCQQYHSSPSWTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLS 
               
               
                   
                   
                 LRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYC 
               
               
                   
                   
                 KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSR 
               
               
                   
                   
                 SADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNP 
               
               
                   
                   
                 QEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYD 
               
               
                   
                   
                 ALHMQALPPR 
               
               
                   
               
               
                 139103-nt 
                 1411 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCCAAGTGCAACTCGTGGAATCTGGTGGAGGACTC 
               
               
                   
                   
                 GTGCAACCCGGAAGATCGCTTAGACTGTCGTGTGCCGCCAGCGGGTTC 
               
               
                   
                   
                 ACTTTCTCGAACTACGCGATGTCCTGGGTCCGCCAGGCACCCGGAAAG 
               
               
                   
                   
                 GGACTCGGTTGGGTGTCCGGCATTTCCCGGTCCGGCGAAAATACCTAC 
               
               
                   
                   
                 TACGCCGACTCCGTGAAGGGCCGCTTCACCATCTCAAGGGACAACAGC 
               
               
                   
                   
                 AAAAACACCCTGTACTTGCAAATGAACTCCCTGCGGGATGAAGATACA 
               
               
                   
                   
                 GCCGTGTACTATTGCGCCCGGTCGCCTGCCCATTACTACGGCGGAATG 
               
               
                   
                   
                 GACGTCTGGGGACAGGGAACCACTGTGACTGTCAGCAGCGCGTCGGGT 
               
               
                   
                   
                 GGCGGCGGCTCAGGGGGTCGGGCCTCCGGGGGGGGAGGGTCCGACATC 
               
               
                   
                   
                 GTGCTGACCCAGTCCCCGGGAACCCTGAGCCTGAGCCCGGGAGAGCGC 
               
               
                   
                   
                 GCGACCCTGTCATGCCGGGCATCCCAGAGCATTAGCTCCTCCTTTCTC 
               
               
                   
                   
                 GCCTGGTATCAGCAGAAGCCCGGACAGGCCCCGAGGCTGCTGATCTAC 
               
               
                   
                   
                 GGCGCTAGCAGAAGGGCTACCGGAATCCCAGACCGGTTCTCCGGCTCC 
               
               
                   
                   
                 GGTTCCGGGACCGATTTCACCCTTACTATCTCGCGCCTGGAACCTGAG 
               
               
                   
                   
                 GACTCCGCCGTCTACTACTGCCAGCAGTACCACTCATCCCCGTCGTGG 
               
               
                   
                   
                 ACGTTCGGACAGGGCACCAAGCTGGAGATTAAGACCACTACCCCAGCA 
               
               
                   
                   
                 CCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCC 
               
               
                   
                   
                 CTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACC 
               
               
                   
                   
                 CGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCT 
               
               
                   
                   
                 GGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGT 
               
               
                   
                   
                 AAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATG 
               
               
                   
                   
                 AGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTC 
               
               
                   
                   
                 CCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGC 
               
               
                   
                   
                 AGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAAC 
               
               
                   
                   
                 GAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGG 
               
               
                   
                   
                 AGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCC 
               
               
                   
                   
                 CAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCC 
               
               
                   
                   
                 TATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCAC 
               
               
                   
                   
                 GACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGAC 
               
               
                   
                   
                 GCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139105 
               
            
           
           
               
               
               
            
               
                 139105-aa 
                 1412 
                 QVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWV 
               
               
                 ScFv 
                   
                 SGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYC 
               
               
                 domain 
                   
                 SVHSFLAYWGQGTLVTVSSASGGGGSGGRASGGGGSDIVMTQTPLSLP 
               
               
                   
                   
                 VTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRA 
               
               
                   
                   
                 SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPYTFGQGTK 
               
               
                   
                   
                 VEIK 
               
               
                   
               
               
                 139105-nt 
                 1413 
                 CAAGTGCAACTCGTCGAATCCGGTGGAGGTCTGGTCCAACCTGGTAGA 
               
               
                 ScFv 
                   
                 AGCCTGAGACTGTCGTGTGCGGCCAGCGGATTCACCTTTGATGACTAT 
               
               
                 domain 
                   
                 GCTATGCACTGGGTGCGGCAGGCCCCAGGAAAGGGCCTGGAATGGGTG 
               
               
                   
                   
                 TCGGGAATTAGCTGGAACTCCGGGTCCATTGGCTACGCCGACTCCGTG 
               
               
                   
                   
                 AAGGGCCGCTTCACCATCTCCCGCGACAACGCAAAGAACTCCCTGTAC 
               
               
                   
                   
                 TTGCAAATGAACTCGCTCAGGGCTGAGGATACCGCGCTGTACTACTGC 
               
               
                   
                   
                 TCCGTGCATTCCTTCCTGGCCTACTGGGGACAGGGAACTCTGGTCACC 
               
               
                   
                   
                 GTGTCGAGCGCCTCCGGCGGCGGGGGCTCGGGTGGACGGGCCTCGGGC 
               
               
                   
                   
                 GGAGGGGGGTCCGACATCGTGATGACCCAGACCCCGCTGAGCTTGCCC 
               
               
                   
                   
                 GTGACTCCCGGAGAGCCTGCATCCATCTCCTGCCGGTCATCCCAGTCC 
               
               
                   
                   
                 CTTCTCCACTCCAACGGATACAACTACCTCGACTGGTACCTCCAGAAG 
               
               
                   
                   
                 CCGGGACAGAGCCCTCAGCTTCTGATCTACCTGGGGTCAAATAGAGCC 
               
               
                   
                   
                 TCAGGAGTGCCGGATCGGTTCAGCGGATCTGGTTCGGGAACTGATTTC 
               
               
                   
                   
                 ACTCTGAAGATTTCCCGCGTGGAAGCCGAGGACGTGGGCGTCTACTAC 
               
               
                   
                   
                 TGTATGCAGGCGCTGCAGACCCCCTATACCTTCGGCCAAGGGACGAAA 
               
               
                   
                   
                 GTGGAGATCAAG 
               
               
                   
               
               
                 139105-aa 
                 1414 
                 QVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWV 
               
               
                 VH 
                   
                 SGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYC 
               
               
                   
                   
                 SVHSFLAYWGQGTLVTVSS 
               
               
                   
               
               
                 139105-aa 
                 1415 
                 DIVMTQTPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQS 
               
               
                 VL 
                   
                 PQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQA 
               
               
                   
                   
                 LQTPYTFGQGTKVEIK 
               
               
                   
               
               
                 139105-aa 
                 1416 
                 MALPVTALLLPLALLLHAARPQVQLVESGGGLVQPGRSLRLSCAASGF 
               
               
                 Full CAR 
                   
                 TFDDYAMHWVRQAPGKGLEWVSGISWNSGSIGYADSVKGRFTISRDNA 
               
               
                   
                   
                 KNSLYLQMNSLRAEDTALYYCSVHSFLAYWGQGTLVTVSSASGGGGSG 
               
               
                   
                   
                 GRASGGGGSDIVMTQTPLSLPVTPGEPASISCRSSQSLLHSNGYNYLD 
               
               
                   
                   
                 WYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAED 
               
               
                   
                   
                 VGVYYCMQALQTPYTFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLR 
               
               
                   
                   
                 PEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKR 
               
               
                   
                   
                 GRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSA 
               
               
                   
                   
                 DAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQE 
               
               
                   
                   
                 GLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDAL 
               
               
                   
                   
                 HMQALPPR 
               
               
                   
               
               
                 139105-nt 
                 1417 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCCAAGTGCAACTCGTCGAATCCGGTGGAGGTCTG 
               
               
                   
                   
                 GTCCAACCTGGTAGAAGCCTGAGACTGTCGTGTGCGGCCAGCGGATTC 
               
               
                   
                   
                 ACCTTTGATGACTATGCTATGCACTGGGTGCGGCAGGCCCCAGGAAAG 
               
               
                   
                   
                 GGCCTGGAATGGGTGTCGGGAATTAGCTGGAACTCCGGGTCCATTGGC 
               
               
                   
                   
                 TACGCCGACTCCGTGAAGGGCCGCTTCACCATCTCCCGCGACAACGCA 
               
               
                   
                   
                 AAGAACTCCCTGTACTTGCAAATGAACTCGCTCAGGGCTGAGGATACC 
               
               
                   
                   
                 GCGCTGTACTACTGCTCCGTGCATTCCTTCCTGGCCTACTGGGGACAG 
               
               
                   
                   
                 GGAACTCTGGTCACCGTGTCGAGCGCCTCCGGCGGCGGGGGCTCGGGT 
               
               
                   
                   
                 GGACGGGCCTCGGGCGGAGGGGGGTCCGACATCGTGATGACCCAGACC 
               
               
                   
                   
                 CCGCTGAGCTTGCCCGTGACTCCCGGAGAGCCTGCATCCATCTCCTGC 
               
               
                   
                   
                 CGGTCATCCCAGTCCCTTCTCCACTCCAACGGATACAACTACCTCGAC 
               
               
                   
                   
                 TGGTACCTCCAGAAGCCGGGACAGAGCCCTCAGCTTCTGATCTACCTG 
               
               
                   
                   
                 GGGTCAAATAGAGCCTCAGGAGTGCCGGATCGGTTCAGCGGATCTGGT 
               
               
                   
                   
                 TCGGGAACTGATTTCACTCTGAAGATTTCCCGCGTGGAAGCCGAGGAC 
               
               
                   
                   
                 GTGGGCGTCTACTACTGTATGCAGGCGCTGCAGACCCCCTATACCTTC 
               
               
                   
                   
                 GGCCAAGGGACGAAAGTGGAGATCAAGACCACTACCCCAGCACCGAGG 
               
               
                   
                   
                 CCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGT 
               
               
                   
                   
                 CCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGT 
               
               
                   
                   
                 CTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACT 
               
               
                   
                   
                 TGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGC 
               
               
                   
                   
                 GGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCT 
               
               
                   
                   
                 GTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAG 
               
               
                   
                   
                 GAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCA 
               
               
                   
                   
                 GATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTC 
               
               
                   
                   
                 AATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGA 
               
               
                   
                   
                 CGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAG 
               
               
                   
                   
                 GGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGC 
               
               
                   
                   
                 GAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGA 
               
               
                   
                   
                 CTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTT 
               
               
                   
                   
                 CACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139111 
               
            
           
           
               
               
               
            
               
                 139111-aa 
                 1418 
                 EVQLLESGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGLEWV 
               
               
                 ScFv 
                   
                 SGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDTAIYYCS 
               
               
                 domain 
                   
                 AHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGSDIVMTQTPLSLS 
               
               
                   
                   
                 VTPGQPASISCKSSQSLLRNDGKTPLYWYLQKAGQPPQLLIYEVSNRF 
               
               
                   
                   
                 SGVPDRFSGSGSGTDFTLKISRVEAEDVGAYYCMQNIQFPSFGGGTKL 
               
               
                   
                   
                 EIK 
               
               
                   
               
               
                 139111-nt 
                 1419 
                 GAAGTGCAATTGTTGGAATCTGGAGGAGGACTTGTGCAGCCTGGAGGA 
               
               
                 ScFv 
                   
                 TCACTGAGACTTTCGTGTGCGGTGTCAGGCTTCGCCCTGAGCAACCAC 
               
               
                 domain 
                   
                 GGCATGAGCTGGGTGCGGAGAGCCCCGGGGAAGGGTCTGGAATGGGTG 
               
               
                   
                   
                 TCCGGGATCGTCTACTCCGGTTCAACTTACTACGCCGCAAGCGTGAAG 
               
               
                   
                   
                 GGTCGCTTCACCATTTCCCGCGATAACTCCCGGAACACCCTGTACCTC 
               
               
                   
                   
                 CAAATGAACTCCCTGCGGCCCGAGGACACCGCCATCTACTACTGTTCC 
               
               
                   
                   
                 GCGCATGGAGGAGAGTCCGATGTCTGGGGACAGGGCACTACCGTGACC 
               
               
                   
                   
                 GTGTCGAGCGCCTCGGGGGGAGGAGGCTCCGGCGGTCGCGCCTCCGGG 
               
               
                   
                   
                 GGGGGTGGCAGCGACATTGTGATGACGCAGACTCCACTCTCGCTGTCC 
               
               
                   
                   
                 GTGACCCCGGGACAGCCCGCGTCCATCTCGTGCAAGAGCTCCCAGAGC 
               
               
                   
                   
                 CTGCTGAGGAACGACGGAAAGACTCCTCTGTATTGGTACCTCCAGAAG 
               
               
                   
                   
                 GCTGGACAGCCCCCGCAACTGCTCATCTACGAAGTGTCAAATCGCTTC 
               
               
                   
                   
                 TCCGGGGTGCCGGATCGGTTTTCCGGCTCGGGATCGGGCACCGACTTC 
               
               
                   
                   
                 ACCCTGAAAATCTCCAGGGTCGAGGCCGAGGACGTGGGAGCCTACTAC 
               
               
                   
                   
                 TGCATGCAAAACATCCAGTTCCCTTCCTTCGGCGGCGGCACAAAGCTG 
               
               
                   
                   
                 GAGATTAAG 
               
               
                   
               
               
                 139111-aa 
                 1420 
                 EVQLLESGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGLEWV 
               
               
                 VH 
                   
                 SGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDTAIYYCS 
               
               
                   
                   
                 AHGGESDVWGQGTTVTVSS 
               
               
                   
               
               
                 139111-aa 
                 1421 
                 DIVMTQTPLSLSVTPGQPASISCKSSQSLLRNDGKTPLYWYLQKAGQP 
               
               
                 VL 
                   
                 PQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGAYYCMQN 
               
               
                   
                   
                 IQFPSFGGGTKLEIK 
               
               
                   
               
               
                 139111-aa 
                 1422 
                 MALPVTALLLPLALLLHAARPEVQLLESGGGLVQPGGSLRLSCAVSGF 
               
               
                 Full CAR 
                   
                 ALSNHGMSWVRRAPGKGLEWVSGIVYSGSTYYAASVKGRFTISRDNSR 
               
               
                   
                   
                 NTLYLQMNSLRPEDTAIYYCSAHGGESDVWGQGTTVTVSSASGGGGSG 
               
               
                   
                   
                 GRASGGGGSDIVMTQTPLSLSVTPGQPASISCKSSQSLLRNDGKTPLY 
               
               
                   
                   
                 WYLQKAGQPPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAED 
               
               
                   
                   
                 VGAYYCMQNIQFPSFGGGTKLEIKTTTPAPRPPTPAPTIASQPLSLRP 
               
               
                   
                   
                 EACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRG 
               
               
                   
                   
                 RKKLLYIFKQPFMRPVQTTQEEDGCSCREPEEEEGGCELRVKFSRSAD 
               
               
                   
                   
                 APAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEG 
               
               
                   
                   
                 LYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALH 
               
               
                   
                   
                 MQALPPR 
               
               
                   
               
               
                 139111-nt 
                 1423 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCGAAGTGCAATTGTTGGAATCTGGAGGAGGACTT 
               
               
                   
                   
                 GTGCAGCCTGGAGGATCACTGAGACTTTCGTGTGCGGTGTCAGGCTTC 
               
               
                   
                   
                 GCCCTGAGCAACCACGGCATGAGCTGGGTGCGGAGAGCCCCGGGGAAG 
               
               
                   
                   
                 GGTCTGGAATGGGTGTCCGGGATCGTCTACTCCGGTTCAACTTACTAC 
               
               
                   
                   
                 GCCGCAAGCGTGAAGGGTCGCTTCACCATTTCCCGCGATAACTCCCGG 
               
               
                   
                   
                 AACACCCTGTACCTCCAAATGAACTCCCTGCGGCCCGAGGACACCGCC 
               
               
                   
                   
                 ATCTACTACTGTTCCGCGCATGGAGGAGAGTCCGATGTCTGGGGACAG 
               
               
                   
                   
                 GGCACTACCGTGACCGTGTCGAGCGCCTCGGGGGGAGGAGGCTCCGGC 
               
               
                   
                   
                 GGTCGCGCCTCCGGGGGGGGTGGCAGCGACATTGTGATGACGCAGACT 
               
               
                   
                   
                 CCACTCTCGCTGTCCGTGACCCCGGGACAGCCCGCGTCCATCTCGTGC 
               
               
                   
                   
                 AAGAGCTCCCAGAGCCTGCTGAGGAACGACGGAAAGACTCCTCTGTAT 
               
               
                   
                   
                 TGGTACCTCCAGAAGGCTGGACAGCCCCCGCAACTGCTCATCTACGAA 
               
               
                   
                   
                 GTGTCAAATCGCTTCTCCGGGGTGCCGGATCGGTTTTCCGGCTCGGGA 
               
               
                   
                   
                 TCGGGCACCGACTTCACCCTGAAAATCTCCAGGGTCGAGGCCGAGGAC 
               
               
                   
                   
                 GTGGGAGCCTACTACTGCATGCAAAACATCCAGTTCCCTTCCTTCGGC 
               
               
                   
                   
                 GGCGGCACAAAGCTGGAGATTAAGACCACTACCCCAGCACCGAGGCCA 
               
               
                   
                   
                 CCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCG 
               
               
                   
                   
                 GAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTT 
               
               
                   
                   
                 GACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGC 
               
               
                   
                   
                 GGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGT 
               
               
                   
                   
                 CGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTG 
               
               
                   
                   
                 CAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAG 
               
               
                   
                   
                 GAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGAT 
               
               
                   
                   
                 GCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAAT 
               
               
                   
                   
                 CTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGG 
               
               
                   
                   
                 GACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGC 
               
               
                   
                   
                 CTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAG 
               
               
                   
                   
                 ATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTG 
               
               
                   
                   
                 TACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCAC 
               
               
                   
                   
                 ATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139100 
               
            
           
           
               
               
               
            
               
                 139100-aa 
                 1424 
                 QVQLVQSGAEVRKTGASVKVSCKASGYIFDNFGINWVRQAPGQGLEWM 
               
               
                 ScFv 
                   
                 GWINPKNNNTNYAQKFQGRVTITADESTNTAYMEVSSLRSEDTAVYYC 
               
               
                 domain 
                   
                 ARGPYYYQSYMDVWGQGTMVTVSSASGGGGSGGRASGGGGSDIVMTQT 
               
               
                   
                   
                 PLSLPVTPGEPASISCRSSQSLLHSNGYNYLNWYLQKPGQSPQLLIYL 
               
               
                   
                   
                 GSKRASGVPDRFSGSGSGTDFTLHITRVGAEDVGVYYCMQALQTPYTF 
               
               
                   
                   
                 GQGTKLEIK 
               
               
                   
               
               
                 139100-nt 
                 1425 
                 CAAGTCCAACTCGTCCAGTCCGGCGCAGAAGTCAGAAAAACCGGTGCT 
               
               
                 ScFv 
                   
                 AGCGTGAAAGTGTCCTGCAAGGCCTCCGGCTACATTTTCGATAACTTC 
               
               
                 domain 
                   
                 GGAATCAACTGGGTCAGACAGGCCCCGGGCCAGGGGCTGGAATGGATG 
               
               
                   
                   
                 GGATGGATCAACCCCAAGAACAACAACACCAACTACGCACAGAAGTTC 
               
               
                   
                   
                 CAGGGCCGCGTGACTATCACCGCCGATGAATCGACCAATACCGCCTAC 
               
               
                   
                   
                 ATGGAGGTGTCCTCCCTGCGGTCGGAGGACACTGCCGTGTATTACTGC 
               
               
                   
                   
                 GCGAGGGGCCCATACTACTACCAAAGCTACATGGACGTCTGGGGACAG 
               
               
                   
                   
                 GGAACCATGGTGACCGTGTCATCCGCCTCCGGTGGTGGAGGCTCCGGG 
               
               
                   
                   
                 GGGCGGGCTTCAGGAGGCGGAGGAAGCGATATTGTGATGACCCAGACT 
               
               
                   
                   
                 CCGCTTAGCCTGCCCGTGACTCCTGGAGAACCGGCCTCCATTTCCTGC 
               
               
                   
                   
                 CGGTCCTCGCAATCACTCCTGCATTCCAACGGTTACAACTACCTGAAT 
               
               
                   
                   
                 TGGTACCTCCAGAAGCCTGGCCAGTCGCCCCAGTTGCTGATCTATCTG 
               
               
                   
                   
                 GGCTCGAAGCGCGCCTCCGGGGTGCCTGACCGGTTTAGCGGATCTGGG 
               
               
                   
                   
                 AGCGGCACGGACTTCACTCTCCACATCACCCGCGTGGGAGCGGAGGAC 
               
               
                   
                   
                 GTGGGAGTGTACTACTGTATGCAGGCGCTGCAGACTCCGTACACATTC 
               
               
                   
                   
                 GGACAGGGCACCAAGCTGGAGATCAAG 
               
               
                   
               
               
                 139100-aa 
                 1426 
                 QVQLVQSGAEVRKTGASVKVSCKASGYIFDNFGINWVRQAPGQGLEWM 
               
               
                 VH 
                   
                 GWINPKNNNTNYAQKFQGRVTITADESTNTAYMEVSSLRSEDTAVYYC 
               
               
                   
                   
                 ARGPYYYQSYMDVWGQGTMVTVSS 
               
               
                   
               
               
                 139100-aa 
                 1427 
                 DIVMTQTPLSLPVTPGEPASISCRSSQSLLHSNGYNYLNWYLQKPGQS 
               
               
                 VL 
                   
                 PQLLIYLGSKRASGVPDRFSGSGSGTDFTLHITRVGAEDVGVYYCMQA 
               
               
                   
                   
                 LQTPYTFGQGTKLEIK 
               
               
                   
               
               
                 139100-aa 
                 1428 
                 MALPVTALLLPLALLLHAARPQVQLVQSGAEVRKTGASVKVSCKASGY 
               
               
                 Full CAR 
                   
                 IFDNFGINWVRQAPGQGLEWMGWINPKNNNTNYAQKFQGRVTITADES 
               
               
                   
                   
                 TNTAYMEVSSLRSEDTAVYYCARGPYYYQSYMDVWGQGTMVTVSSASG 
               
               
                   
                   
                 GGGSGGRASGGGGSDIVMTQTPLSLPVTPGEPASISCRSSQSLLHSNG 
               
               
                   
                   
                 YNYLNWYLQKPGQSPQLLIYLGSKRASGVPDRFSGSGSGTDFTLHITR 
               
               
                   
                   
                 VGAEDVGVYYCMQALQTPYTFGQGTKLEIKTTTPAPRPPTPAPTIASQ 
               
               
                   
                   
                 PLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVIT 
               
               
                   
                   
                 LYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVK 
               
               
                   
                   
                 FSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRR 
               
               
                   
                   
                 KNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKD 
               
               
                   
                   
                 TYDALHMQALPPR 
               
               
                   
               
               
                 139100-nt 
                 1429 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCCAAGTCCAACTCGTCCAGTCCGGCGCAGAAGTC 
               
               
                   
                   
                 AGAAAAACCGGTGCTAGCGTGAAAGTGTCCTGCAAGGCCTCCGGCTAC 
               
               
                   
                   
                 ATTTTCGATAACTTCGGAATCAACTGGGTCAGACAGGCCCCGGGCCAG 
               
               
                   
                   
                 GGGCTGGAATGGATGGGATGGATCAACCCCAAGAACAACAACACCAAC 
               
               
                   
                   
                 TACGCACAGAAGTTCCAGGGCCGCGTGACTATCACCGCCGATGAATCG 
               
               
                   
                   
                 ACCAATACCGCCTACATGGAGGTGTCCTCCCTGCGGTCGGAGGACACT 
               
               
                   
                   
                 GCCGTGTATTACTGCGCGAGGGGCCCATACTACTACCAAAGCTACATG 
               
               
                   
                   
                 GACGTCTGGGGACAGGGAACCATGGTGACCGTGTCATCCGCCTCCGGT 
               
               
                   
                   
                 GGTGGAGGCTCCGGGGGGCGGGCTTCAGGAGGCGGAGGAAGCGATATT 
               
               
                   
                   
                 GTGATGACCCAGACTCCGCTTAGCCTGCCCGTGACTCCTGGAGAACCG 
               
               
                   
                   
                 GCCTCCATTTCCTGCCGGTCCTCGCAATCACTCCTGCATTCCAACGGT 
               
               
                   
                   
                 TACAACTACCTGAATTGGTACCTCCAGAAGCCTGGCCAGTCGCCCCAG 
               
               
                   
                   
                 TTGCTGATCTATCTGGGCTCGAAGCGCGCCTCCGGGGTGCCTGACCGG 
               
               
                   
                   
                 TTTAGCGGATCTGGGAGCGGCACGGACTTCACTCTCCACATCACCCGC 
               
               
                   
                   
                 GTGGGAGCGGAGGACGTGGGAGTGTACTACTGTATGCAGGCGCTGCAG 
               
               
                   
                   
                 ACTCCGTACACATTCGGACAGGGCACCAAGCTGGAGATCAAGACCACT 
               
               
                   
                   
                 ACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAG 
               
               
                   
                   
                 CCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCC 
               
               
                   
                   
                 GTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCC 
               
               
                   
                   
                 CCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACT 
               
               
                   
                   
                 CTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAA 
               
               
                   
                   
                 CCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCA 
               
               
                   
                   
                 TGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAA 
               
               
                   
                   
                 TTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAG 
               
               
                   
                   
                 CTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTG 
               
               
                   
                   
                 GACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGA 
               
               
                   
                   
                 AAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATG 
               
               
                   
                   
                 GCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGC 
               
               
                   
                   
                 AAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGAC 
               
               
                   
                   
                 ACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139101 
               
            
           
           
               
               
               
            
               
                 139101-aa 
                 1430 
                 QVQLQESGGGLVQPGGSLRLSCAASGFTFSSDAMTWVRQAPGKGLEWV 
               
               
                 ScFv 
                   
                 SVISGSGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC 
               
               
                 domain 
                   
                 AKLDSSGYYYARGPRYWGQGTLVTVSSASGGGGSGGRASGGGGSDIQL 
               
               
                   
                   
                 TQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYGAS 
               
               
                   
                   
                 TLASGVPARFSGSGSGTHFTLTINSLQSEDSATYYCQQSYKRASFGQG 
               
               
                   
                   
                 TKVEIK 
               
               
                   
               
               
                 139101-nt 
                 1431 
                 CAAGTGCAACTTCAAGAATCAGGCGGAGGACTCGTGCAGCCCGGAGGA 
               
               
                 ScFv 
                   
                 TCATTGCGGCTCTCGTGCGCCGCCTCGGGCTTCACCTTCTCGAGCGAC 
               
               
                 domain 
                   
                 GCCATGACCTGGGTCCGCCAGGCCCCGGGGAAGGGGCTGGAATGGGTG 
               
               
                   
                   
                 TCTGTGATTTCCGGCTCCGGGGGAACTACGTACTACGCCGATTCCGTG 
               
               
                   
                   
                 AAAGGTCGCTTCACTATCTCCCGGGACAACAGCAAGAACACCCTTTAT 
               
               
                   
                   
                 CTGCAAATGAATTCCCTCCGCGCCGAGGACACCGCCGTGTACTACTGC 
               
               
                   
                   
                 GCCAAGCTGGACTCCTCGGGCTACTACTATGCCCGGGGTCCGAGATAC 
               
               
                   
                   
                 TGGGGACAGGGAACCCTCGTGACCGTGTCCTCCGCGTCCGGCGGAGGA 
               
               
                   
                   
                 GGGTCGGGAGGGCGGGCCTCCGGCGGCGGCGGTTCGGACATCCAGCTG 
               
               
                   
                   
                 ACCCAGTCCCCATCCTCACTGAGCGCAAGCGTGGGCGACAGAGTCACC 
               
               
                   
                   
                 ATTACATGCAGGGCGTCCCAGAGCATCAGCTCCTACCTGAACTGGTAC 
               
               
                   
                   
                 CAACAGAAGCCTGGAAAGGCTCCTAAGCTGTTGATCTACGGGGCTTCG 
               
               
                   
                   
                 ACCCTGGCATCCGGGGTGCCCGCGAGGTTTAGCGGAAGCGGTAGCGGC 
               
               
                   
                   
                 ACTCACTTCACTCTGACCATTAACAGCCTCCAGTCCGAGGATTCAGCC 
               
               
                   
                   
                 ACTTACTACTGTCAGCAGTCCTACAAGCGGGCCAGCTTCGGACAGGGC 
               
               
                   
                   
                 ACTAAGGTCGAGATCAAG 
               
               
                   
               
               
                 139101-aa 
                 1432 
                 QVQLQESGGGLVQPGGSLRLSCAASGFTFSSDAMTWVRQAPGKGLEWV 
               
               
                 VH 
                   
                 SVISGSGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC 
               
               
                   
                   
                 AKLDSSGYYYARGPRYWGQGTLVTVSS 
               
               
                   
               
               
                 139101-aa 
                 1433 
                 DIQLTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLI 
               
               
                 VL 
                   
                 YGASTLASGVPARFSGSGSGTHFTLTINSLQSEDSATYYCQQSYKRAS 
               
               
                   
                   
                 FGQGTKVEIK 
               
               
                   
               
               
                 139101-aa 
                 1434 
                 MALPVTALLLPLALLLHAARPQVQLQESGGGLVQPGGSLRLSCAASGF 
               
               
                 Full CAR 
                   
                 TFSSDAMTWVRQAPGKGLEWVSVISGSGGTTYYADSVKGRFTISRDNS 
               
               
                   
                   
                 KNTLYLQMNSLRAEDTAVYYCAKLDSSGYYYARGPRYWGQGTLVTVSS 
               
               
                   
                   
                 ASGGGGSGGRASGGGGSDIQLTQSPSSLSASVGDRVTITCRASQSISS 
               
               
                   
                   
                 YLNWYQQKPGKAPKLLIYGASTLASGVPARFSGSGSGTHFTLTINSLQ 
               
               
                   
                   
                 SEDSATYYCQQSYKRASFGQGTKVEIKTTTPAPRPPTPAPTIASQPLS 
               
               
                   
                   
                 LRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYC 
               
               
                   
                   
                 KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSR 
               
               
                   
                   
                 SADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNP 
               
               
                   
                   
                 QEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYD 
               
               
                   
                   
                 ALHMQALPPR 
               
               
                   
               
               
                 139101-nt 
                 1435 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCCAAGTGCAACTTCAAGAATCAGGCGGAGGACTC 
               
               
                   
                   
                 GTGCAGCCCGGAGGATCATTGCGGCTCTCGTGCGCCGCCTCGGGCTTC 
               
               
                   
                   
                 ACCTTCTCGAGCGACGCCATGACCTGGGTCCGCCAGGCCCCGGGGAAG 
               
               
                   
                   
                 GGGCTGGAATGGGTGTCTGTGATTTCCGGCTCCGGGGGAACTACGTAC 
               
               
                   
                   
                 TACGCCGATTCCGTGAAAGGTCGCTTCACTATCTCCCGGGACAACAGC 
               
               
                   
                   
                 AAGAACACCCTTTATCTGCAAATGAATTCCCTCCGCGCCGAGGACACC 
               
               
                   
                   
                 GCCGTGTACTACTGCGCCAAGCTGGACTCCTCGGGCTACTACTATGCC 
               
               
                   
                   
                 CGGGGTCCGAGATACTGGGGACAGGGAACCCTCGTGACCGTGTCCTCC 
               
               
                   
                   
                 GCGTCCGGCGGAGGAGGGTCGGGAGGGCGGGCCTCCGGCGGCGGCGGT 
               
               
                   
                   
                 TCGGACATCCAGCTGACCCAGTCCCCATCCTCACTGAGCGCAAGCGTG 
               
               
                   
                   
                 GGCGACAGAGTCACCATTACATGCAGGGCGTCCCAGAGCATCAGCTCC 
               
               
                   
                   
                 TACCTGAACTGGTACCAACAGAAGCCTGGAAAGGCTCCTAAGCTGTTG 
               
               
                   
                   
                 ATCTACGGGGCTTCGACCCTGGCATCCGGGGTGCCCGCGAGGTTTAGC 
               
               
                   
                   
                 GGAAGCGGTAGCGGCACTCACTTCACTCTGACCATTAACAGCCTCCAG 
               
               
                   
                   
                 TCCGAGGATTCAGCCACTTACTACTGTCAGCAGTCCTACAAGCGGGCC 
               
               
                   
                   
                 AGCTTCGGACAGGGCACTAAGGTCGAGATCAAGACCACTACCCCAGCA 
               
               
                   
                   
                 CCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCC 
               
               
                   
                   
                 CTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACC 
               
               
                   
                   
                 CGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCT 
               
               
                   
                   
                 GGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGT 
               
               
                   
                   
                 AAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATG 
               
               
                   
                   
                 AGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTC 
               
               
                   
                   
                 CCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGC 
               
               
                   
                   
                 AGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAAC 
               
               
                   
                   
                 GAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGG 
               
               
                   
                   
                 AGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCC 
               
               
                   
                   
                 CAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCC 
               
               
                   
                   
                 TATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCAC 
               
               
                   
                   
                 GACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGAC 
               
               
                   
                   
                 GCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139102 
               
            
           
           
               
               
               
            
               
                 139102-aa 
                 1436 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGITWVRQAPGQGLEWM 
               
               
                 ScFv 
                   
                 GWISAYNGNTNYAQKFQGRVTMTRNTSISTAYMELSSLRSEDTAVYYC 
               
               
                 domain 
                   
                 ARGPYYYYMDVWGKGTMVTVSSASGGGGSGGRASGGGGSEIVMTQSPL 
               
               
                   
                   
                 SLPVTPGEPASISCRSSQSLLYSNGYNYVDWYLQKPGQSPQLLIYLGS 
               
               
                   
                   
                 NRASGVPDRFSGSGSGTDFKLQISRVEAEDVGIYYCMQGRQFPYSFGQ 
               
               
                   
                   
                 GTKVEIK 
               
               
                   
               
               
                 139102-nt 
                 1437 
                 CAAGTCCAACTGGTCCAGAGCGGTGCAGAAGTGAAGAAGCCCGGAGCG 
               
               
                 ScFv 
                   
                 AGCGTGAAAGTGTCCTGCAAGGCTTCCGGGTACACCTTCTCCAACTAC 
               
               
                 domain 
                   
                 GGCATCACTTGGGTGCGCCAGGCCCCGGGACAGGGCCTGGAATGGATG 
               
               
                   
                   
                 GGGTGGATTTCCGCGTACAACGGCAATACGAACTACGCTCAGAAGTTC 
               
               
                   
                   
                 CAGGGTAGAGTGACCATGACTAGGAACACCTCCATTTCCACCGCCTAC 
               
               
                   
                   
                 ATGGAACTGTCCTCCCTGCGGAGCGAGGACACCGCCGTGTACTATTGC 
               
               
                   
                   
                 GCCCGGGGACCATACTACTACTACATGGATGTCTGGGGGAAGGGGACT 
               
               
                   
                   
                 ATGGTCACCGTGTCATCCGCCTCGGGAGGCGGCGGATCAGGAGGACGC 
               
               
                   
                   
                 GCCTCTGGTGGTGGAGGATCGGAGATCGTGATGACCCAGAGCCCTCTC 
               
               
                   
                   
                 TCCTTGCCCGTGACTCCTGGGGAGCCCGCATCCATTTCATGCCGGAGC 
               
               
                   
                   
                 TCCCAGTCACTTCTCTACTCCAACGGCTATAACTACGTGGATTGGTAC 
               
               
                   
                   
                 CTCCAAAAGCCGGGCCAGAGCCCGCAGCTGCTGATCTACCTGGGCTCG 
               
               
                   
                   
                 AACAGGGCCAGCGGAGTGCCTGACCGGTTCTCCGGGTCGGGAAGCGGG 
               
               
                   
                   
                 ACCGACTTCAAGCTGCAAATCTCGAGAGTGGAGGCCGAGGACGTGGGA 
               
               
                   
                   
                 ATCTACTACTGTATGCAGGGCCGCCAGTTTCCGTACTCGTTCGGACAG 
               
               
                   
                   
                 GGCACCAAAGTGGAAATCAAG 
               
               
                   
               
               
                 139102-aa 
                 1438 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGITWVRQAPGQGLEWM 
               
               
                 VH 
                   
                 GWISAYNGNTNYAQKFQGRVTMTRNTSISTAYMELSSLRSEDTAVYYC 
               
               
                   
                   
                 ARGPYYYYMDVWGKGTMVTVSS 
               
               
                   
               
               
                 139102-aa 
                 1439 
                 EIVMTQSPLSLPVTPGEPASISCRSSQSLLYSNGYNYVDWYLQKPGQS 
               
               
                 VL 
                   
                 PQLLIYLGSNRASGVPDRFSGSGSGTDFKLQISRVEAEDVGIYYCMQG 
               
               
                   
                   
                 RQFPYSFGQGTKVEIK 
               
               
                   
               
               
                 139102-aa 
                 1440 
                 MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGASVKVSCKASGY 
               
               
                 Full CAR 
                   
                 TFSNYGITWVRQAPGQGLEWMGWISAYNGNTNYAQKFQGRVTMTRNTS 
               
               
                   
                   
                 ISTAYMELSSLRSEDTAVYYCARGPYYYYMDVWGKGTMVTVSSASGGG 
               
               
                   
                   
                 GSGGRASGGGGSEIVMTQSPLSLPVTPGEPASISCRSSQSLLYSNGYN 
               
               
                   
                   
                 YVDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFKLQISRVE 
               
               
                   
                   
                 AEDVGIYYCMQGRQFPYSFGQGTKVEIKTTTPAPRPPTPAPTIASQPL 
               
               
                   
                   
                 SLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLY 
               
               
                   
                   
                 CKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFS 
               
               
                   
                   
                 RSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKN 
               
               
                   
                   
                 PQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTY 
               
               
                   
                   
                 DALHMQALPPR 
               
               
                   
               
               
                 139102-nt 
                 1441 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCCAAGTCCAACTGGTCCAGAGCGGTGCAGAAGTG 
               
               
                   
                   
                 AAGAAGCCCGGAGCGAGCGTGAAAGTGTCCTGCAAGGCTTCCGGGTAC 
               
               
                   
                   
                 ACCTTCTCCAACTACGGCATCACTTGGGTGCGCCAGGCCCCGGGACAG 
               
               
                   
                   
                 GGCCTGGAATGGATGGGGTGGATTTCCGCGTACAACGGCAATACGAAC 
               
               
                   
                   
                 TACGCTCAGAAGTTCCAGGGTAGAGTGACCATGACTAGGAACACCTCC 
               
               
                   
                   
                 ATTTCCACCGCCTACATGGAACTGTCCTCCCTGCGGAGCGAGGACACC 
               
               
                   
                   
                 GCCGTGTACTATTGCGCCCGGGGACCATACTACTACTACATGGATGTC 
               
               
                   
                   
                 TGGGGGAAGGGGACTATGGTCACCGTGTCATCCGCCTCGGGAGGCGGC 
               
               
                   
                   
                 GGATCAGGAGGACGCGCCTCTGGTGGTGGAGGATCGGAGATCGTGATG 
               
               
                   
                   
                 ACCCAGAGCCCTCTCTCCTTGCCCGTGACTCCTGGGGAGCCCGCATCC 
               
               
                   
                   
                 ATTTCATGCCGGAGCTCCCAGTCACTTCTCTACTCCAACGGCTATAAC 
               
               
                   
                   
                 TACGTGGATTGGTACCTCCAAAAGCCGGGCCAGAGCCCGCAGCTGCTG 
               
               
                   
                   
                 ATCTACCTGGGCTCGAACAGGGCCAGCGGAGTGCCTGACCGGTTCTCC 
               
               
                   
                   
                 GGGTCGGGAAGCGGGACCGACTTCAAGCTGCAAATCTCGAGAGTGGAG 
               
               
                   
                   
                 GCCGAGGACGTGGGAATCTACTACTGTATGCAGGGCCGCCAGTTTCCG 
               
               
                   
                   
                 TACTCGTTCGGACAGGGCACCAAAGTGGAAATCAAGACCACTACCCCA 
               
               
                   
                   
                 GCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTG 
               
               
                   
                   
                 TCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCAT 
               
               
                   
                   
                 ACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTG 
               
               
                   
                   
                 GCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTAC 
               
               
                   
                   
                 TGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTC 
               
               
                   
                   
                 ATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGG 
               
               
                   
                   
                 TTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGC 
               
               
                   
                   
                 CGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTAC 
               
               
                   
                   
                 AACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAG 
               
               
                   
                   
                 CGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAAT 
               
               
                   
                   
                 CCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAA 
               
               
                   
                   
                 GCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGC 
               
               
                   
                   
                 CACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTAT 
               
               
                   
                   
                 GACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139104 
               
            
           
           
               
               
               
            
               
                 139104-aa 
                 1442 
                 EVQLLETGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGLEWV 
               
               
                 ScFv 
                   
                 SGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDTAIYYCS 
               
               
                 domain 
                   
                 AHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGSEIVLTQSPATLS 
               
               
                   
                   
                 VSPGESATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRASGIPD 
               
               
                   
                   
                 RFSGSGSGTDFTLTISSLQAEDVAVYYCQQYGSSLTFGGGTKVEIK 
               
               
                   
               
               
                 139104-nt 
                 1443 
                 GAAGTGCAATTGCTCGAAACTGGAGGAGGTCTGGTGCAACCTGGAGGA 
               
               
                 ScFv 
                   
                 TCACTTCGCCTGTCCTGCGCCGTGTCGGGCTTTGCCCTGTCCAACCAT 
               
               
                 domain 
                   
                 GGAATGAGCTGGGTCCGCCGCGCGCCGGGGAAGGGCCTCGAATGGGTG 
               
               
                   
                   
                 TCCGGCATCGTCTACTCCGGCTCCACCTACTACGCCGCGTCCGTGAAG 
               
               
                   
                   
                 GGCCGGTTCACGATTTCACGGGACAACTCGCGGAACACCCTGTACCTC 
               
               
                   
                   
                 CAAATGAATTCCCTTCGGCCGGAGGATACTGCCATCTACTACTGCTCC 
               
               
                   
                   
                 GCCCACGGTGGCGAATCCGACGTCTGGGGCCAGGGAACCACCGTGACC 
               
               
                   
                   
                 GTGTCCAGCGCGTCCGGGGGAGGAGGAAGCGGGGGTAGAGCATCGGGT 
               
               
                   
                   
                 GGAGGCGGATCAGAGATCGTGCTGACCCAGTCCCCCGCCACCTTGAGC 
               
               
                   
                   
                 GTGTCACCAGGAGAGTCCGCCACCCTGTCATGCCGCGCCAGCCAGTCC 
               
               
                   
                   
                 GTGTCCTCCAACCTGGCTTGGTACCAGCAGAAGCCGGGGCAGGCCCCT 
               
               
                   
                   
                 AGACTCCTGATCTATGGGGCGTCGACCCGGGCATCTGGAATTCCCGAT 
               
               
                   
                   
                 AGGTTCAGCGGATCGGGCTCGGGCACTGACTTCACTCTGACCATCTCC 
               
               
                   
                   
                 TCGCTGCAAGCCGAGGACGTGGCTGTGTACTACTGTCAGCAGTACGGA 
               
               
                   
                   
                 AGCTCCCTGACTTTCGGTGGCGGGACCAAAGTCGAGATTAAG 
               
               
                   
               
               
                 139104-aa 
                 1444 
                 EVQLLETGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGLEWV 
               
               
                 VH 
                   
                 SGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDTAIYYCS 
               
               
                   
                   
                 AHGGESDVWGQGTTVTVSS 
               
               
                   
               
               
                 139104-aa 
                 1445 
                 EIVLTQSPATLSVSPGESATLSCRASQSVSSNLAWYQQKPGQAPRLLI 
               
               
                 VL 
                   
                 YGASTRASGIPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYGSSLT 
               
               
                   
                   
                 FGGGTKVEIK 
               
               
                   
               
               
                 139104-aa 
                 1446 
                 MALPVTALLLPLALLLHAARPEVQLLETGGGLVQPGGSLRLSCAVSGF 
               
               
                 Full CAR 
                   
                 ALSNHGMSWVRRAPGKGLEWVSGIVYSGSTYYAASVKGRFTISRDNSR 
               
               
                   
                   
                 NTLYLQMNSLRPEDTAIYYCSAHGGESDVWGQGTTVTVSSASGGGGSG 
               
               
                   
                   
                 GRASGGGGSEIVLTQSPATLSVSPGESATLSCRASQSVSSNLAWYQQK 
               
               
                   
                   
                 PGQAPRLLIYGASTRASGIPDRFSGSGSGTDFTLTISSLQAEDVAVYY 
               
               
                   
                   
                 CQQYGSSLTFGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRP 
               
               
                   
                   
                 AAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLL 
               
               
                   
                   
                 YIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYK 
               
               
                   
                   
                 QGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNEL 
               
               
                   
                   
                 QKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALP 
               
               
                   
                   
                 PR 
               
               
                   
               
               
                 139104-nt 
                 1447 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCGAAGTGCAATTGCTCGAAACTGGAGGAGGTCTG 
               
               
                   
                   
                 GTGCAACCTGGAGGATCACTTCGCCTGTCCTGCGCCGTGTCGGGCTTT 
               
               
                   
                   
                 GCCCTGTCCAACCATGGAATGAGCTGGGTCCGCCGCGCGCCGGGGAAG 
               
               
                   
                   
                 GGCCTCGAATGGGTGTCCGGCATCGTCTACTCCGGCTCCACCTACTAC 
               
               
                   
                   
                 GCCGCGTCCGTGAAGGGCCGGTTCACGATTTCACGGGACAACTCGCGG 
               
               
                   
                   
                 AACACCCTGTACCTCCAAATGAATTCCCTTCGGCCGGAGGATACTGCC 
               
               
                   
                   
                 ATCTACTACTGCTCCGCCCACGGTGGCGAATCCGACGTCTGGGGCCAG 
               
               
                   
                   
                 GGAACCACCGTGACCGTGTCCAGCGCGTCCGGGGGAGGAGGAAGCGGG 
               
               
                   
                   
                 GGTAGAGCATCGGGTGGAGGCGGATCAGAGATCGTGCTGACCCAGTCC 
               
               
                   
                   
                 CCCGCCACCTTGAGCGTGTCACCAGGAGAGTCCGCCACCCTGTCATGC 
               
               
                   
                   
                 CGCGCCAGCCAGTCCGTGTCCTCCAACCTGGCTTGGTACCAGCAGAAG 
               
               
                   
                   
                 CCGGGGCAGGCCCCTAGACTCCTGATCTATGGGGCGTCGACCCGGGCA 
               
               
                   
                   
                 TCTGGAATTCCCGATAGGTTCAGCGGATCGGGCTCGGGCACTGACTTC 
               
               
                   
                   
                 ACTCTGACCATCTCCTCGCTGCAAGCCGAGGACGTGGCTGTGTACTAC 
               
               
                   
                   
                 TGTCAGCAGTACGGAAGCTCCCTGACTTTCGGTGGCGGGACCAAAGTC 
               
               
                   
                   
                 GAGATTAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCT 
               
               
                   
                   
                 ACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCC 
               
               
                   
                   
                 GCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGAT 
               
               
                   
                   
                 ATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTT 
               
               
                   
                   
                 TCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTG 
               
               
                   
                   
                 TACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAG 
               
               
                   
                   
                 GAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGC 
               
               
                   
                   
                 GAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAG 
               
               
                   
                   
                 CAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAG 
               
               
                   
                   
                 GAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGC 
               
               
                   
                   
                 GGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTC 
               
               
                   
                   
                 CAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGG 
               
               
                   
                   
                 GAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGC 
               
               
                   
                   
                 ACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCG 
               
               
                   
                   
                 CCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139106 
               
            
           
           
               
               
               
            
               
                 139106-aa 
                 1448 
                 EVQLVETGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGLEWV 
               
               
                 ScFv 
                   
                 SGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDTAIYYCS 
               
               
                 domain 
                   
                 AHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGSEIVMTQSPATLS 
               
               
                   
                   
                 VSPGERATLSCRASQSVSSKLAWYQQKPGQAPRLLMYGASIRATGIPD 
               
               
                   
                   
                 RFSGSGSGTEFTLTISSLEPEDFAVYYCQQYGSSSWTFGQGTKVEIK 
               
               
                   
               
               
                 139106-nt 
                 1449 
                 GAAGTGCAATTGGTGGAAACTGGAGGAGGACTTGTGCAACCTGGAGGA 
               
               
                 ScFv 
                   
                 TCATTGAGACTGAGCTGCGCAGTGTCGGGATTCGCCCTGAGCAACCAT 
               
               
                 domain 
                   
                 GGAATGTCCTGGGTCAGAAGGGCCCCTGGAAAAGGCCTCGAATGGGTG 
               
               
                   
                   
                 TCAGGGATCGTGTACTCCGGTTCCACTTACTACGCCGCCTCCGTGAAG 
               
               
                   
                   
                 GGGCGCTTCACTATCTCACGGGATAACTCCCGCAATACCCTGTACCTC 
               
               
                   
                   
                 CAAATGAACAGCCTGCGGCCGGAGGATACCGCCATCTACTACTGTTCC 
               
               
                   
                   
                 GCCCACGGTGGAGAGTCTGACGTCTGGGGCCAGGGAACTACCGTGACC 
               
               
                   
                   
                 GTGTCCTCCGCGTCCGGCGGTGGAGGGAGCGGCGGCCGCGCCAGCGGC 
               
               
                   
                   
                 GGCGGAGGCTCCGAGATCGTGATGACCCAGAGCCCCGCTACTCTGTCG 
               
               
                   
                   
                 GTGTCGCCCGGAGAAAGGGCGACCCTGTCCTGCCGGGCGTCGCAGTCC 
               
               
                   
                   
                 GTGAGCAGCAAGCTGGCTTGGTACCAGCAGAAGCCGGGCCAGGCACCA 
               
               
                   
                   
                 CGCCTGCTTATGTACGGTGCCTCCATTCGGGCCACCGGAATCCCGGAC 
               
               
                   
                   
                 CGGTTCTCGGGGTCGGGGTCCGGTACCGAGTTCACACTGACCATTTCC 
               
               
                   
                   
                 TCGCTCGAGCCCGAGGACTTTGCCGTCTATTACTGCCAGCAGTACGGC 
               
               
                   
                   
                 TCCTCCTCATGGACGTTCGGCCAGGGGACCAAGGTCGAAATCAAG 
               
               
                   
               
               
                 139106-aa 
                 1450 
                 EVQLVETGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGLEWV 
               
               
                 VH 
                   
                 SGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDTAIYYCS 
               
               
                   
                   
                 AHGGESDVWGQGTTVTVSS 
               
               
                   
               
               
                 139106-aa 
                 1451 
                 EIVMTQSPATLSVSPGERATLSCRASQSVSSKLAWYQQKPGQAPRLLM 
               
               
                 VL 
                   
                 YGASIRATGIPDRFSGSGSGTEFTLTISSLEPEDFAVYYCQQYGSSSW 
               
               
                   
                   
                 TFGQGTKVEIK 
               
               
                   
               
               
                 139106-aa 
                 1452 
                 MALPVTALLLPLALLLHAARPEVQLVETGGGLVQPGGSLRLSCAVSGF 
               
               
                 Full CAR 
                   
                 ALSNHGMSWVRRAPGKGLEWVSGIVYSGSTYYAASVKGRFTISRDNSR 
               
               
                   
                   
                 NTLYLQMNSLRPEDTAIYYCSAHGGESDVWGQGTTVTVSSASGGGGSG 
               
               
                   
                   
                 GRASGGGGSEIVMTQSPATLSVSPGERATLSCRASQSVSSKLAWYQQK 
               
               
                   
                   
                 PGQAPRLLMYGASIRATGIPDRFSGSGSGTEFTLTISSLEPEDFAVYY 
               
               
                   
                   
                 CQQYGSSSWTFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACR 
               
               
                   
                   
                 PAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKL 
               
               
                   
                   
                 LYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAY 
               
               
                   
                   
                 KQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNE 
               
               
                   
                   
                 LQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQAL 
               
               
                   
                   
                 PPR 
               
               
                   
               
               
                 139106-nt 
                 1453 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCGAAGTGCAATTGGTGGAAACTGGAGGAGGACTT 
               
               
                   
                   
                 GTGCAACCTGGAGGATCATTGAGACTGAGCTGCGCAGTGTCGGGATTC 
               
               
                   
                   
                 GCCCTGAGCAACCATGGAATGTCCTGGGTCAGAAGGGCCCCTGGAAAA 
               
               
                   
                   
                 GGCCTCGAATGGGTGTCAGGGATCGTGTACTCCGGTTCCACTTACTAC 
               
               
                   
                   
                 GCCGCCTCCGTGAAGGGGCGCTTCACTATCTCACGGGATAACTCCCGC 
               
               
                   
                   
                 AATACCCTGTACCTCCAAATGAACAGCCTGCGGCCGGAGGATACCGCC 
               
               
                   
                   
                 ATCTACTACTGTTCCGCCCACGGTGGAGAGTCTGACGTCTGGGGCCAG 
               
               
                   
                   
                 GGAACTACCGTGACCGTGTCCTCCGCGTCCGGCGGTGGAGGGAGCGGC 
               
               
                   
                   
                 GGCCGCGCCAGCGGCGGCGGAGGCTCCGAGATCGTGATGACCCAGAGC 
               
               
                   
                   
                 CCCGCTACTCTGTCGGTGTCGCCCGGAGAAAGGGCGACCCTGTCCTGC 
               
               
                   
                   
                 CGGGCGTCGCAGTCCGTGAGCAGCAAGCTGGCTTGGTACCAGCAGAAG 
               
               
                   
                   
                 CCGGGCCAGGCACCACGCCTGCTTATGTACGGTGCCTCCATTCGGGCC 
               
               
                   
                   
                 ACCGGAATCCCGGACCGGTTCTCGGGGTCGGGGTCCGGTACCGAGTTC 
               
               
                   
                   
                 ACACTGACCATTTCCTCGCTCGAGCCCGAGGACTTTGCCGTCTATTAC 
               
               
                   
                   
                 TGCCAGCAGTACGGCTCCTCCTCATGGACGTTCGGCCAGGGGACCAAG 
               
               
                   
                   
                 GTCGAAATCAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCT 
               
               
                   
                   
                 CCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGA 
               
               
                   
                   
                 CCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGC 
               
               
                   
                   
                 GATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTG 
               
               
                   
                   
                 CTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTG 
               
               
                   
                   
                 CTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAA 
               
               
                   
                   
                 GAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGC 
               
               
                   
                   
                 TGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTAC 
               
               
                   
                   
                 AAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGA 
               
               
                   
                   
                 GAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATG 
               
               
                   
                   
                 GGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAG 
               
               
                   
                   
                 CTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAA 
               
               
                   
                   
                 GGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTC 
               
               
                   
                   
                 AGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTG 
               
               
                   
                   
                 CCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139107 
               
            
           
           
               
               
               
            
               
                 139107-aa 
                 1454 
                 EVQLVETGGGVVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGLEWV 
               
               
                 ScFv 
                   
                 SGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDTAIYYCS 
               
               
                 domain 
                   
                 AHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGSEIVLTQSPGTLS 
               
               
                   
                   
                 LSPGERATLSCRASQSVGSTNLAWYQQKPGQAPRLLIYDASNRATGIP 
               
               
                   
                   
                 DRFSGGGSGTDFTLTISRLEPEDFAVYYCQQYGSSPPWTFGQGTKVEI 
               
               
                   
                   
                 K 
               
               
                   
               
               
                 139107-nt 
                 1455 
                 GAAGTGCAATTGGTGGAGACTGGAGGAGGAGTGGTGCAACCTGGAGGA 
               
               
                 ScFv 
                   
                 AGCCTGAGACTGTCATGCGCGGTGTCGGGCTTCGCCCTCTCCAACCAC 
               
               
                 domain 
                   
                 GGAATGTCCTGGGTCCGCCGGGCCCCTGGGAAAGGACTTGAATGGGTG 
               
               
                   
                   
                 TCCGGCATCGTGTACTCGGGTTCCACCTACTACGCGGCCTCAGTGAAG 
               
               
                   
                   
                 GGCCGGTTTACTATTAGCCGCGACAACTCCAGAAACACACTGTACCTC 
               
               
                   
                   
                 CAAATGAACTCGCTGCGGCCGGAAGATACCGCTATCTACTACTGCTCC 
               
               
                   
                   
                 GCCCATGGGGGAGAGTCGGACGTCTGGGGACAGGGCACCACTGTCACT 
               
               
                   
                   
                 GTGTCCAGCGCTTCCGGCGGTGGTGGAAGCGGGGGACGGGCCTCAGGA 
               
               
                   
                   
                 GGCGGTGGCAGCGAGATTGTGCTGACCCAGTCCCCCGGGACCCTGAGC 
               
               
                   
                   
                 CTGTCCCCGGGAGAAAGGGCCACCCTCTCCTGTCGGGCATCCCAGTCC 
               
               
                   
                   
                 GTGGGGTCTACTAACCTTGCATGGTACCAGCAGAAGCCCGGCCAGGCC 
               
               
                   
                   
                 CCTCGCCTGCTGATCTACGACGCGTCCAATAGAGCCACCGGCATCCCG 
               
               
                   
                   
                 GATCGCTTCAGCGGAGGCGGATCGGGCACCGACTTCACCCTCACCATT 
               
               
                   
                   
                 TCAAGGCTGGAACCGGAGGACTTCGCCGTGTACTACTGCCAGCAGTAT 
               
               
                   
                   
                 GGTTCGTCCCCACCCTGGACGTTCGGCCAGGGGACTAAGGTCGAGATC 
               
               
                   
                   
                 AAG 
               
               
                   
               
               
                 139107-aa 
                 1456 
                 EVQLVETGGGVVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGLEWV 
               
               
                 VH 
                   
                 SGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDTAIYYCS 
               
               
                   
                   
                 AHGGESDVWGQGTTVTVSS 
               
               
                   
               
               
                 139107-aa 
                 1457 
                 EIVLTQSPGTLSLSPGERATLSCRASQSVGSTNLAWYQQKPGQAPRLL 
               
               
                 VL 
                   
                 IYDASNRATGIPDRFSGGGSGTDFTLTISRLEPEDFAVYYCQQYGSSP 
               
               
                   
                   
                 PWTFGQGTKVEIK 
               
               
                   
               
               
                 139107-aa 
                 1458 
                 MALPVTALLLPLALLLHAARPEVQLVETGGGVVQPGGSLRLSCAVSGF 
               
               
                 Full CAR 
                   
                 ALSNHGMSWVRRAPGKGLEWVSGIVYSGSTYYAASVKGRFTISRDNSR 
               
               
                   
                   
                 NTLYLQMNSLRPEDTAIYYCSAHGGESDVWGQGTTVTVSSASGGGGSG 
               
               
                   
                   
                 GRASGGGGSEIVLTQSPGTLSLSPGERATLSCRASQSVGSTNLAWYQQ 
               
               
                   
                   
                 KPGQAPRLLIYDASNRATGIPDRFSGGGSGTDFTLTISRLEPEDFAVY 
               
               
                   
                   
                 YCQQYGSSPPWTFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEA 
               
               
                   
                   
                 CRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRK 
               
               
                   
                   
                 KLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAP 
               
               
                   
                   
                 AYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLY 
               
               
                   
                   
                 NELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQ 
               
               
                   
                   
                 ALPPR 
               
               
                   
               
               
                 139107-nt 
                 1459 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCGAAGTGCAATTGGTGGAGACTGGAGGAGGAGTG 
               
               
                   
                   
                 GTGCAACCTGGAGGAAGCCTGAGACTGTCATGCGCGGTGTCGGGCTTC 
               
               
                   
                   
                 GCCCTCTCCAACCACGGAATGTCCTGGGTCCGCCGGGCCCCTGGGAAA 
               
               
                   
                   
                 GGACTTGAATGGGTGTCCGGCATCGTGTACTCGGGTTCCACCTACTAC 
               
               
                   
                   
                 GCGGCCTCAGTGAAGGGCCGGTTTACTATTAGCCGCGACAACTCCAGA 
               
               
                   
                   
                 AACACACTGTACCTCCAAATGAACTCGCTGCGGCCGGAAGATACCGCT 
               
               
                   
                   
                 ATCTACTACTGCTCCGCCCATGGGGGAGAGTCGGACGTCTGGGGACAG 
               
               
                   
                   
                 GGCACCACTGTCACTGTGTCCAGCGCTTCCGGCGGTGGTGGAAGCGGG 
               
               
                   
                   
                 GGACGGGCCTCAGGAGGCGGTGGCAGCGAGATTGTGCTGACCCAGTCC 
               
               
                   
                   
                 CCCGGGACCCTGAGCCTGTCCCCGGGAGAAAGGGCCACCCTCTCCTGT 
               
               
                   
                   
                 CGGGCATCCCAGTCCGTGGGGTCTACTAACCTTGCATGGTACCAGCAG 
               
               
                   
                   
                 AAGCCCGGCCAGGCCCCTCGCCTGCTGATCTACGACGCGTCCAATAGA 
               
               
                   
                   
                 GCCACCGGCATCCCGGATCGCTTCAGCGGAGGCGGATCGGGCACCGAC 
               
               
                   
                   
                 TTCACCCTCACCATTTCAAGGCTGGAACCGGAGGACTTCGCCGTGTAC 
               
               
                   
                   
                 TACTGCCAGCAGTATGGTTCGTCCCCACCCTGGACGTTCGGCCAGGGG 
               
               
                   
                   
                 ACTAAGGTCGAGATCAAGACCACTACCCCAGCACCGAGGCCACCCACC 
               
               
                   
                   
                 CCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCA 
               
               
                   
                   
                 TGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTC 
               
               
                   
                   
                 GCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTC 
               
               
                   
                   
                 CTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAG 
               
               
                   
                   
                 AAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACT 
               
               
                   
                   
                 ACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAA 
               
               
                   
                   
                 GGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCA 
               
               
                   
                   
                 GCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGT 
               
               
                   
                   
                 CGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCA 
               
               
                   
                   
                 GAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTAC 
               
               
                   
                   
                 AACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGT 
               
               
                   
                   
                 ATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAG 
               
               
                   
                   
                 GGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAG 
               
               
                   
                   
                 GCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139108 
               
            
           
           
               
               
               
            
               
                 139108-aa 
                 1460 
                 QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWV 
               
               
                 ScFv 
                   
                 SYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC 
               
               
                 domain 
                   
                 ARESGDGMDVWGQGTTVTVSSASGGGGSGGRASGGGGSDIQMTQSPSS 
               
               
                   
                   
                 LSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGV 
               
               
                   
                   
                 PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTLAFGQGTKVDIK 
               
               
                   
               
               
                 139108-nt 
                 1461 
                 CAAGTGCAACTCGTGGAATCTGGTGGAGGACTCGTGAAACCTGGAGGA 
               
               
                 ScFv 
                   
                 TCATTGAGACTGTCATGCGCGGCCTCGGGATTCACGTTCTCCGATTAC 
               
               
                 domain 
                   
                 TACATGAGCTGGATTCGCCAGGCTCCGGGGAAGGGACTGGAATGGGTG 
               
               
                   
                   
                 TCCTACATTTCCTCATCCGGCTCCACCATCTACTACGCGGACTCCGTG 
               
               
                   
                   
                 AAGGGGAGATTCACCATTAGCCGCGATAACGCCAAGAACAGCCTGTAC 
               
               
                   
                   
                 CTTCAGATGAACTCCCTGCGGGCTGAAGATACTGCCGTCTACTACTGC 
               
               
                   
                   
                 GCAAGGGAGAGCGGAGATGGGATGGACGTCTGGGGACAGGGTACCACT 
               
               
                   
                   
                 GTGACCGTGTCGTCGGCCTCCGGCGGAGGGGGTTCGGGTGGAAGGGCC 
               
               
                   
                   
                 AGCGGCGGCGGAGGCAGCGACATCCAGATGACCCAGTCCCCCTCATCG 
               
               
                   
                   
                 CTGTCCGCCTCCGTGGGCGACCGCGTCACCATCACATGCCGGGCCTCA 
               
               
                   
                   
                 CAGTCGATCTCCTCCTACCTCAATTGGTATCAGCAGAAGCCCGGAAAG 
               
               
                   
                   
                 GCCCCTAAGCTTCTGATCTACGCAGCGTCCTCCCTGCAATCCGGGGTC 
               
               
                   
                   
                 CCATCTCGGTTCTCCGGCTCGGGCAGCGGTACCGACTTCACTCTGACC 
               
               
                   
                   
                 ATCTCGAGCCTGCAGCCGGAGGACTTCGCCACTTACTACTGTCAGCAA 
               
               
                   
                   
                 AGCTACACCCTCGCGTTTGGCCAGGGCACCAAAGTGGACATCAAG 
               
               
                   
               
               
                 139108-aa 
                 1462 
                 QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWV 
               
               
                 VH 
                   
                 SYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC 
               
               
                   
                   
                 ARESGDGMDVWGQGTTVTVSS 
               
               
                   
               
               
                 139108-aa 
                 1463 
                 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLI 
               
               
                 VL 
                   
                 YAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTLAF 
               
               
                   
                   
                 GQGTKVDIK 
               
               
                   
               
               
                 139108-aa 
                 1464 
                 MALPVTALLLPLALLLHAARPQVQLVESGGGLVKPGGSLRLSCAASGF 
               
               
                 Full CAR 
                   
                 TFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNA 
               
               
                   
                   
                 KNSLYLQMNSLRAEDTAVYYCARESGDGMDVWGQGTTVTVSSASGGGG 
               
               
                   
                   
                 SGGRASGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQ 
               
               
                   
                   
                 QKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAT 
               
               
                   
                   
                 YYCQQSYTLAFGQGTKVDIKTTTPAPRPPTPAPTIASQPLSLRPEACR 
               
               
                   
                   
                 PAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKL 
               
               
                   
                   
                 LYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAY 
               
               
                   
                   
                 KQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNE 
               
               
                   
                   
                 LQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQAL 
               
               
                   
                   
                 PPR 
               
               
                   
               
               
                 139108-nt 
                 1465 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCCAAGTGCAACTCGTGGAATCTGGTGGAGGACTC 
               
               
                   
                   
                 GTGAAACCTGGAGGATCATTGAGACTGTCATGCGCGGCCTCGGGATTC 
               
               
                   
                   
                 ACGTTCTCCGATTACTACATGAGCTGGATTCGCCAGGCTCCGGGGAAG 
               
               
                   
                   
                 GGACTGGAATGGGTGTCCTACATTTCCTCATCCGGCTCCACCATCTAC 
               
               
                   
                   
                 TACGCGGACTCCGTGAAGGGGAGATTCACCATTAGCCGCGATAACGCC 
               
               
                   
                   
                 AAGAACAGCCTGTACCTTCAGATGAACTCCCTGCGGGCTGAAGATACT 
               
               
                   
                   
                 GCCGTCTACTACTGCGCAAGGGAGAGCGGAGATGGGATGGACGTCTGG 
               
               
                   
                   
                 GGACAGGGTACCACTGTGACCGTGTCGTCGGCCTCCGGCGGAGGGGGT 
               
               
                   
                   
                 TCGGGTGGAAGGGCCAGCGGCGGCGGAGGCAGCGACATCCAGATGACC 
               
               
                   
                   
                 CAGTCCCCCTCATCGCTGTCCGCCTCCGTGGGCGACCGCGTCACCATC 
               
               
                   
                   
                 ACATGCCGGGCCTCACAGTCGATCTCCTCCTACCTCAATTGGTATCAG 
               
               
                   
                   
                 CAGAAGCCCGGAAAGGCCCCTAAGCTTCTGATCTACGCAGCGTCCTCC 
               
               
                   
                   
                 CTGCAATCCGGGGTCCCATCTCGGTTCTCCGGCTCGGGCAGCGGTACC 
               
               
                   
                   
                 GACTTCACTCTGACCATCTCGAGCCTGCAGCCGGAGGACTTCGCCACT 
               
               
                   
                   
                 TACTACTGTCAGCAAAGCTACACCCTCGCGTTTGGCCAGGGCACCAAA 
               
               
                   
                   
                 GTGGACATCAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCT 
               
               
                   
                   
                 CCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGA 
               
               
                   
                   
                 CCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGC 
               
               
                   
                   
                 GATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTG 
               
               
                   
                   
                 CTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTG 
               
               
                   
                   
                 CTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAA 
               
               
                   
                   
                 GAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGC 
               
               
                   
                   
                 TGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTAC 
               
               
                   
                   
                 AAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGA 
               
               
                   
                   
                 GAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATG 
               
               
                   
                   
                 GGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAG 
               
               
                   
                   
                 CTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAA 
               
               
                   
                   
                 GGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTC 
               
               
                   
                   
                 AGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTG 
               
               
                   
                   
                 CCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139110 
               
            
           
           
               
               
               
            
               
                 139110-aa 
                 1466 
                 QVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWV 
               
               
                 ScFv 
                   
                 SYISSSGNTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC 
               
               
                 domain 
                   
                 ARSTMVREDYWGQGTLVTVSSASGGGGSGGRASGGGGSDIVLTQSPLS 
               
               
                   
                   
                 LPVTLGQPASISCKSSESLVHNSGKTYLNWFHQRPGQSPRRLIYEVSN 
               
               
                   
                   
                 RDSGVPDRFTGSGSGTDFTLKISRVEAEDVGVYYCMQGTHWPGTFGQG 
               
               
                   
                   
                 TKLEIK 
               
               
                   
               
               
                 139110-nt 
                 1467 
                 CAAGTGCAACTGGTGCAAAGCGGAGGAGGATTGGTCAAACCCGGAGGA 
               
               
                 ScFv 
                   
                 AGCCTGAGACTGTCATGCGCGGCCTCTGGATTCACCTTCTCCGATTAC 
               
               
                 domain 
                   
                 TACATGTCATGGATCAGACAGGCCCCGGGGAAGGGCCTCGAATGGGTG 
               
               
                   
                   
                 TCCTACATCTCGTCCTCCGGGAACACCATCTACTACGCCGACAGCGTG 
               
               
                   
                   
                 AAGGGCCGCTTTACCATTTCCCGCGACAACGCAAAGAACTCGCTGTAC 
               
               
                   
                   
                 CTTCAGATGAATTCCCTGCGGGCTGAAGATACCGCGGTGTACTATTGC 
               
               
                   
                   
                 GCCCGGTCCACTATGGTCCGGGAGGACTACTGGGGACAGGGCACACTC 
               
               
                   
                   
                 GTGACCGTGTCCAGCGCGAGCGGGGGTGGAGGCAGCGGTGGACGCGCC 
               
               
                   
                   
                 TCCGGCGGCGGCGGTTCAGACATCGTGCTGACTCAGTCGCCCCTGTCG 
               
               
                   
                   
                 CTGCCGGTCACCCTGGGCCAACCGGCCTCAATTAGCTGCAAGTCCTCG 
               
               
                   
                   
                 GAGAGCCTGGTGCACAACTCAGGAAAGACTTACCTGAACTGGTTCCAT 
               
               
                   
                   
                 CAGCGGCCTGGACAGTCCCCACGGAGGCTCATCTATGAAGTGTCCAAC 
               
               
                   
                   
                 AGGGATTCGGGGGTGCCCGACCGCTTCACTGGCTCCGGGTCCGGCACC 
               
               
                   
                   
                 GACTTCACCTTGAAAATCTCCAGAGTGGAAGCCGAGGACGTGGGCGTG 
               
               
                   
                   
                 TACTACTGTATGCAGGGTACCCACTGGCCTGGAACCTTTGGACAAGGA 
               
               
                   
                   
                 ACTAAGCTCGAGATTAAG 
               
               
                   
               
               
                 139110-aa 
                 1468 
                 QVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWV 
               
               
                 VH 
                   
                 SYISSSGNTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC 
               
               
                   
                   
                 ARSTMVREDYWGQGTLVTVSS 
               
               
                   
               
               
                 139110-aa 
                 1469 
                 DIVLTQSPLSLPVTLGQPASISCKSSESLVHNSGKTYLNWFHQRPGQS 
               
               
                 VL 
                   
                 PRRLIYEVSNRDSGVPDRFTGSGSGTDFTLKISRVEAEDVGVYYCMQG 
               
               
                   
                   
                 THWPGTFGQGTKLEIK 
               
               
                   
               
               
                 139110-aa 
                 1470 
                 MALPVTALLLPLALLLHAARPQVQLVQSGGGLVKPGGSLRLSCAASGF 
               
               
                 Full CAR 
                   
                 TFSDYYMSWIRQAPGKGLEWVSYISSSGNTIYYADSVKGRFTISRDNA 
               
               
                   
                   
                 KNSLYLQMNSLRAEDTAVYYCARSTMVREDYWGQGTLVTVSSASGGGG 
               
               
                   
                   
                 SGGRASGGGGSDIVLTQSPLSLPVTLGQPASISCKSSESLVHNSGKTY 
               
               
                   
                   
                 LNWFHQRPGQSPRRLIYEVSNRDSGVPDRFTGSGSGTDFTLKISRVEA 
               
               
                   
                   
                 EDVGVYYCMQGTHWPGTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLS 
               
               
                   
                   
                 LRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYC 
               
               
                   
                   
                 KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSR 
               
               
                   
                   
                 SADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNP 
               
               
                   
                   
                 QEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYD 
               
               
                   
                   
                 ALHMQALPPR 
               
               
                   
               
               
                 139110-nt 
                 1471 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCCAAGTGCAACTGGTGCAAAGCGGAGGAGGATTG 
               
               
                   
                   
                 GTCAAACCCGGAGGAAGCCTGAGACTGTCATGCGCGGCCTCTGGATTC 
               
               
                   
                   
                 ACCTTCTCCGATTACTACATGTCATGGATCAGACAGGCCCCGGGGAAG 
               
               
                   
                   
                 GGCCTCGAATGGGTGTCCTACATCTCGTCCTCCGGGAACACCATCTAC 
               
               
                   
                   
                 TACGCCGACAGCGTGAAGGGCCGCTTTACCATTTCCCGCGACAACGCA 
               
               
                   
                   
                 AAGAACTCGCTGTACCTTCAGATGAATTCCCTGCGGGCTGAAGATACC 
               
               
                   
                   
                 GCGGTGTACTATTGCGCCCGGTCCACTATGGTCCGGGAGGACTACTGG 
               
               
                   
                   
                 GGACAGGGCACACTCGTGACCGTGTCCAGCGCGAGCGGGGGTGGAGGC 
               
               
                   
                   
                 AGCGGTGGACGCGCCTCCGGCGGCGGCGGTTCAGACATCGTGCTGACT 
               
               
                   
                   
                 CAGTCGCCCCTGTCGCTGCCGGTCACCCTGGGCCAACCGGCCTCAATT 
               
               
                   
                   
                 AGCTGCAAGTCCTCGGAGAGCCTGGTGCACAACTCAGGAAAGACTTAC 
               
               
                   
                   
                 CTGAACTGGTTCCATCAGCGGCCTGGACAGTCCCCACGGAGGCTCATC 
               
               
                   
                   
                 TATGAAGTGTCCAACAGGGATTCGGGGGTGCCCGACCGCTTCACTGGC 
               
               
                   
                   
                 TCCGGGTCCGGCACCGACTTCACCTTGAAAATCTCCAGAGTGGAAGCC 
               
               
                   
                   
                 GAGGACGTGGGCGTGTACTACTGTATGCAGGGTACCCACTGGCCTGGA 
               
               
                   
                   
                 ACCTTTGGACAAGGAACTAAGCTCGAGATTAAGACCACTACCCCAGCA 
               
               
                   
                   
                 CCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCC 
               
               
                   
                   
                 CTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACC 
               
               
                   
                   
                 CGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCT 
               
               
                   
                   
                 GGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGT 
               
               
                   
                   
                 AAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATG 
               
               
                   
                   
                 AGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTC 
               
               
                   
                   
                 CCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGC 
               
               
                   
                   
                 AGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAAC 
               
               
                   
                   
                 GAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGG 
               
               
                   
                   
                 AGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCC 
               
               
                   
                   
                 CAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCC 
               
               
                   
                   
                 TATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCAC 
               
               
                   
                   
                 GACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGAC 
               
               
                   
                   
                 GCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139112 
               
            
           
           
               
               
               
            
               
                 139112-aa 
                 1472 
                 QVQLVESGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGLEWV 
               
               
                 ScFv 
                   
                 SGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDTAIYYCS 
               
               
                 domain 
                   
                 AHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGSDIRLTQSPSPLS 
               
               
                   
                   
                 ASVGDRVTITCQASEDINKFLNWYHQTPGKAPKLLIYDASTLQTGVPS 
               
               
                   
                   
                 RFSGSGSGTDFTLTINSLQPEDIGTYYCQQYESLPLTFGGGTKVEIK 
               
               
                   
               
               
                 139112-nt 
                 1473 
                 CAAGTGCAACTCGTGGAATCTGGTGGAGGACTCGTGCAACCCGGTGGA 
               
               
                 ScFv 
                   
                 AGCCTTAGGCTGTCGTGCGCCGTCAGCGGGTTTGCTCTGAGCAACCAT 
               
               
                 domain 
                   
                 GGAATGTCCTGGGTCCGCCGGGCACCGGGAAAAGGGCTGGAATGGGTG 
               
               
                   
                   
                 TCCGGCATCGTGTACAGCGGGTCAACCTATTACGCCGCGTCCGTGAAG 
               
               
                   
                   
                 GGCAGATTCACTATCTCAAGAGACAACAGCCGGAACACCCTGTACTTG 
               
               
                   
                   
                 CAAATGAATTCCCTGCGCCCCGAGGACACCGCCATCTACTACTGCTCC 
               
               
                   
                   
                 GCCCACGGAGGAGAGTCGGACGTGTGGGGCCAGGGAACGACTGTGACT 
               
               
                   
                   
                 GTGTCCAGCGCATCAGGAGGGGGTGGTTCGGGCGGCCGGGCCTCGGGG 
               
               
                   
                   
                 GGAGGAGGTTCCGACATTCGGCTGACCCAGTCCCCGTCCCCACTGTCG 
               
               
                   
                   
                 GCCTCCGTCGGCGACCGCGTGACCATCACTTGTCAGGCGTCCGAGGAC 
               
               
                   
                   
                 ATTAACAAGTTCCTGAACTGGTACCACCAGACCCCTGGAAAGGCCCCC 
               
               
                   
                   
                 AAGCTGCTGATCTACGATGCCTCGACCCTTCAAACTGGAGTGCCTAGC 
               
               
                   
                   
                 CGGTTCTCCGGGTCCGGCTCCGGCACTGATTTCACTCTGACCATCAAC 
               
               
                   
                   
                 TCATTGCAGCCGGAAGATATCGGGACCTACTATTGCCAGCAGTACGAA 
               
               
                   
                   
                 TCCCTCCCGCTCACATTCGGCGGGGGAACCAAGGTCGAGATTAAG 
               
               
                   
               
               
                 139112-aa 
                 1474 
                 QVQLVESGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGLEWV 
               
               
                 VH 
                   
                 SGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDTAIYYCS 
               
               
                   
                   
                 AHGGESDVWGQGTTVTVSS 
               
               
                   
               
               
                 139112-aa 
                 1475 
                 DIRLTQSPSPLSASVGDRVTITCQASEDINKFLNWYHQTPGKAPKLLI 
               
               
                 VL 
                   
                 YDASTLQTGVPSRFSGSGSGTDFTLTINSLQPEDIGTYYCQQYESLPL 
               
               
                   
                   
                 TFGGGTKVEIK 
               
               
                   
               
               
                 139112-aa 
                 1476 
                 MALPVTALLLPLALLLHAARPQVQLVESGGGLVQPGGSLRLSCAVSGF 
               
               
                 Full CAR 
                   
                 ALSNHGMSWVRRAPGKGLEWVSGIVYSGSTYYAASVKGRFTISRDNSR 
               
               
                   
                   
                 NTLYLQMNSLRPEDTAIYYCSAHGGESDVWGQGTTVTVSSASGGGGSG 
               
               
                   
                   
                 GRASGGGGSDIRLTQSPSPLSASVGDRVTITCQASEDINKFLNWYHQT 
               
               
                   
                   
                 PGKAPKLLIYDASTLQTGVPSRFSGSGSGTDFTLTINSLQPEDIGTYY 
               
               
                   
                   
                 CQQYESLPLTFGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACR 
               
               
                   
                   
                 PAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKL 
               
               
                   
                   
                 LYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAY 
               
               
                   
                   
                 KQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNE 
               
               
                   
                   
                 LQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQAL 
               
               
                   
                   
                 PPR 
               
               
                   
               
               
                 139112-nt 
                 1477 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCCAAGTGCAACTCGTGGAATCTGGTGGAGGACTC 
               
               
                   
                   
                 GTGCAACCCGGTGGAAGCCTTAGGCTGTCGTGCGCCGTCAGCGGGTTT 
               
               
                   
                   
                 GCTCTGAGCAACCATGGAATGTCCTGGGTCCGCCGGGCACCGGGAAAA 
               
               
                   
                   
                 GGGCTGGAATGGGTGTCCGGCATCGTGTACAGCGGGTCAACCTATTAC 
               
               
                   
                   
                 GCCGCGTCCGTGAAGGGCAGATTCACTATCTCAAGAGACAACAGCCGG 
               
               
                   
                   
                 AACACCCTGTACTTGCAAATGAATTCCCTGCGCCCCGAGGACACCGCC 
               
               
                   
                   
                 ATCTACTACTGCTCCGCCCACGGAGGAGAGTCGGACGTGTGGGGCCAG 
               
               
                   
                   
                 GGAACGACTGTGACTGTGTCCAGCGCATCAGGAGGGGGTGGTTCGGGC 
               
               
                   
                   
                 GGCCGGGCCTCGGGGGGAGGAGGTTCCGACATTCGGCTGACCCAGTCC 
               
               
                   
                   
                 CCGTCCCCACTGTCGGCCTCCGTCGGCGACCGCGTGACCATCACTTGT 
               
               
                   
                   
                 CAGGCGTCCGAGGACATTAACAAGTTCCTGAACTGGTACCACCAGACC 
               
               
                   
                   
                 CCTGGAAAGGCCCCCAAGCTGCTGATCTACGATGCCTCGACCCTTCAA 
               
               
                   
                   
                 ACTGGAGTGCCTAGCCGGTTCTCCGGGTCCGGCTCCGGCACTGATTTC 
               
               
                   
                   
                 ACTCTGACCATCAACTCATTGCAGCCGGAAGATATCGGGACCTACTAT 
               
               
                   
                   
                 TGCCAGCAGTACGAATCCCTCCCGCTCACATTCGGCGGGGGAACCAAG 
               
               
                   
                   
                 GTCGAGATTAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCT 
               
               
                   
                   
                 CCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGA 
               
               
                   
                   
                 CCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGC 
               
               
                   
                   
                 GATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTG 
               
               
                   
                   
                 CTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTG 
               
               
                   
                   
                 CTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAA 
               
               
                   
                   
                 GAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGC 
               
               
                   
                   
                 TGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTAC 
               
               
                   
                   
                 AAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGA 
               
               
                   
                   
                 GAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATG 
               
               
                   
                   
                 GGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAG 
               
               
                   
                   
                 CTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAA 
               
               
                   
                   
                 GGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTC 
               
               
                   
                   
                 AGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTG 
               
               
                   
                   
                 CCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139113 
               
            
           
           
               
               
               
            
               
                 139113-aa 
                 1478 
                 EVQLVETGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGLEWV 
               
               
                 ScFv 
                   
                 SGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDTAIYYCS 
               
               
                 domain 
                   
                 AHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGSETTLTQSPATLS 
               
               
                   
                   
                 VSPGERATLSCRASQSVGSNLAWYQQKPGQGPRLLIYGASTRATGIPA 
               
               
                   
                   
                 RFSGSGSGTEFTLTISSLQPEDFAVYYCQQYNDWLPVTFGQGTKVEIK 
               
               
                   
               
               
                 139113-nt 
                 1480 
                 GAAGTGCAATTGGTGGAAACTGGAGGAGGACTTGTGCAACCTGGAGGA 
               
               
                 ScFv 
                   
                 TCATTGCGGCTCTCATGCGCTGTCTCCGGCTTCGCCCTGTCAAATCAC 
               
               
                 domain 
                   
                 GGGATGTCGTGGGTCAGACGGGCCCCGGGAAAGGGTCTGGAATGGGTG 
               
               
                   
                   
                 TCGGGGATTGTGTACAGCGGCTCCACCTACTACGCCGCTTCGGTCAAG 
               
               
                   
                   
                 GGCCGCTTCACTATTTCACGGGACAACAGCCGCAACACCCTCTATCTG 
               
               
                   
                   
                 CAAATGAACTCTCTCCGCCCGGAGGATACCGCCATCTACTACTGCTCC 
               
               
                   
                   
                 GCACACGGCGGCGAATCCGACGTGTGGGGACAGGGAACCACTGTCACC 
               
               
                   
                   
                 GTGTCGTCCGCATCCGGTGGCGGAGGATCGGGTGGCCGGGCCTCCGGG 
               
               
                   
                   
                 GGCGGCGGCAGCGAGACTACCCTGACCCAGTCCCCTGCCACTCTGTCC 
               
               
                   
                   
                 GTGAGCCCGGGAGAGAGAGCCACCCTTAGCTGCCGGGCCAGCCAGAGC 
               
               
                   
                   
                 GTGGGCTCCAACCTGGCCTGGTACCAGCAGAAGCCAGGACAGGGTCCC 
               
               
                   
                   
                 AGGCTGCTGATCTACGGAGCCTCCACTCGCGCGACCGGCATCCCCGCG 
               
               
                   
                   
                 AGGTTCTCCGGGTCGGGTTCCGGGACCGAGTTCACCCTGACCATCTCC 
               
               
                   
                   
                 TCCCTCCAACCGGAGGACTTCGCGGTGTACTACTGTCAGCAGTACAAC 
               
               
                   
                   
                 GATTGGCTGCCCGTGACATTTGGACAGGGGACGAAGGTGGAAATCAAA 
               
               
                   
               
               
                 139113-aa 
                 1481 
                 EVQLVETGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGLEWV 
               
               
                 VH 
                   
                 SGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDTAIYYCS 
               
               
                   
                   
                 AHGGESDVWGQGTTVTVSS 
               
               
                   
               
               
                 139113-aa 
                 1482 
                 ETTLTQSPATLSVSPGERATLSCRASQSVGSNLAWYQQKPGQGPRLLI 
               
               
                 VL 
                   
                 YGASTRATGIPARFSGSGSGTEFTLTISSLQPEDFAVYYCQQYNDWLP 
               
               
                   
                   
                 VTFGQGTKVEIK 
               
               
                   
               
               
                 139113-aa 
                 1483 
                 MALPVTALLLPLALLLHAARPEVQLVETGGGLVQPGGSLRLSCAVSGF 
               
               
                 Full CAR 
                   
                 ALSNHGMSWVRRAPGKGLEWVSGIVYSGSTYYAASVKGRFTISRDNSR 
               
               
                   
                   
                 NTLYLQMNSLRPEDTAIYYCSAHGGESDVWGQGTTVTVSSASGGGGSG 
               
               
                   
                   
                 GRASGGGGSETTLTQSPATLSVSPGERATLSCRASQSVGSNLAWYQQK 
               
               
                   
                   
                 PGQGPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQPEDFAVYY 
               
               
                   
                   
                 CQQYNDWLPVTFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEAC 
               
               
                   
                   
                 RPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKK 
               
               
                   
                   
                 LLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPA 
               
               
                   
                   
                 YKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYN 
               
               
                   
                   
                 ELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQA 
               
               
                   
                   
                 LPPR 
               
               
                   
               
               
                 139113-nt 
                 1484 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCGAAGTGCAATTGGTGGAAACTGGAGGAGGACTT 
               
               
                   
                   
                 GTGCAACCTGGAGGATCATTGCGGCTCTCATGCGCTGTCTCCGGCTTC 
               
               
                   
                   
                 GCCCTGTCAAATCACGGGATGTCGTGGGTCAGACGGGCCCCGGGAAAG 
               
               
                   
                   
                 GGTCTGGAATGGGTGTCGGGGATTGTGTACAGCGGCTCCACCTACTAC 
               
               
                   
                   
                 GCCGCTTCGGTCAAGGGCCGCTTCACTATTTCACGGGACAACAGCCGC 
               
               
                   
                   
                 AACACCCTCTATCTGCAAATGAACTCTCTCCGCCCGGAGGATACCGCC 
               
               
                   
                   
                 ATCTACTACTGCTCCGCACACGGCGGCGAATCCGACGTGTGGGGACAG 
               
               
                   
                   
                 GGAACCACTGTCACCGTGTCGTCCGCATCCGGTGGCGGAGGATCGGGT 
               
               
                   
                   
                 GGCCGGGCCTCCGGGGGCGGCGGCAGCGAGACTACCCTGACCCAGTCC 
               
               
                   
                   
                 CCTGCCACTCTGTCCGTGAGCCCGGGAGAGAGAGCCACCCTTAGCTGC 
               
               
                   
                   
                 CGGGCCAGCCAGAGCGTGGGCTCCAACCTGGCCTGGTACCAGCAGAAG 
               
               
                   
                   
                 CCAGGACAGGGTCCCAGGCTGCTGATCTACGGAGCCTCCACTCGCGCG 
               
               
                   
                   
                 ACCGGCATCCCCGCGAGGTTCTCCGGGTCGGGTTCCGGGACCGAGTTC 
               
               
                   
                   
                 ACCCTGACCATCTCCTCCCTCCAACCGGAGGACTTCGCGGTGTACTAC 
               
               
                   
                   
                 TGTCAGCAGTACAACGATTGGCTGCCCGTGACATTTGGACAGGGGACG 
               
               
                   
                   
                 AAGGTGGAAATCAAAACCACTACCCCAGCACCGAGGCCACCCACCCCG 
               
               
                   
                   
                 GCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGT 
               
               
                   
                   
                 AGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCC 
               
               
                   
                   
                 TGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTG 
               
               
                   
                   
                 CTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAG 
               
               
                   
                   
                 CTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACT 
               
               
                   
                   
                 CAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGC 
               
               
                   
                   
                 GGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCC 
               
               
                   
                   
                 TACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGG 
               
               
                   
                   
                 AGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAA 
               
               
                   
                   
                 ATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAAC 
               
               
                   
                   
                 GAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATG 
               
               
                   
                   
                 AAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGA 
               
               
                   
                   
                 CTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCC 
               
               
                   
                   
                 CTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139114 
               
            
           
           
               
               
               
            
               
                 139114-aa 
                 1485 
                 EVQLVESGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGLEWV 
               
               
                 ScFv 
                   
                 SGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDTAIYYCS 
               
               
                 domain 
                   
                 AHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGSEIVLTQSPGTLS 
               
               
                   
                   
                 LSPGERATLSCRASQSIGSSSLAWYQQKPGQAPRLLMYGASSRASGIP 
               
               
                   
                   
                 DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYAGSPPFTFGQGTKVEI 
               
               
                   
                   
                 K 
               
               
                   
               
               
                 139114-nt 
                 1486 
                 GAAGTGCAATTGGTGGAATCTGGTGGAGGACTTGTGCAACCTGGAGGA 
               
               
                 ScFv 
                   
                 TCACTGAGACTGTCATGCGCGGTGTCCGGTTTTGCCCTGAGCAATCAT 
               
               
                 domain 
                   
                 GGGATGTCGTGGGTCCGGCGCGCCCCCGGAAAGGGTCTGGAATGGGTG 
               
               
                   
                   
                 TCGGGTATCGTCTACTCCGGGAGCACTTACTACGCCGCGAGCGTGAAG 
               
               
                   
                   
                 GGCCGCTTCACCATTTCCCGCGATAACTCCCGCAACACCCTGTACTTG 
               
               
                   
                   
                 CAAATGAACTCGCTCCGGCCTGAGGACACTGCCATCTACTACTGCTCC 
               
               
                   
                   
                 GCACACGGAGGAGAATCCGACGTGTGGGGCCAGGGAACTACCGTGACC 
               
               
                   
                   
                 GTCAGCAGCGCCTCCGGCGGCGGGGGCTCAGGCGGACGGGCTAGCGGC 
               
               
                   
                   
                 GGCGGTGGCTCCGAGATCGTGCTGACCCAGTCGCCTGGCACTCTCTCG 
               
               
                   
                   
                 CTGAGCCCCGGGGAAAGGGCAACCCTGTCCTGTCGGGCCAGCCAGTCC 
               
               
                   
                   
                 ATTGGATCATCCTCCCTCGCCTGGTATCAGCAGAAACCGGGACAGGCT 
               
               
                   
                   
                 CCGCGGCTGCTTATGTATGGGGCCAGCTCAAGAGCCTCCGGCATTCCC 
               
               
                   
                   
                 GACCGGTTCTCCGGGTCCGGTTCCGGCACCGATTTCACCCTGACTATC 
               
               
                   
                   
                 TCGAGGCTGGAGCCAGAGGACTTCGCCGTGTACTACTGCCAGCAGTAC 
               
               
                   
                   
                 GCGGGGTCCCCGCCGTTCACGTTCGGACAGGGAACCAAGGTCGAGATC 
               
               
                   
                   
                 AAG 
               
               
                   
               
               
                 139114-aa 
                 1487 
                 EVQLVESGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGLEWV 
               
               
                 VH 
                   
                 SGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDTAIYYCS 
               
               
                   
                   
                 AHGGESDVWGQGTTVTVSS 
               
               
                   
               
               
                 139114-aa 
                 1488 
                 EIVLTQSPGTLSLSPGERATLSCRASQSIGSSSLAWYQQKPGQAPRLL 
               
               
                 VL 
                   
                 MYGASSRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYAGSP 
               
               
                   
                   
                 PFTFGQGTKVEIK 
               
               
                   
               
               
                 139114-aa 
                 1489 
                 MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAVSGF 
               
               
                 Full CAR 
                   
                 ALSNHGMSWVRRAPGKGLEWVSGIVYSGSTYYAASVKGRFTISRDNSR 
               
               
                   
                   
                 NTLYLQMNSLRPEDTAIYYCSAHGGESDVWGQGTTVTVSSASGGGGSG 
               
               
                   
                   
                 GRASGGGGSEIVLTQSPGTLSLSPGERATLSCRASQSIGSSSLAWYQQ 
               
               
                   
                   
                 KPGQAPRLLMYGASSRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVY 
               
               
                   
                   
                 YCQQYAGSPPFTFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEA 
               
               
                   
                   
                 CRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRK 
               
               
                   
                   
                 KLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAP 
               
               
                   
                   
                 AYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLY 
               
               
                   
                   
                 NELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQ 
               
               
                   
                   
                 ALPPR 
               
               
                   
               
               
                 139114-nt 
                 1490 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCGAAGTGCAATTGGTGGAATCTGGTGGAGGACTT 
               
               
                   
                   
                 GTGCAACCTGGAGGATCACTGAGACTGTCATGCGCGGTGTCCGGTTTT 
               
               
                   
                   
                 GCCCTGAGCAATCATGGGATGTCGTGGGTCCGGCGCGCCCCCGGAAAG 
               
               
                   
                   
                 GGTCTGGAATGGGTGTCGGGTATCGTCTACTCCGGGAGCACTTACTAC 
               
               
                   
                   
                 GCCGCGAGCGTGAAGGGCCGCTTCACCATTTCCCGCGATAACTCCCGC 
               
               
                   
                   
                 AACACCCTGTACTTGCAAATGAACTCGCTCCGGCCTGAGGACACTGCC 
               
               
                   
                   
                 ATCTACTACTGCTCCGCACACGGAGGAGAATCCGACGTGTGGGGCCAG 
               
               
                   
                   
                 GGAACTACCGTGACCGTCAGCAGCGCCTCCGGCGGCGGGGGCTCAGGC 
               
               
                   
                   
                 GGACGGGCTAGCGGCGGCGGTGGCTCCGAGATCGTGCTGACCCAGTCG 
               
               
                   
                   
                 CCTGGCACTCTCTCGCTGAGCCCCGGGGAAAGGGCAACCCTGTCCTGT 
               
               
                   
                   
                 CGGGCCAGCCAGTCCATTGGATCATCCTCCCTCGCCTGGTATCAGCAG 
               
               
                   
                   
                 AAACCGGGACAGGCTCCGCGGCTGCTTATGTATGGGGCCAGCTCAAGA 
               
               
                   
                   
                 GCCTCCGGCATTCCCGACCGGTTCTCCGGGTCCGGTTCCGGCACCGAT 
               
               
                   
                   
                 TTCACCCTGACTATCTCGAGGCTGGAGCCAGAGGACTTCGCCGTGTAC 
               
               
                   
                   
                 TACTGCCAGCAGTACGCGGGGTCCCCGCCGTTCACGTTCGGACAGGGA 
               
               
                   
                   
                 ACCAAGGTCGAGATCAAGACCACTACCCCAGCACCGAGGCCACCCACC 
               
               
                   
                   
                 CCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCA 
               
               
                   
                   
                 TGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTC 
               
               
                   
                   
                 GCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTC 
               
               
                   
                   
                 CTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAG 
               
               
                   
                   
                 AAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACT 
               
               
                   
                   
                 ACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAA 
               
               
                   
                   
                 GGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCA 
               
               
                   
                   
                 GCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGT 
               
               
                   
                   
                 CGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCA 
               
               
                   
                   
                 GAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTAC 
               
               
                   
                   
                 AACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGT 
               
               
                   
                   
                 ATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAG 
               
               
                   
                   
                 GGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAG 
               
               
                   
                   
                 GCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 149362 
               
            
           
           
               
               
               
            
               
                 149362-aa 
                 1491 
                 QVQLQESGPGLVKPSETLSLTCTVSGGSISSSYYYWGWIRQPPGKGLE 
               
               
                 ScFv 
                   
                 WIGSIYYSGSAYYNPSLKSRVTISVDTSKNQFSLRLSSVTAADTAVYY 
               
               
                 domain 
                   
                 CARHWQEWPDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSETTLTQSP 
               
               
                   
                   
                 AFMSATPGDKVIISCKASQDIDDAMNWYQQKPGEAPLFIIQSATSPVP 
               
               
                   
                   
                 GIPPRFSGSGFGTDFSLTINNIESEDAAYYFCLQHDNFPLTFGQGTKL 
               
               
                   
                   
                 EIK 
               
               
                   
               
               
                 149362-nt 
                 1492 
                 CAAGTGCAGCTTCAGGAAAGCGGACCGGGCCTGGTCAAGCCATCCGAA 
               
               
                 ScFv 
                   
                 ACTCTCTCCCTGACTTGCACTGTGTCTGGCGGTTCCATCTCATCGTCG 
               
               
                 domain 
                   
                 TACTACTACTGGGGCTGGATTAGGCAGCCGCCCGGAAAGGGACTGGAG 
               
               
                   
                   
                 TGGATCGGAAGCATCTACTATTCCGGCTCGGCGTACTACAACCCTAGC 
               
               
                   
                   
                 CTCAAGTCGAGAGTGACCATCTCCGTGGATACCTCCAAGAACCAGTTT 
               
               
                   
                   
                 TCCCTGCGCCTGAGCTCCGTGACCGCCGCTGACACCGCCGTGTACTAC 
               
               
                   
                   
                 TGTGCTCGGCATTGGCAGGAATGGCCCGATGCCTTCGACATTTGGGGC 
               
               
                   
                   
                 CAGGGCACTATGGTCACTGTGTCATCCGGGGGTGGAGGCAGCGGGGGA 
               
               
                   
                   
                 GGAGGGTCCGGGGGGGGAGGTTCAGAGACAACCTTGACCCAGTCACCC 
               
               
                   
                   
                 GCATTCATGTCCGCCACTCCGGGAGACAAGGTCATCATCTCGTGCAAA 
               
               
                   
                   
                 GCGTCCCAGGATATCGACGATGCCATGAATTGGTACCAGCAGAAGCCT 
               
               
                   
                   
                 GGCGAAGCGCCGCTGTTCATTATCCAATCCGCAACCTCGCCCGTGCCT 
               
               
                   
                   
                 GGAATCCCACCGCGGTTCAGCGGCAGCGGTTTCGGAACCGACTTTTCC 
               
               
                   
                   
                 CTGACCATTAACAACATTGAGTCCGAGGACGCCGCCTACTACTTCTGC 
               
               
                   
                   
                 CTGCAACACGACAACTTCCCTCTCACGTTCGGCCAGGGAACCAAGCTG 
               
               
                   
                   
                 GAAATCAAG 
               
               
                   
               
               
                 149362-aa 
                 1493 
                 QVQLQESGPGLVKPSETLSLTCTVSGGSISSSYYYWGWIRQPPGKGLE 
               
               
                 VH 
                   
                 WIGSIYYSGSAYYNPSLKSRVTISVDTSKNQFSLRLSSVTAADTAVYY 
               
               
                   
                   
                 CARHWQEWPDAFDIWGQGTMVTVSS 
               
               
                   
               
               
                 149362-aa 
                 1494 
                 ETTLTQSPAFMSATPGDKVIISCKASQDIDDAMNWYQQKPGEAPLFII 
               
               
                 VL 
                   
                 QSATSPVPGIPPRFSGSGFGTDFSLTINNIESEDAAYYFCLQHDNFPL 
               
               
                   
                   
                 TFGQGTKLEIK 
               
               
                   
               
               
                 149362-aa 
                 1495 
                 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGG 
               
               
                 Full CAR 
                   
                 SISSSYYYWGWIRQPPGKGLEWIGSIYYSGSAYYNPSLKSRVTISVDT 
               
               
                   
                   
                 SKNQFSLRLSSVTAADTAVYYCARHWQEWPDAFDIWGQGTMVTVSSGG 
               
               
                   
                   
                 GGSGGGGSGGGGSETTLTQSPAFMSATPGDKVIISCKASQDIDDAMNW 
               
               
                   
                   
                 YQQKPGEAPLFIIQSATSPVPGIPPRFSGSGFGTDFSLTINNIESEDA 
               
               
                   
                   
                 AYYFCLQHDNFPLTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRP 
               
               
                   
                   
                 EACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRG 
               
               
                   
                   
                 RKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSAD 
               
               
                   
                   
                 APAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEG 
               
               
                   
                   
                 LYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALH 
               
               
                   
                   
                 MQALPPR 
               
               
                   
               
               
                 149362-nt 
                 1496 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCCAAGTGCAGCTTCAGGAAAGCGGACCGGGCCTG 
               
               
                   
                   
                 GTCAAGCCATCCGAAACTCTCTCCCTGACTTGCACTGTGTCTGGCGGT 
               
               
                   
                   
                 TCCATCTCATCGTCGTACTACTACTGGGGCTGGATTAGGCAGCCGCCC 
               
               
                   
                   
                 GGAAAGGGACTGGAGTGGATCGGAAGCATCTACTATTCCGGCTCGGCG 
               
               
                   
                   
                 TACTACAACCCTAGCCTCAAGTCGAGAGTGACCATCTCCGTGGATACC 
               
               
                   
                   
                 TCCAAGAACCAGTTTTCCCTGCGCCTGAGCTCCGTGACCGCCGCTGAC 
               
               
                   
                   
                 ACCGCCGTGTACTACTGTGCTCGGCATTGGCAGGAATGGCCCGATGCC 
               
               
                   
                   
                 TTCGACATTTGGGGCCAGGGCACTATGGTCACTGTGTCATCCGGGGGT 
               
               
                   
                   
                 GGAGGCAGCGGGGGAGGAGGGTCCGGGGGGGGAGGTTCAGAGACAACC 
               
               
                   
                   
                 TTGACCCAGTCACCCGCATTCATGTCCGCCACTCCGGGAGACAAGGTC 
               
               
                   
                   
                 ATCATCTCGTGCAAAGCGTCCCAGGATATCGACGATGCCATGAATTGG 
               
               
                   
                   
                 TACCAGCAGAAGCCTGGCGAAGCGCCGCTGTTCATTATCCAATCCGCA 
               
               
                   
                   
                 ACCTCGCCCGTGCCTGGAATCCCACCGCGGTTCAGCGGCAGCGGTTTC 
               
               
                   
                   
                 GGAACCGACTTTTCCCTGACCATTAACAACATTGAGTCCGAGGACGCC 
               
               
                   
                   
                 GCCTACTACTTCTGCCTGCAACACGACAACTTCCCTCTCACGTTCGGC 
               
               
                   
                   
                 CAGGGAACCAAGCTGGAAATCAAGACCACTACCCCAGCACCGAGGCCA 
               
               
                   
                   
                 CCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCG 
               
               
                   
                   
                 GAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTT 
               
               
                   
                   
                 GACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGC 
               
               
                   
                   
                 GGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGT 
               
               
                   
                   
                 CGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTG 
               
               
                   
                   
                 CAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAG 
               
               
                   
                   
                 GAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGAT 
               
               
                   
                   
                 GCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAAT 
               
               
                   
                   
                 CTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGG 
               
               
                   
                   
                 GACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGC 
               
               
                   
                   
                 CTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAG 
               
               
                   
                   
                 ATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTG 
               
               
                   
                   
                 TACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCAC 
               
               
                   
                   
                 ATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 149363 
               
            
           
           
               
               
               
            
               
                 149363-aa 
                 1497 
                 VNLRESGPALVKPTQTLTLTCTFSGFSLRTSGMCVSWIRQPPGKALEW 
               
               
                 ScFv 
                   
                 LARIDWDEDKFYSTSLKTRLTISKDTSDNQVVLRMTNMDPADTATYYC 
               
               
                 domain 
                   
                 ARSGAGGTSATAFDIWGPGTMVTVSSGGGGSGGGGSGGGGSDIQMTQS 
               
               
                   
                   
                 PSSLSASVGDRVTITCRASQDIYNNLAWFQLKPGSAPRSLMYAANKSQ 
               
               
                   
                   
                 SGVPSRFSGSASGTDFTLTISSLQPEDFATYYCQHYYRFPYSFGQGTK 
               
               
                   
                   
                 LEIK 
               
               
                   
               
               
                 149363-nt 
                 1498 
                 CAAGTCAATCTGCGCGAATCCGGCCCCGCCTTGGTCAAGCCTACCCAG 
               
               
                 ScFv 
                   
                 ACCCTCACTCTGACCTGTACTTTCTCCGGCTTCTCCCTGCGGACTTCC 
               
               
                 domain 
                   
                 GGGATGTGCGTGTCCTGGATCAGACAGCCTCCGGGAAAGGCCCTGGAG 
               
               
                   
                   
                 TGGCTCGCTCGCATTGACTGGGATGAGGACAAGTTCTACTCCACCTCA 
               
               
                   
                   
                 CTCAAGACCAGGCTGACCATCAGCAAAGATACCTCTGACAACCAAGTG 
               
               
                   
                   
                 GTGCTCCGCATGACCAACATGGACCCAGCCGACACTGCCACTTACTAC 
               
               
                   
                   
                 TGCGCGAGGAGCGGAGCGGGCGGAACCTCCGCCACCGCCTTCGATATT 
               
               
                   
                   
                 TGGGGCCCGGGTACCATGGTCACCGTGTCAAGCGGAGGAGGGGGGTCC 
               
               
                   
                   
                 GGGGGCGGCGGTTCCGGGGGAGGCGGATCGGACATTCAGATGACTCAG 
               
               
                   
                   
                 TCACCATCGTCCCTGAGCGCTAGCGTGGGCGACAGAGTGACAATCACT 
               
               
                   
                   
                 TGCCGGGCATCCCAGGACATCTATAACAACCTTGCGTGGTTCCAGCTG 
               
               
                   
                   
                 AAGCCTGGTTCCGCACCGCGGTCACTTATGTACGCCGCCAACAAGAGC 
               
               
                   
                   
                 CAGTCGGGAGTGCCGTCCCGGTTTTCCGGTTCGGCCTCGGGAACTGAC 
               
               
                   
                   
                 TTCACCCTGACGATCTCCAGCCTGCAACCCGAGGATTTCGCCACCTAC 
               
               
                   
                   
                 TACTGCCAGCACTACTACCGCTTTCCCTACTCGTTCGGACAGGGAACC 
               
               
                   
                   
                 AAGCTGGAAATCAAG 
               
               
                   
               
               
                 149363-aa 
                 1499 
                 QVNLRESGPALVKPTQTLTLTCTFSGFSLRTSGMCVSWIRQPPGKALE 
               
               
                 VH 
                   
                 WLARIDWDEDKFYSTSLKTRLTISKDTSDNQVVLRMTNMDPADTATYY 
               
               
                   
                   
                 CARSGAGGTSATAFDIWGPGTMVTVSS 
               
               
                   
               
               
                 149363-aa 
                 1500 
                 DIQMTQSPSSLSASVGDRVTITCRASQDIYNNLAWFQLKPGSAPRSLM 
               
               
                 VL 
                   
                 YAANKSQSGVPSRFSGSASGTDFTLTISSLQPEDFATYYCQHYYRFPY 
               
               
                   
                   
                 SFGQGTKLEIK 
               
               
                   
               
               
                 149363-aa 
                 1501 
                 MALPVTALLLPLALLLHAARPQVNLRESGPALVKPTQTLTLTCTFSGF 
               
               
                 Full CAR 
                   
                 SLRTSGMCVSWIRQPPGKALEWLARIDWDEDKFYSTSLKTRLTISKDT 
               
               
                   
                   
                 SDNQVVLRMTNMDPADTATYYCARSGAGGTSATAFDIWGPGTMVTVSS 
               
               
                   
                   
                 GGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIYNNL 
               
               
                   
                   
                 AWFQLKPGSAPRSLMYAANKSQSGVPSRFSGSASGTDFTLTISSLQPE 
               
               
                   
                   
                 DFATYYCQHYYRFPYSFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSL 
               
               
                   
                   
                 RPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCK 
               
               
                   
                   
                 RGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRS 
               
               
                   
                   
                 ADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQ 
               
               
                   
                   
                 EGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDA 
               
               
                   
                   
                 LHMQALPPR 
               
               
                   
               
               
                 149363-nt 
                 1502 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCCAAGTCAATCTGCGCGAATCCGGCCCCGCCTTG 
               
               
                   
                   
                 GTCAAGCCTACCCAGACCCTCACTCTGACCTGTACTTTCTCCGGCTTC 
               
               
                   
                   
                 TCCCTGCGGACTTCCGGGATGTGCGTGTCCTGGATCAGACAGCCTCCG 
               
               
                   
                   
                 GGAAAGGCCCTGGAGTGGCTCGCTCGCATTGACTGGGATGAGGACAAG 
               
               
                   
                   
                 TTCTACTCCACCTCACTCAAGACCAGGCTGACCATCAGCAAAGATACC 
               
               
                   
                   
                 TCTGACAACCAAGTGGTGCTCCGCATGACCAACATGGACCCAGCCGAC 
               
               
                   
                   
                 ACTGCCACTTACTACTGCGCGAGGAGCGGAGCGGGCGGAACCTCCGCC 
               
               
                   
                   
                 ACCGCCTTCGATATTTGGGGCCCGGGTACCATGGTCACCGTGTCAAGC 
               
               
                   
                   
                 GGAGGAGGGGGGTCCGGGGGCGGCGGTTCCGGGGGAGGCGGATCGGAC 
               
               
                   
                   
                 ATTCAGATGACTCAGTCACCATCGTCCCTGAGCGCTAGCGTGGGCGAC 
               
               
                   
                   
                 AGAGTGACAATCACTTGCCGGGCATCCCAGGACATCTATAACAACCTT 
               
               
                   
                   
                 GCGTGGTTCCAGCTGAAGCCTGGTTCCGCACCGCGGTCACTTATGTAC 
               
               
                   
                   
                 GCCGCCAACAAGAGCCAGTCGGGAGTGCCGTCCCGGTTTTCCGGTTCG 
               
               
                   
                   
                 GCCTCGGGAACTGACTTCACCCTGACGATCTCCAGCCTGCAACCCGAG 
               
               
                   
                   
                 GATTTCGCCACCTACTACTGCCAGCACTACTACCGCTTTCCCTACTCG 
               
               
                   
                   
                 TTCGGACAGGGAACCAAGCTGGAAATCAAGACCACTACCCCAGCACCG 
               
               
                   
                   
                 AGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTG 
               
               
                   
                   
                 CGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGG 
               
               
                   
                   
                 GGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGT 
               
               
                   
                   
                 ACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAG 
               
               
                   
                   
                 CGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGG 
               
               
                   
                   
                 CCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCA 
               
               
                   
                   
                 GAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGC 
               
               
                   
                   
                 GCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAA 
               
               
                   
                   
                 CTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGA 
               
               
                   
                   
                 GGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAA 
               
               
                   
                   
                 GAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTAT 
               
               
                   
                   
                 AGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGAC 
               
               
                   
                   
                 GGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCT 
               
               
                   
                   
                 CTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 149364 
               
            
           
           
               
               
               
            
               
                 149364-aa 
                 1503 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWV 
               
               
                 ScFv 
                   
                 SSISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC 
               
               
                 domain 
                   
                 AKTIAAVYAFDIWGQGTTVTVSSGGGGSGGGGSGGGGSEIVLTQSPLS 
               
               
                   
                   
                 LPVTPEEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSN 
               
               
                   
                   
                 RASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPYTFGQG 
               
               
                   
                   
                 TKLEIK 
               
               
                   
               
               
                 149364-nt 
                 1504 
                 GAAGTGCAGCTTGTCGAATCCGGGGGGGGACTGGTCAAGCCGGGCGGA 
               
               
                 ScFv 
                   
                 TCACTGAGACTGTCCTGCGCCGCGAGCGGCTTCACGTTCTCCTCCTAC 
               
               
                 domain 
                   
                 TCCATGAACTGGGTCCGCCAAGCCCCCGGGAAGGGACTGGAATGGGTG 
               
               
                   
                   
                 TCCTCTATCTCCTCGTCGTCGTCCTACATCTACTACGCCGACTCCGTG 
               
               
                   
                   
                 AAGGGAAGATTCACCATTTCCCGCGACAACGCAAAGAACTCACTGTAC 
               
               
                   
                   
                 TTGCAAATGAACTCACTCCGGGCCGAAGATACTGCTGTGTACTATTGC 
               
               
                   
                   
                 GCCAAGACTATTGCCGCCGTCTACGCTTTCGACATCTGGGGCCAGGGA 
               
               
                   
                   
                 ACCACCGTGACTGTGTCGTCCGGTGGTGGTGGCTCGGGCGGAGGAGGA 
               
               
                   
                   
                 AGCGGCGGCGGGGGGTCCGAGATTGTGCTGACCCAGTCGCCACTGAGC 
               
               
                   
                   
                 CTCCCTGTGACCCCCGAGGAACCCGCCAGCATCAGCTGCCGGTCCAGC 
               
               
                   
                   
                 CAGTCCCTGCTCCACTCCAACGGATACAATTACCTCGATTGGTACCTT 
               
               
                   
                   
                 CAGAAGCCTGGACAAAGCCCGCAGCTGCTCATCTACTTGGGATCAAAC 
               
               
                   
                   
                 CGCGCGTCAGGAGTGCCTGACCGGTTCTCCGGCTCGGGCAGCGGTACC 
               
               
                   
                   
                 GATTTCACCCTGAAAATCTCCAGGGTGGAGGCAGAGGACGTGGGAGTG 
               
               
                   
                   
                 TATTACTGTATGCAGGCGCTGCAGACTCCGTACACATTTGGGCAGGGC 
               
               
                   
                   
                 ACCAAGCTGGAGATCAAG 
               
               
                   
               
               
                 149364-aa 
                 1505 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWV 
               
               
                 VH 
                   
                 SSISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC 
               
               
                   
                   
                 AKTIAAVYAFDIWGQGTTVTVSS 
               
               
                   
               
               
                 149364-aa 
                 1506 
                 EIVLTQSPLSLPVTPEEPASISCRSSQSLLHSNGYNYLDWYLQKPGQS 
               
               
                 VL 
                   
                 PQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQA 
               
               
                   
                   
                 LQTPYTFGQGTKLEIK 
               
               
                   
               
               
                 149364-aa 
                 1507 
                 MALPVTALLLPLALLLHAARPEVQLVESGGGLVKPGGSLRLSCAASGF 
               
               
                 Full CAR 
                   
                 TFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRFTISRDNA 
               
               
                   
                   
                 KNSLYLQMNSLRAEDTAVYYCAKTIAAVYAFDIWGQGTTVTVSSGGGG 
               
               
                   
                   
                 SGGGGSGGGGSEIVLTQSPLSLPVTPEEPASISCRSSQSLLHSNGYNY 
               
               
                   
                   
                 LDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEA 
               
               
                   
                   
                 EDVGVYYCMQALQTPYTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLS 
               
               
                   
                   
                 LRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYC 
               
               
                   
                   
                 KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSR 
               
               
                   
                   
                 SADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNP 
               
               
                   
                   
                 QEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYD 
               
               
                   
                   
                 ALHMQALPPR 
               
               
                   
               
               
                 149364-nt 
                 1508 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCGAAGTGCAGCTTGTCGAATCCGGGGGGGGACTG 
               
               
                   
                   
                 GTCAAGCCGGGCGGATCACTGAGACTGTCCTGCGCCGCGAGCGGCTTC 
               
               
                   
                   
                 ACGTTCTCCTCCTACTCCATGAACTGGGTCCGCCAAGCCCCCGGGAAG 
               
               
                   
                   
                 GGACTGGAATGGGTGTCCTCTATCTCCTCGTCGTCGTCCTACATCTAC 
               
               
                   
                   
                 TACGCCGACTCCGTGAAGGGAAGATTCACCATTTCCCGCGACAACGCA 
               
               
                   
                   
                 AAGAACTCACTGTACTTGCAAATGAACTCACTCCGGGCCGAAGATACT 
               
               
                   
                   
                 GCTGTGTACTATTGCGCCAAGACTATTGCCGCCGTCTACGCTTTCGAC 
               
               
                   
                   
                 ATCTGGGGCCAGGGAACCACCGTGACTGTGTCGTCCGGTGGTGGTGGC 
               
               
                   
                   
                 TCGGGCGGAGGAGGAAGCGGCGGCGGGGGGTCCGAGATTGTGCTGACC 
               
               
                   
                   
                 CAGTCGCCACTGAGCCTCCCTGTGACCCCCGAGGAACCCGCCAGCATC 
               
               
                   
                   
                 AGCTGCCGGTCCAGCCAGTCCCTGCTCCACTCCAACGGATACAATTAC 
               
               
                   
                   
                 CTCGATTGGTACCTTCAGAAGCCTGGACAAAGCCCGCAGCTGCTCATC 
               
               
                   
                   
                 TACTTGGGATCAAACCGCGCGTCAGGAGTGCCTGACCGGTTCTCCGGC 
               
               
                   
                   
                 TCGGGCAGCGGTACCGATTTCACCCTGAAAATCTCCAGGGTGGAGGCA 
               
               
                   
                   
                 GAGGACGTGGGAGTGTATTACTGTATGCAGGCGCTGCAGACTCCGTAC 
               
               
                   
                   
                 ACATTTGGGCAGGGCACCAAGCTGGAGATCAAGACCACTACCCCAGCA 
               
               
                   
                   
                 CCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCC 
               
               
                   
                   
                 CTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACC 
               
               
                   
                   
                 CGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCT 
               
               
                   
                   
                 GGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGT 
               
               
                   
                   
                 AAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATG 
               
               
                   
                   
                 AGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTC 
               
               
                   
                   
                 CCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGC 
               
               
                   
                   
                 AGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAAC 
               
               
                   
                   
                 GAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGG 
               
               
                   
                   
                 AGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCC 
               
               
                   
                   
                 CAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCC 
               
               
                   
                   
                 TATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCAC 
               
               
                   
                   
                 GACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGAC 
               
               
                   
                   
                 GCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 149365 
               
            
           
           
               
               
               
            
               
                 149365-aa 
                 1509 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWV 
               
               
                 ScFv 
                   
                 SYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC 
               
               
                 domain 
                   
                 ARDLRGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSSYVLTQSPSVSA 
               
               
                   
                   
                 APGYTATISCGGNNIGTKSVHWYQQKPGQAPLLVIRDDSVRPSKIPGR 
               
               
                   
                   
                 FSGSNSGNMATLTISGVQAGDEADFYCQVWDSDSEHVVFGGGTKLTVL 
               
               
                   
               
               
                 149365-nt 
                 1510 
                 GAAGTCCAGCTCGTGGAGTCCGGCGGAGGCCTTGTGAAGCCTGGAGGT 
               
               
                 ScFv 
                   
                 TCGCTGAGACTGTCCTGCGCCGCCTCCGGCTTCACCTTCTCCGACTAC 
               
               
                 domain 
                   
                 TACATGTCCTGGATCAGACAGGCCCCGGGAAAGGGCCTGGAATGGGTG 
               
               
                   
                   
                 TCCTACATCTCGTCATCGGGCAGCACTATCTACTACGCGGACTCAGTG 
               
               
                   
                   
                 AAGGGGCGGTTCACCATTTCCCGGGATAACGCGAAGAACTCGCTGTAT 
               
               
                   
                   
                 CTGCAAATGAACTCACTGAGGGCCGAGGACACCGCCGTGTACTACTGC 
               
               
                   
                   
                 GCCCGCGATCTCCGCGGGGCATTTGACATCTGGGGACAGGGAACCATG 
               
               
                   
                   
                 GTCACAGTGTCCAGCGGAGGGGGAGGATCGGGTGGCGGAGGTTCCGGG 
               
               
                   
                   
                 GGTGGAGGCTCCTCCTACGTGCTGACTCAGAGCCCAAGCGTCAGCGCT 
               
               
                   
                   
                 GCGCCCGGTTACACGGCAACCATCTCCTGTGGCGGAAACAACATTGGG 
               
               
                   
                   
                 ACCAAGTCTGTGCACTGGTATCAGCAGAAGCCGGGCCAAGCTCCCCTG 
               
               
                   
                   
                 TTGGTGATCCGCGATGACTCCGTGCGGCCTAGCAAAATTCCGGGACGG 
               
               
                   
                   
                 TTCTCCGGCTCCAACAGCGGCAATATGGCCACTCTCACCATCTCGGGA 
               
               
                   
                   
                 GTGCAGGCCGGAGATGAAGCCGACTTCTACTGCCAAGTCTGGGACTCA 
               
               
                   
                   
                 GACTCCGAGCATGTGGTGTTCGGGGGCGGAACCAAGCTGACTGTGCTC 
               
               
                   
               
               
                 149365-aa 
                 1511 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWV 
               
               
                 VH 
                   
                 SYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC 
               
               
                   
                   
                 ARDLRGAFDIWGQGTMVTVSS 
               
               
                   
               
               
                 149365-aa 
                 1512 
                 SYVLTQSPSVSAAPGYTATISCGGNNIGTKSVHWYQQKPGQAPLLVIR 
               
               
                 VL 
                   
                 DDSVRPSKIPGRFSGSNSGNMATLTISGVQAGDEADFYCQVWDSDSEH 
               
               
                   
                   
                 VVFGGGTKLTVL 
               
               
                   
               
               
                 149365-aa 
                 1513 
                 MALPVTALLLPLALLLHAARPEVQLVESGGGLVKPGGSLRLSCAASGF 
               
               
                 Full CAR 
                   
                 TFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNA 
               
               
                   
                   
                 KNSLYLQMNSLRAEDTAVYYCARDLRGAFDIWGQGTMVTVSSGGGGSG 
               
               
                   
                   
                 GGGSGGGGSSYVLTQSPSVSAAPGYTATISCGGNNIGTKSVHWYQQKP 
               
               
                   
                   
                 GQAPLLVIRDDSVRPSKIPGRFSGSNSGNMATLTISGVQAGDEADFYC 
               
               
                   
                   
                 QVWDSDSEHVVFGGGTKLTVLTTTPAPRPPTPAPTIASQPLSLRPEAC 
               
               
                   
                   
                 RPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKK 
               
               
                   
                   
                 LLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPA 
               
               
                   
                   
                 YKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYN 
               
               
                   
                   
                 ELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQA 
               
               
                   
                   
                 LPPR 
               
               
                   
               
               
                 149365-nt 
                 1514 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCGAAGTCCAGCTCGTGGAGTCCGGCGGAGGCCTT 
               
               
                   
                   
                 GTGAAGCCTGGAGGTTCGCTGAGACTGTCCTGCGCCGCCTCCGGCTTC 
               
               
                   
                   
                 ACCTTCTCCGACTACTACATGTCCTGGATCAGACAGGCCCCGGGAAAG 
               
               
                   
                   
                 GGCCTGGAATGGGTGTCCTACATCTCGTCATCGGGCAGCACTATCTAC 
               
               
                   
                   
                 TACGCGGACTCAGTGAAGGGGCGGTTCACCATTTCCCGGGATAACGCG 
               
               
                   
                   
                 AAGAACTCGCTGTATCTGCAAATGAACTCACTGAGGGCCGAGGACACC 
               
               
                   
                   
                 GCCGTGTACTACTGCGCCCGCGATCTCCGCGGGGCATTTGACATCTGG 
               
               
                   
                   
                 GGACAGGGAACCATGGTCACAGTGTCCAGCGGAGGGGGAGGATCGGGT 
               
               
                   
                   
                 GGCGGAGGTTCCGGGGGTGGAGGCTCCTCCTACGTGCTGACTCAGAGC 
               
               
                   
                   
                 CCAAGCGTCAGCGCTGCGCCCGGTTACACGGCAACCATCTCCTGTGGC 
               
               
                   
                   
                 GGAAACAACATTGGGACCAAGTCTGTGCACTGGTATCAGCAGAAGCCG 
               
               
                   
                   
                 GGCCAAGCTCCCCTGTTGGTGATCCGCGATGACTCCGTGCGGCCTAGC 
               
               
                   
                   
                 AAAATTCCGGGACGGTTCTCCGGCTCCAACAGCGGCAATATGGCCACT 
               
               
                   
                   
                 CTCACCATCTCGGGAGTGCAGGCCGGAGATGAAGCCGACTTCTACTGC 
               
               
                   
                   
                 CAAGTCTGGGACTCAGACTCCGAGCATGTGGTGTTCGGGGGCGGAACC 
               
               
                   
                   
                 AAGCTGACTGTGCTCACCACTACCCCAGCACCGAGGCCACCCACCCCG 
               
               
                   
                   
                 GCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGT 
               
               
                   
                   
                 AGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCC 
               
               
                   
                   
                 TGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTG 
               
               
                   
                   
                 CTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAG 
               
               
                   
                   
                 CTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACT 
               
               
                   
                   
                 CAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGC 
               
               
                   
                   
                 GGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCC 
               
               
                   
                   
                 TACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGG 
               
               
                   
                   
                 AGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAA 
               
               
                   
                   
                 ATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAAC 
               
               
                   
                   
                 GAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATG 
               
               
                   
                   
                 AAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGA 
               
               
                   
                   
                 CTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCC 
               
               
                   
                   
                 CTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 149366 
               
            
           
           
               
               
               
            
               
                 149366-aa 
                 1515 
                 QVQLVQSGAEVKKPGASVKVSCKPSGYTVTSHYIHWVRRAPGQGLEWM 
               
               
                 ScFv 
                   
                 GMINPSGGVTAYSQTLQGRVTMTSDTSSSTVYMELSSLRSEDTAMYYC 
               
               
                 domain 
                   
                 AREGSGSGWYFDFWGRGTLVTVSSGGGGSGGGGSGGGGSSYVLTQPPS 
               
               
                   
                   
                 VSVSPGQTASITCSGDGLSKKYVSWYQQKAGQSPVVLISRDKERPSGI 
               
               
                   
                   
                 PDRFSGSNSADTATLTISGTQAMDEADYYCQAWDDTTVVFGGGTKLTV 
               
               
                   
                   
                 L 
               
               
                   
               
               
                 149366-nt 
                 1516 
                 CAAGTGCAGCTGGTGCAGAGCGGGGCCGAAGTCAAGAAGCCGGGAGCC 
               
               
                 ScFv 
                   
                 TCCGTGAAAGTGTCCTGCAAGCCTTCGGGATACACCGTGACCTCCCAC 
               
               
                 domain 
                   
                 TACATTCATTGGGTCCGCCGCGCCCCCGGCCAAGGACTCGAGTGGATG 
               
               
                   
                   
                 GGCATGATCAACCCTAGCGGCGGAGTGACCGCGTACAGCCAGACGCTG 
               
               
                   
                   
                 CAGGGACGCGTGACTATGACCTCGGATACCTCCTCCTCCACCGTCTAT 
               
               
                   
                   
                 ATGGAACTGTCCAGCCTGCGGTCCGAGGATACCGCCATGTACTACTGC 
               
               
                   
                   
                 GCCCGGGAAGGATCAGGCTCCGGGTGGTATTTCGACTTCTGGGGAAGA 
               
               
                   
                   
                 GGCACCCTCGTGACTGTGTCATCTGGGGGAGGGGGTTCCGGTGGTGGC 
               
               
                   
                   
                 GGATCGGGAGGAGGCGGTTCATCCTACGTGCTGACCCAGCCACCCTCC 
               
               
                   
                   
                 GTGTCCGTGAGCCCCGGCCAGACTGCATCGATTACATGTAGCGGCGAC 
               
               
                   
                   
                 GGCCTCTCCAAGAAATACGTGTCGTGGTACCAGCAGAAGGCCGGACAG 
               
               
                   
                   
                 AGCCCGGTGGTGCTGATCTCAAGAGATAAGGAGCGGCCTAGCGGAATC 
               
               
                   
                   
                 CCGGACAGGTTCTCGGGTTCCAACTCCGCGGACACTGCTACTCTGACC 
               
               
                   
                   
                 ATCTCGGGGACCCAGGCTATGGACGAAGCCGATTACTACTGCCAAGCC 
               
               
                   
                   
                 TGGGACGACACTACTGTCGTGTTTGGAGGGGGCACCAAGTTGACCGTC 
               
               
                   
                   
                 CTT 
               
               
                   
               
               
                 149366-aa 
                 1517 
                 QVQLVQSGAEVKKPGASVKVSCKPSGYTVTSHYIHWVRRAPGQGLEWM 
               
               
                 VH 
                   
                 GMINPSGGVTAYSQTLQGRVTMTSDTSSSTVYMELSSLRSEDTAMYYC 
               
               
                   
                   
                 AREGSGSGWYFDFWGRGTLVTVSS 
               
               
                   
               
               
                 149366-aa 
                 1518 
                 SYVLTQPPSVSVSPGQTASITCSGDGLSKKYVSWYQQKAGQSPVVLIS 
               
               
                 VL 
                   
                 RDKERPSGIPDRFSGSNSADTATLTISGTQAMDEADYYCQAWDDTTVV 
               
               
                   
                   
                 FGGGTKLTVL 
               
               
                   
               
               
                 149366-aa 
                 1519 
                 MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGASVKVSCKPSGY 
               
               
                 Full CAR 
                   
                 TVTSHYIHWVRRAPGQGLEWMGMINPSGGVTAYSQTLQGRVTMTSDTS 
               
               
                   
                   
                 SSTVYMELSSLRSEDTAMYYCAREGSGSGWYFDFWGRGTLVTVSSGGG 
               
               
                   
                   
                 GSGGGGSGGGGSSYVLTQPPSVSVSPGQTASITCSGDGLSKKYVSWYQ 
               
               
                   
                   
                 QKAGQSPVVLISRDKERPSGIPDRFSGSNSADTATLTISGTQAMDEAD 
               
               
                   
                   
                 YYCQAWDDTTVVFGGGTKLTVLTTTPAPRPPTPAPTIASQPLSLRPEA 
               
               
                   
                   
                 CRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRK 
               
               
                   
                   
                 KLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAP 
               
               
                   
                   
                 AYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLY 
               
               
                   
                   
                 NELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQ 
               
               
                   
                   
                 ALPPR 
               
               
                   
               
               
                 149366-nt 
                 1520 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCCAAGTGCAGCTGGTGCAGAGCGGGGCCGAAGTC 
               
               
                   
                   
                 AAGAAGCCGGGAGCCTCCGTGAAAGTGTCCTGCAAGCCTTCGGGATAC 
               
               
                   
                   
                 ACCGTGACCTCCCACTACATTCATTGGGTCCGCCGCGCCCCCGGCCAA 
               
               
                   
                   
                 GGACTCGAGTGGATGGGCATGATCAACCCTAGCGGCGGAGTGACCGCG 
               
               
                   
                   
                 TACAGCCAGACGCTGCAGGGACGCGTGACTATGACCTCGGATACCTCC 
               
               
                   
                   
                 TCCTCCACCGTCTATATGGAACTGTCCAGCCTGCGGTCCGAGGATACC 
               
               
                   
                   
                 GCCATGTACTACTGCGCCCGGGAAGGATCAGGCTCCGGGTGGTATTTC 
               
               
                   
                   
                 GACTTCTGGGGAAGAGGCACCCTCGTGACTGTGTCATCTGGGGGAGGG 
               
               
                   
                   
                 GGTTCCGGTGGTGGCGGATCGGGAGGAGGCGGTTCATCCTACGTGCTG 
               
               
                   
                   
                 ACCCAGCCACCCTCCGTGTCCGTGAGCCCCGGCCAGACTGCATCGATT 
               
               
                   
                   
                 ACATGTAGCGGCGACGGCCTCTCCAAGAAATACGTGTCGTGGTACCAG 
               
               
                   
                   
                 CAGAAGGCCGGACAGAGCCCGGTGGTGCTGATCTCAAGAGATAAGGAG 
               
               
                   
                   
                 CGGCCTAGCGGAATCCCGGACAGGTTCTCGGGTTCCAACTCCGCGGAC 
               
               
                   
                   
                 ACTGCTACTCTGACCATCTCGGGGACCCAGGCTATGGACGAAGCCGAT 
               
               
                   
                   
                 TACTACTGCCAAGCCTGGGACGACACTACTGTCGTGTTTGGAGGGGGC 
               
               
                   
                   
                 ACCAAGTTGACCGTCCTTACCACTACCCCAGCACCGAGGCCACCCACC 
               
               
                   
                   
                 CCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCA 
               
               
                   
                   
                 TGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTC 
               
               
                   
                   
                 GCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTC 
               
               
                   
                   
                 CTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAG 
               
               
                   
                   
                 AAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACT 
               
               
                   
                   
                 ACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAA 
               
               
                   
                   
                 GGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCA 
               
               
                   
                   
                 GCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGT 
               
               
                   
                   
                 CGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCA 
               
               
                   
                   
                 GAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTAC 
               
               
                   
                   
                 AACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGT 
               
               
                   
                   
                 ATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAG 
               
               
                   
                   
                 GGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAG 
               
               
                   
                   
                 GCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 149367 
               
            
           
           
               
               
               
            
               
                 149367-aa 
                 1521 
                 QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLE 
               
               
                 ScFv 
                   
                 WIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYY 
               
               
                 domain 
                   
                 CARAGIAARLRGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSDIVMTQ 
               
               
                   
                   
                 SPSSVSASVGDRVIITCRASQGIRNWLAWYQQKPGKAPNLLIYAASNL 
               
               
                   
                   
                 QSGVPSRFSGSGSGADFTLTISSLQPEDVATYYCQKYNSAPFTFGPGT 
               
               
                   
                   
                 KVDIK 
               
               
                   
               
               
                 149367-nt 
                 1522 
                 CAAGTGCAGCTTCAGGAGAGCGGCCCGGGACTCGTGAAGCCGTCCCAG 
               
               
                 ScFv 
                   
                 ACCCTGTCCCTGACTTGCACCGTGTCGGGAGGAAGCATCTCGAGCGGA 
               
               
                 domain 
                   
                 GGCTACTATTGGTCGTGGATTCGGCAGCACCCTGGAAAGGGCCTGGAA 
               
               
                   
                   
                 TGGATCGGCTACATCTACTACTCCGGCTCGACCTACTACAACCCATCG 
               
               
                   
                   
                 CTGAAGTCCAGAGTGACAATCTCAGTGGACACGTCCAAGAATCAGTTC 
               
               
                   
                   
                 AGCCTGAAGCTCTCTTCCGTGACTGCGGCCGACACCGCCGTGTACTAC 
               
               
                   
                   
                 TGCGCACGCGCTGGAATTGCCGCCCGGCTGAGGGGTGCCTTCGACATT 
               
               
                   
                   
                 TGGGGACAGGGCACCATGGTCACCGTGTCCTCCGGCGGCGGAGGTTCC 
               
               
                   
                   
                 GGGGGTGGAGGCTCAGGAGGAGGGGGGTCCGACATCGTCATGACTCAG 
               
               
                   
                   
                 TCGCCCTCAAGCGTCAGCGCGTCCGTCGGGGACAGAGTGATCATCACC 
               
               
                   
                   
                 TGTCGGGCGTCCCAGGGAATTCGCAACTGGCTGGCCTGGTATCAGCAG 
               
               
                   
                   
                 AAGCCCGGAAAGGCCCCCAACCTGTTGATCTACGCCGCCTCAAACCTC 
               
               
                   
                   
                 CAATCCGGGGTGCCGAGCCGCTTCAGCGGCTCCGGTTCGGGTGCCGAT 
               
               
                   
                   
                 TTCACTCTGACCATCTCCTCCCTGCAACCTGAAGATGTGGCTACCTAC 
               
               
                   
                   
                 TACTGCCAAAAGTACAACTCCGCACCTTTTACTTTCGGACCGGGGACC 
               
               
                   
                   
                 AAAGTGGACATTAAG 
               
               
                   
               
               
                 149367-aa 
                 1523 
                 QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLE 
               
               
                 VH 
                   
                 WIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYY 
               
               
                   
                   
                 CARAGIAARLRGAFDIWGQGTMVTVSS 
               
               
                   
               
               
                 149367-aa 
                 1524 
                 DIVMTQSPSSVSASVGDRVIITCRASQGIRNWLAWYQQKPGKAPNLLI 
               
               
                 VL 
                   
                 YAASNLQSGVPSRFSGSGSGADFTLTISSLQPEDVATYYCQKYNSAPF 
               
               
                   
                   
                 TFGPGTKVDIK 
               
               
                   
               
               
                 149367-aa 
                 1525 
                 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSQTLSLTCTVSGG 
               
               
                 Full CAR 
                   
                 SISSGGYYWSWIRQHPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDT 
               
               
                   
                   
                 SKNQFSLKLSSVTAADTAVYYCARAGIAARLRGAFDIWGQGTMVTVSS 
               
               
                   
                   
                 GGGGSGGGGSGGGGSDIVMTQSPSSVSASVGDRVIITCRASQGIRNWL 
               
               
                   
                   
                 AWYQQKPGKAPNLLIYAASNLQSGVPSRFSGSGSGADFTLTISSLQPE 
               
               
                   
                   
                 DVATYYCQKYNSAPFTFGPGTKVDIKTTTPAPRPPTPAPTIASQPLSL 
               
               
                   
                   
                 RPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCK 
               
               
                   
                   
                 RGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRS 
               
               
                   
                   
                 ADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQ 
               
               
                   
                   
                 EGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDA 
               
               
                   
                   
                 LHMQALPPR 
               
               
                   
               
               
                 149367-nt 
                 1526 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCCAAGTGCAGCTTCAGGAGAGCGGCCCGGGACTC 
               
               
                   
                   
                 GTGAAGCCGTCCCAGACCCTGTCCCTGACTTGCACCGTGTCGGGAGGA 
               
               
                   
                   
                 AGCATCTCGAGCGGAGGCTACTATTGGTCGTGGATTCGGCAGCACCCT 
               
               
                   
                   
                 GGAAAGGGCCTGGAATGGATCGGCTACATCTACTACTCCGGCTCGACC 
               
               
                   
                   
                 TACTACAACCCATCGCTGAAGTCCAGAGTGACAATCTCAGTGGACACG 
               
               
                   
                   
                 TCCAAGAATCAGTTCAGCCTGAAGCTCTCTTCCGTGACTGCGGCCGAC 
               
               
                   
                   
                 ACCGCCGTGTACTACTGCGCACGCGCTGGAATTGCCGCCCGGCTGAGG 
               
               
                   
                   
                 GGTGCCTTCGACATTTGGGGACAGGGCACCATGGTCACCGTGTCCTCC 
               
               
                   
                   
                 GGCGGCGGAGGTTCCGGGGGTGGAGGCTCAGGAGGAGGGGGGTCCGAC 
               
               
                   
                   
                 ATCGTCATGACTCAGTCGCCCTCAAGCGTCAGCGCGTCCGTCGGGGAC 
               
               
                   
                   
                 AGAGTGATCATCACCTGTCGGGCGTCCCAGGGAATTCGCAACTGGCTG 
               
               
                   
                   
                 GCCTGGTATCAGCAGAAGCCCGGAAAGGCCCCCAACCTGTTGATCTAC 
               
               
                   
                   
                 GCCGCCTCAAACCTCCAATCCGGGGTGCCGAGCCGCTTCAGCGGCTCC 
               
               
                   
                   
                 GGTTCGGGTGCCGATTTCACTCTGACCATCTCCTCCCTGCAACCTGAA 
               
               
                   
                   
                 GATGTGGCTACCTACTACTGCCAAAAGTACAACTCCGCACCTTTTACT 
               
               
                   
                   
                 TTCGGACCGGGGACCAAAGTGGACATTAAGACCACTACCCCAGCACCG 
               
               
                   
                   
                 AGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTG 
               
               
                   
                   
                 CGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGG 
               
               
                   
                   
                 GGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGT 
               
               
                   
                   
                 ACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAG 
               
               
                   
                   
                 CGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGG 
               
               
                   
                   
                 CCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCA 
               
               
                   
                   
                 GAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGC 
               
               
                   
                   
                 GCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAA 
               
               
                   
                   
                 CTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGA 
               
               
                   
                   
                 GGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAA 
               
               
                   
                   
                 GAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTAT 
               
               
                   
                   
                 AGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGAC 
               
               
                   
                   
                 GGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCT 
               
               
                   
                   
                 CTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 149368 
               
            
           
           
               
               
               
            
               
                 149368-aa 
                 1527 
                 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWM 
               
               
                 ScFv 
                   
                 GGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC 
               
               
                 domain 
                   
                 ARRGGYQLLRWDVGLLRSAFDIWGQGTMVTVSSGGGGSGGGGSGGGGS 
               
               
                   
                   
                 SYVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVLY 
               
               
                   
                   
                 GKNNRPSGVPDRFSGSRSGTTASLTITGAQAEDEADYYCSSRDSSGDH 
               
               
                   
                   
                 LRVFGTGTKVTVL 
               
               
                   
               
               
                 149368-nt 
                 1528 
                 CAAGTGCAGCTGGTCCAGTCGGGCGCCGAGGTCAAGAAGCCCGGGAGC 
               
               
                 ScFv 
                   
                 TCTGTGAAAGTGTCCTGCAAGGCCTCCGGGGGCACCTTTAGCTCCTAC 
               
               
                 domain 
                   
                 GCCATCTCCTGGGTCCGCCAAGCACCGGGTCAAGGCCTGGAGTGGATG 
               
               
                   
                   
                 GGGGGAATTATCCCTATCTTCGGCACTGCCAACTACGCCCAGAAGTTC 
               
               
                   
                   
                 CAGGGACGCGTGACCATTACCGCGGACGAATCCACCTCCACCGCTTAT 
               
               
                   
                   
                 ATGGAGCTGTCCAGCTTGCGCTCGGAAGATACCGCCGTGTACTACTGC 
               
               
                   
                   
                 GCCCGGAGGGGTGGATACCAGCTGCTGAGATGGGACGTGGGCCTCCTG 
               
               
                   
                   
                 CGGTCGGCGTTCGACATCTGGGGCCAGGGCACTATGGTCACTGTGTCC 
               
               
                   
                   
                 AGCGGAGGAGGCGGATCGGGAGGCGGCGGATCAGGGGGAGGCGGTTCC 
               
               
                   
                   
                 AGCTACGTGCTTACTCAACCCCCTTCGGTGTCCGTGGCCCCGGGACAG 
               
               
                   
                   
                 ACCGCCAGAATCACTTGCGGAGGAAACAACATTGGGTCCAAGAGCGTG 
               
               
                   
                   
                 CATTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTGCTGGTGCTCTAC 
               
               
                   
                   
                 GGGAAGAACAATCGGCCCAGCGGAGTGCCGGACAGGTTCTCGGGTTCA 
               
               
                   
                   
                 CGCTCCGGTACAACCGCTTCACTGACTATCACCGGGGCCCAGGCAGAG 
               
               
                   
                   
                 GATGAAGCGGACTACTACTGTTCCTCCCGGGATTCATCCGGCGACCAC 
               
               
                   
                   
                 CTCCGGGTGTTCGGAACCGGAACGAAGGTCACCGTGCTG 
               
               
                   
               
               
                 149368-aa 
                 1529 
                 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWM 
               
               
                 VH 
                   
                 GGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYC 
               
               
                   
                   
                 ARRGGYQLLRWDVGLLRSAFDIWGQGTMVTVSS 
               
               
                   
               
               
                 149368-aa 
                 1530 
                 SYVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVLY 
               
               
                 VL 
                   
                 GKNNRPSGVPDRFSGSRSGTTASLTITGAQAEDEADYYCSSRDSSGDH 
               
               
                   
                   
                 LRVFGTGTKVTVL 
               
               
                   
               
               
                 149368-aa 
                 1531 
                 MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGSSVKVSCKASGG 
               
               
                 Full CAR 
                   
                 TESSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADES 
               
               
                   
                   
                 TSTAYMELSSLRSEDTAVYYCARRGGYQLLRWDVGLLRSAFDIWGQGT 
               
               
                   
                   
                 MVTVSSGGGGSGGGGSGGGGSSYVLTQPPSVSVAPGQTARITCGGNNI 
               
               
                   
                   
                 GSKSVHWYQQKPGQAPVLVLYGKNNRPSGVPDRFSGSRSGTTASLTIT 
               
               
                   
                   
                 GAQAEDEADYYCSSRDSSGDHLRVFGTGTKVTVLTTTPAPRPPTPAPT 
               
               
                   
                   
                 IASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLS 
               
               
                   
                   
                 LVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCE 
               
               
                   
                   
                 LRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGG 
               
               
                   
                   
                 KPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLST 
               
               
                   
                   
                 ATKDTYDALHMQALPPR 
               
               
                   
               
               
                 149368-nt 
                 1532 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCCAAGTGCAGCTGGTCCAGTCGGGCGCCGAGGTC 
               
               
                   
                   
                 AAGAAGCCCGGGAGCTCTGTGAAAGTGTCCTGCAAGGCCTCCGGGGGC 
               
               
                   
                   
                 ACCTTTAGCTCCTACGCCATCTCCTGGGTCCGCCAAGCACCGGGTCAA 
               
               
                   
                   
                 GGCCTGGAGTGGATGGGGGGAATTATCCCTATCTTCGGCACTGCCAAC 
               
               
                   
                   
                 TACGCCCAGAAGTTCCAGGGACGCGTGACCATTACCGCGGACGAATCC 
               
               
                   
                   
                 ACCTCCACCGCTTATATGGAGCTGTCCAGCTTGCGCTCGGAAGATACC 
               
               
                   
                   
                 GCCGTGTACTACTGCGCCCGGAGGGGTGGATACCAGCTGCTGAGATGG 
               
               
                   
                   
                 GACGTGGGCCTCCTGCGGTCGGCGTTCGACATCTGGGGCCAGGGCACT 
               
               
                   
                   
                 ATGGTCACTGTGTCCAGCGGAGGAGGCGGATCGGGAGGCGGCGGATCA 
               
               
                   
                   
                 GGGGGAGGCGGTTCCAGCTACGTGCTTACTCAACCCCCTTCGGTGTCC 
               
               
                   
                   
                 GTGGCCCCGGGACAGACCGCCAGAATCACTTGCGGAGGAAACAACATT 
               
               
                   
                   
                 GGGTCCAAGAGCGTGCATTGGTACCAGCAGAAGCCAGGACAGGCCCCT 
               
               
                   
                   
                 GTGCTGGTGCTCTACGGGAAGAACAATCGGCCCAGCGGAGTGCCGGAC 
               
               
                   
                   
                 AGGTTCTCGGGTTCACGCTCCGGTACAACCGCTTCACTGACTATCACC 
               
               
                   
                   
                 GGGGCCCAGGCAGAGGATGAAGCGGACTACTACTGTTCCTCCCGGGAT 
               
               
                   
                   
                 TCATCCGGCGACCACCTCCGGGTGTTCGGAACCGGAACGAAGGTCACC 
               
               
                   
                   
                 GTGCTGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACC 
               
               
                   
                   
                 ATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCA 
               
               
                   
                   
                 GCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATC 
               
               
                   
                   
                 TACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCA 
               
               
                   
                   
                 CTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTAC 
               
               
                   
                   
                 ATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAG 
               
               
                   
                   
                 GACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAA 
               
               
                   
                   
                 CTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAG 
               
               
                   
                   
                 GGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAG 
               
               
                   
                   
                 TACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGG 
               
               
                   
                   
                 AAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAA 
               
               
                   
                   
                 AAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAA 
               
               
                   
                   
                 CGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACC 
               
               
                   
                   
                 GCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCT 
               
               
                   
                   
                 CGG 
               
               
                   
               
            
           
           
               
            
               
                 149369 
               
            
           
           
               
               
               
            
               
                 149369-aa 
                 1533 
                 EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLE 
               
               
                 ScFv 
                   
                 WLGRTYYRSKWYSFYAISLKSRIIINPDTSKNQFSLQLKSVTPEDTAV 
               
               
                 domain 
                   
                 YYCARSSPEGLFLYWFDPWGQGTLVTVSSGGDGSGGGGSGGGGSSSEL 
               
               
                   
                   
                 TQDPAVSVALGQTIRITCQGDSLGNYYATWYQQKPGQAPVLVIYGTNN 
               
               
                   
                   
                 RPSGIPDRFSASSSGNTASLTITGAQAEDEADYYCNSRDSSGHHLLFG 
               
               
                   
                   
                 TGTKVTVL 
               
               
                   
               
               
                 149369-nt 
                 1534 
                 GAAGTGCAGCTCCAACAGTCAGGACCGGGGCTCGTGAAGCCATCCCAG 
               
               
                 ScFv 
                   
                 ACCCTGTCCCTGACTTGTGCCATCTCGGGAGATAGCGTGTCATCGAAC 
               
               
                 domain 
                   
                 TCCGCCGCCTGGAACTGGATTCGGCAGAGCCCGTCCCGCGGACTGGAG 
               
               
                   
                   
                 TGGCTTGGAAGGACCTACTACCGGTCCAAGTGGTACTCTTTCTACGCG 
               
               
                   
                   
                 ATCTCGCTGAAGTCCCGCATTATCATTAACCCTGATACCTCCAAGAAT 
               
               
                   
                   
                 CAGTTCTCCCTCCAACTGAAATCCGTCACCCCCGAGGACACAGCAGTG 
               
               
                   
                   
                 TATTACTGCGCACGGAGCAGCCCCGAAGGACTGTTCCTGTATTGGTTT 
               
               
                   
                   
                 GACCCCTGGGGCCAGGGGACTCTTGTGACCGTGTCGAGCGGCGGAGAT 
               
               
                   
                   
                 GGGTCCGGTGGCGGTGGTTCGGGGGGCGGCGGATCATCATCCGAACTG 
               
               
                   
                   
                 ACCCAGGACCCGGCTGTGTCCGTGGCGCTGGGACAAACCATCCGCATT 
               
               
                   
                   
                 ACGTGCCAGGGAGACTCCCTGGGCAACTACTACGCCACTTGGTACCAG 
               
               
                   
                   
                 CAGAAGCCGGGCCAAGCCCCTGTGTTGGTCATCTACGGGACCAACAAC 
               
               
                   
                   
                 AGACCTTCCGGCATCCCCGACCGGTTCAGCGCTTCGTCCTCCGGCAAC 
               
               
                   
                   
                 ACTGCCAGCCTGACCATCACTGGAGCGCAGGCCGAAGATGAGGCCGAC 
               
               
                   
                   
                 TACTACTGCAACAGCAGAGACTCCTCGGGTCATCACCTCTTGTTCGGA 
               
               
                   
                   
                 ACTGGAACCAAGGTCACCGTGCTG 
               
               
                   
               
               
                 149369-aa 
                 1535 
                 EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLE 
               
               
                 VH 
                   
                 WLGRTYYRSKWYSFYAISLKSRIIINPDTSKNQFSLQLKSVTPEDTAV 
               
               
                   
                   
                 YYCARSSPEGLFLYWFDPWGQGTLVTVSS 
               
               
                   
               
               
                 149369-aa 
                 1536 
                 SSELTQDPAVSVALGQTIRITCQGDSLGNYYATWYQQKPGQAPVLVIY 
               
               
                 VL 
                   
                 GTNNRPSGIPDRFSASSSGNTASLTITGAQAEDEADYYCNSRDSSGHH 
               
               
                   
                   
                 LLFGTGTKVTVL 
               
               
                   
               
               
                 149369-aa 
                 1537 
                 MALPVTALLLPLALLLHAARPEVQLQQSGPGLVKPSQTLSLTCAISGD 
               
               
                 Full CAR 
                   
                 SVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWYSFYAISLKSRIIINP 
               
               
                   
                   
                 DTSKNQFSLQLKSVTPEDTAVYYCARSSPEGLFLYWFDPWGQGTLVTV 
               
               
                   
                   
                 SSGGDGSGGGGSGGGGSSSELTQDPAVSVALGQTIRITCQGDSLGNYY 
               
               
                   
                   
                 ATWYQQKPGQAPVLVIYGTNNRPSGIPDRFSASSSGNTASLTITGAQA 
               
               
                   
                   
                 EDEADYYCNSRDSSGHHLLFGTGTKVTVLTTTPAPRPPTPAPTIASQP 
               
               
                   
                   
                 LSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITL 
               
               
                   
                   
                 YCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKF 
               
               
                   
                   
                 SRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRK 
               
               
                   
                   
                 NPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDT 
               
               
                   
                   
                 YDALHMQALPPR 
               
               
                   
               
               
                 149369-nt 
                 1538 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 Full CAR 
                   
                 CACGCCGCTCGGCCCGAAGTGCAGCTCCAACAGTCAGGACCGGGGCTC 
               
               
                   
                   
                 GTGAAGCCATCCCAGACCCTGTCCCTGACTTGTGCCATCTCGGGAGAT 
               
               
                   
                   
                 AGCGTGTCATCGAACTCCGCCGCCTGGAACTGGATTCGGCAGAGCCCG 
               
               
                   
                   
                 TCCCGCGGACTGGAGTGGCTTGGAAGGACCTACTACCGGTCCAAGTGG 
               
               
                   
                   
                 TACTCTTTCTACGCGATCTCGCTGAAGTCCCGCATTATCATTAACCCT 
               
               
                   
                   
                 GATACCTCCAAGAATCAGTTCTCCCTCCAACTGAAATCCGTCACCCCC 
               
               
                   
                   
                 GAGGACACAGCAGTGTATTACTGCGCACGGAGCAGCCCCGAAGGACTG 
               
               
                   
                   
                 TTCCTGTATTGGTTTGACCCCTGGGGCCAGGGGACTCTTGTGACCGTG 
               
               
                   
                   
                 TCGAGCGGCGGAGATGGGTCCGGTGGCGGTGGTTCGGGGGGCGGCGGA 
               
               
                   
                   
                 TCATCATCCGAACTGACCCAGGACCCGGCTGTGTCCGTGGCGCTGGGA 
               
               
                   
                   
                 CAAACCATCCGCATTACGTGCCAGGGAGACTCCCTGGGCAACTACTAC 
               
               
                   
                   
                 GCCACTTGGTACCAGCAGAAGCCGGGCCAAGCCCCTGTGTTGGTCATC 
               
               
                   
                   
                 TACGGGACCAACAACAGACCTTCCGGCATCCCCGACCGGTTCAGCGCT 
               
               
                   
                   
                 TCGTCCTCCGGCAACACTGCCAGCCTGACCATCACTGGAGCGCAGGCC 
               
               
                   
                   
                 GAAGATGAGGCCGACTACTACTGCAACAGCAGAGACTCCTCGGGTCAT 
               
               
                   
                   
                 CACCTCTTGTTCGGAACTGGAACCAAGGTCACCGTGCTGACCACTACC 
               
               
                   
                   
                 CCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCT 
               
               
                   
                   
                 CTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTG 
               
               
                   
                   
                 CATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCT 
               
               
                   
                   
                 CTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTT 
               
               
                   
                   
                 TACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCC 
               
               
                   
                   
                 TTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGC 
               
               
                   
                   
                 CGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTC 
               
               
                   
                   
                 AGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTC 
               
               
                   
                   
                 TACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGAC 
               
               
                   
                   
                 AAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAG 
               
               
                   
                   
                 AATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCA 
               
               
                   
                   
                 GAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAA 
               
               
                   
                   
                 GGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACC 
               
               
                   
                   
                 TATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-A4 
               
            
           
           
               
               
               
            
               
                 BCMA_EB 
                 1539 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1978-A4- 
                   
                 SAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC 
               
               
                 aa 
                   
                 AKVEGSGSLDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPGTL 
               
               
                 ScFv 
                   
                 SLSPGERATLSCRASQSVSSAYLAWYQQKPGQPPRLLISGASTRATGI 
               
               
                 domain 
                   
                 PDRFGGSGSGTDFTLTISRLEPEDFAVYYCQHYGSSFNGSSLFTFGQG 
               
               
                   
                   
                 TRLEIK 
               
               
                   
               
               
                 BCMA_EB 
                 1540 
                 GAAGTGCAGCTCGTGGAGTCAGGAGGCGGCCTGGTCCAGCCGGGAGGG 
               
               
                 B-C1978-A4- 
                   
                 TCCCTTAGACTGTCATGCGCCGCAAGCGGATTCACTTTCTCCTCCTAT 
               
               
                 nt 
                   
                 GCCATGAGCTGGGTCCGCCAAGCCCCCGGAAAGGGACTGGAATGGGTG 
               
               
                 ScFv 
                   
                 TCCGCCATCTCGGGGTCTGGAGGCTCAACTTACTACGCTGACTCCGTG 
               
               
                 domain 
                   
                 AAGGGACGGTTCACCATTAGCCGCGACAACTCCAAGAACACCCTCTAC 
               
               
                   
                   
                 CTCCAAATGAACTCCCTGCGGGCCGAGGATACCGCCGTCTACTACTGC 
               
               
                   
                   
                 GCCAAAGTGGAAGGTTCAGGATCGCTGGACTACTGGGGACAGGGTACT 
               
               
                   
                   
                 CTCGTGACCGTGTCATCGGGCGGAGGAGGTTCCGGCGGTGGCGGCTCC 
               
               
                   
                   
                 GGCGGCGGAGGGTCGGAGATCGTGATGACCCAGAGCCCTGGTACTCTG 
               
               
                   
                   
                 AGCCTTTCGCCGGGAGAAAGGGCCACCCTGTCCTGCCGCGCTTCCCAA 
               
               
                   
                   
                 TCCGTGTCCTCCGCGTACTTGGCGTGGTACCAGCAGAAGCCGGGACAG 
               
               
                   
                   
                 CCCCCTCGGCTGCTGATCAGCGGGGCCAGCACCCGGGCAACCGGAATC 
               
               
                   
                   
                 CCAGACAGATTCGGGGGTTCCGGCAGCGGCACAGATTTCACCCTGACT 
               
               
                   
                   
                 ATTTCGAGGTTGGAGCCCGAGGACTTTGCGGTGTATTACTGTCAGCAC 
               
               
                   
                   
                 TACGGGTCGTCCTTTAATGGCTCCAGCCTGTTCACGTTCGGACAGGGG 
               
               
                   
                   
                 ACCCGCCTGGAAATCAAG 
               
               
                   
               
               
                 BCMA_EB 
                 1541 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1978-A4- 
                   
                 SAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC 
               
               
                 aa 
                   
                 AKVEGSGSLDYWGQGTLVTVSS 
               
               
                 VH 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1542 
                 EIVMTQSPGTLSLSPGERATLSCRASQSVSSAYLAWYQQKPGQPPRLL 
               
               
                 B-C1978-A4 
                   
                 ISGASTRATGIPDRFGGSGSGTDFTLTISRLEPEDFAVYYCQHYGSSF 
               
               
                 -aa 
                   
                 NGSSLFTFGQGTRLEIK 
               
               
                 VL 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1543 
                 MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGF 
               
               
                 B-C1978-A4- 
                   
                 TFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNS 
               
               
                 aa 
                   
                 KNTLYLQMNSLRAEDTAVYYCAKVEGSGSLDYWGQGTLVTVSSGGGGS 
               
               
                 Full CART 
                   
                 GGGGSGGGGSEIVMTQSPGTLSLSPGERATLSCRASQSVSSAYLAWYQ 
               
               
                   
                   
                 QKPGQPPRLLISGASTRATGIPDRFGGSGSGTDFTLTISRLEPEDFAV 
               
               
                   
                   
                 YYCQHYGSSFNGSSLFTFGQGTRLEIKTTTPAPRPPTPAPTIASQPLS 
               
               
                   
                   
                 LRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYC 
               
               
                   
                   
                 KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSR 
               
               
                   
                   
                 SADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNP 
               
               
                   
                   
                 QEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYD 
               
               
                   
                   
                 ALHMQALPPR 
               
               
                   
               
               
                 BCMA_EB 
                 1544 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 B-C1978-A4- 
                   
                 CACGCCGCTCGGCCCGAAGTGCAGCTCGTGGAGTCAGGAGGCGGCCTG 
               
               
                 nt 
                   
                 GTCCAGCCGGGAGGGTCCCTTAGACTGTCATGCGCCGCAAGCGGATTC 
               
               
                 Full CART 
                   
                 ACTTTCTCCTCCTATGCCATGAGCTGGGTCCGCCAAGCCCCCGGAAAG 
               
               
                   
                   
                 GGACTGGAATGGGTGTCCGCCATCTCGGGGTCTGGAGGCTCAACTTAC 
               
               
                   
                   
                 TACGCTGACTCCGTGAAGGGACGGTTCACCATTAGCCGCGACAACTCC 
               
               
                   
                   
                 AAGAACACCCTCTACCTCCAAATGAACTCCCTGCGGGCCGAGGATACC 
               
               
                   
                   
                 GCCGTCTACTACTGCGCCAAAGTGGAAGGTTCAGGATCGCTGGACTAC 
               
               
                   
                   
                 TGGGGACAGGGTACTCTCGTGACCGTGTCATCGGGCGGAGGAGGTTCC 
               
               
                   
                   
                 GGCGGTGGCGGCTCCGGCGGCGGAGGGTCGGAGATCGTGATGACCCAG 
               
               
                   
                   
                 AGCCCTGGTACTCTGAGCCTTTCGCCGGGAGAAAGGGCCACCCTGTCC 
               
               
                   
                   
                 TGCCGCGCTTCCCAATCCGTGTCCTCCGCGTACTTGGCGTGGTACCAG 
               
               
                   
                   
                 CAGAAGCCGGGACAGCCCCCTCGGCTGCTGATCAGCGGGGCCAGCACC 
               
               
                   
                   
                 CGGGCAACCGGAATCCCAGACAGATTCGGGGGTTCCGGCAGCGGCACA 
               
               
                   
                   
                 GATTTCACCCTGACTATTTCGAGGTTGGAGCCCGAGGACTTTGCGGTG 
               
               
                   
                   
                 TATTACTGTCAGCACTACGGGTCGTCCTTTAATGGCTCCAGCCTGTTC 
               
               
                   
                   
                 ACGTTCGGACAGGGGACCCGCCTGGAAATCAAGACCACTACCCCAGCA 
               
               
                   
                   
                 CCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCC 
               
               
                   
                   
                 CTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACC 
               
               
                   
                   
                 CGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCT 
               
               
                   
                   
                 GGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGT 
               
               
                   
                   
                 AAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATG 
               
               
                   
                   
                 AGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTC 
               
               
                   
                   
                 CCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGC 
               
               
                   
                   
                 AGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAAC 
               
               
                   
                   
                 GAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGG 
               
               
                   
                   
                 AGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCC 
               
               
                   
                   
                 CAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCC 
               
               
                   
                   
                 TATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCAC 
               
               
                   
                   
                 GACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGAC 
               
               
                   
                   
                 GCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-G1 
               
            
           
           
               
               
               
            
               
                 BCMA_EB 
                 1545 
                 EVQLVETGGGLVQPGGSLRLSCAASGITFSRYPMSWVRQAPGKG 
               
               
                 B-C1978-G1- 
                   
                 LEWVSGISDSGVSTYYADSAKGRFTISRDNSKNTLFLQMSSLRDE 
               
               
                 aa 
                   
                 DTAVYYCVTRAGSEASDIWGQGTMVTVSSGGGGSGGGGSGGG 
               
               
                 ScFv 
                   
                 GSEIVLTQSPATLSLSPGERATLSCRASQSVSNSLAWYQQKPGQA 
               
               
                 domain 
                   
                 PRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAIYYCQQ 
               
               
                   
                   
                 FGTSSGLTFGGGTKLEIK 
               
               
                   
               
               
                 BCMA_EB 
                 1546 
                 GAAGTGCAACTGGTGGAAACCGGTGGCGGCCTGGTGCAGCCTGGAGGA 
               
               
                 B-C1978-G1- 
                   
                 TCATTGAGGCTGTCATGCGCGGCCAGCGGTATTACCTTCTCCCGGTAC 
               
               
                 nt 
                   
                 CCCATGTCCTGGGTCAGACAGGCCCCGGGGAAAGGGCTTGAATGGGTG 
               
               
                 ScFv 
                   
                 TCCGGGATCTCGGACTCCGGTGTCAGCACTTACTACGCCGACTCCGCC 
               
               
                 domain 
                   
                 AAGGGACGCTTCACCATTTCCCGGGACAACTCGAAGAACACCCTGTTC 
               
               
                   
                   
                 CTCCAAATGAGCTCCCTCCGGGACGAGGATACTGCAGTGTACTACTGC 
               
               
                   
                   
                 GTGACCCGCGCCGGGTCCGAGGCGTCTGACATTTGGGGACAGGGCACT 
               
               
                   
                   
                 ATGGTCACCGTGTCGTCCGGCGGAGGGGGCTCGGGAGGCGGTGGCAGC 
               
               
                   
                   
                 GGAGGAGGAGGGTCCGAGATCGTGCTGACCCAATCCCCGGCCACCCTC 
               
               
                   
                   
                 TCGCTGAGCCCTGGAGAAAGGGCAACCTTGTCCTGTCGCGCGAGCCAG 
               
               
                   
                   
                 TCCGTGAGCAACTCCCTGGCCTGGTACCAGCAGAAGCCCGGACAGGCT 
               
               
                   
                   
                 CCGAGACTTCTGATCTACGACGCTTCGAGCCGGGCCACTGGAATCCCC 
               
               
                   
                   
                 GACCGCTTTTCGGGGTCCGGCTCAGGAACCGATTTCACCCTGACAATC 
               
               
                   
                   
                 TCACGGCTGGAGCCAGAGGATTTCGCCATCTATTACTGCCAGCAGTTC 
               
               
                   
                   
                 GGTACTTCCTCCGGCCTGACTTTCGGAGGCGGCACGAAGCTCGAAATC 
               
               
                   
                   
                 AAG 
               
               
                   
               
               
                 BCMA_EB 
                 1547 
                 EVQLVETGGGLVQPGGSLRLSCAASGITFSRYPMSWVRQAPGKGLEWV 
               
               
                 B-C1978-G1- 
                   
                 SGISDSGVSTYYADSAKGRFTISRDNSKNTLFLQMSSLRDEDTAVYYC 
               
               
                 aa 
                   
                 VTRAGSEASDIWGQGTMVTVSS 
               
               
                 VH 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1548 
                 EIVLTQSPATLSLSPGERATLSCRASQSVSNSLAWYQQKPGQAPRLLI 
               
               
                 B-C1978-G1- 
                   
                 YDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAIYYCQQFGTSSG 
               
               
                 aa 
                   
                 LTFGGGTKLEIK 
               
               
                 VL 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1549 
                 MALPVTALLLPLALLLHAARPEVQLVETGGGLVQPGGSLRLSCA 
               
               
                 B-C1978-G1- 
                   
                 ASGITFSRYPMSWVRQAPGKGLEWVSGISDSGVSTYYADSAKGR 
               
               
                 aa 
                   
                 FTISRDNSKNTLFLQMSSLRDEDTAVYYCVTRAGSEASDIWGQG 
               
               
                 Full CART 
                   
                 TMVTVSSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSC 
               
               
                   
                   
                 RASQSVSNSLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSG 
               
               
                   
                   
                 TDFTLTISRLEPEDFAIYYCQQFGTSSGLTFGGGTKLEIKTTTPAPR 
               
               
                   
                   
                 PPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPL 
               
               
                   
                   
                 AGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDG 
               
               
                   
                   
                 CSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRR 
               
               
                   
                   
                 EEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAY 
               
               
                   
                   
                 SEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                 BCMA_EB 
                 1550 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 B-C1978-G1- 
                   
                 CACGCCGCTCGGCCCGAAGTGCAACTGGTGGAAACCGGTGGCGGCCTG 
               
               
                 nt 
                   
                 GTGCAGCCTGGAGGATCATTGAGGCTGTCATGCGCGGCCAGCGGTATT 
               
               
                 Full CART 
                   
                 ACCTTCTCCCGGTACCCCATGTCCTGGGTCAGACAGGCCCCGGGGAAA 
               
               
                   
                   
                 GGGCTTGAATGGGTGTCCGGGATCTCGGACTCCGGTGTCAGCACTTAC 
               
               
                   
                   
                 TACGCCGACTCCGCCAAGGGACGCTTCACCATTTCCCGGGACAACTCG 
               
               
                   
                   
                 AAGAACACCCTGTTCCTCCAAATGAGCTCCCTCCGGGACGAGGATACT 
               
               
                   
                   
                 GCAGTGTACTACTGCGTGACCCGCGCCGGGTCCGAGGCGTCTGACATT 
               
               
                   
                   
                 TGGGGACAGGGCACTATGGTCACCGTGTCGTCCGGCGGAGGGGGCTCG 
               
               
                   
                   
                 GGAGGCGGTGGCAGCGGAGGAGGAGGGTCCGAGATCGTGCTGACCCAA 
               
               
                   
                   
                 TCCCCGGCCACCCTCTCGCTGAGCCCTGGAGAAAGGGCAACCTTGTCC 
               
               
                   
                   
                 TGTCGCGCGAGCCAGTCCGTGAGCAACTCCCTGGCCTGGTACCAGCAG 
               
               
                   
                   
                 AAGCCCGGACAGGCTCCGAGACTTCTGATCTACGACGCTTCGAGCCGG 
               
               
                   
                   
                 GCCACTGGAATCCCCGACCGCTTTTCGGGGTCCGGCTCAGGAACCGAT 
               
               
                   
                   
                 TTCACCCTGACAATCTCACGGCTGGAGCCAGAGGATTTCGCCATCTAT 
               
               
                   
                   
                 TACTGCCAGCAGTTCGGTACTTCCTCCGGCCTGACTTTCGGAGGCGGC 
               
               
                   
                   
                 ACGAAGCTCGAAATCAAGACCACTACCCCAGCACCGAGGCCACCCACC 
               
               
                   
                   
                 CCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCA 
               
               
                   
                   
                 TGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTC 
               
               
                   
                   
                 GCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTC 
               
               
                   
                   
                 CTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAG 
               
               
                   
                   
                 AAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACT 
               
               
                   
                   
                 ACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAA 
               
               
                   
                   
                 GGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCA 
               
               
                   
                   
                 GCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGT 
               
               
                   
                   
                 CGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCA 
               
               
                   
                   
                 GAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTAC 
               
               
                   
                   
                 AACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGT 
               
               
                   
                   
                 ATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAG 
               
               
                   
                   
                 GGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAG 
               
               
                   
                   
                 GCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1979-C1 
               
            
           
           
               
               
               
            
               
                 BCMA_EB 
                 1551 
                 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1979-C1- 
                   
                 SAISGSGGSTYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAIYYC 
               
               
                 aa 
                   
                 ARATYKRELRYYYGMDVWGQGTMVTVSSGGGGSGGGGSGGGGSEIVMT 
               
               
                 ScFv 
                   
                 QSPGTVSLSPGERATLSCRASQSVSSSFLAWYQQKPGQAPRLLIYGAS 
               
               
                 domain 
                   
                 SRATGIPDRFSGSGSGTDFTLTISRLEPEDSAVYYCQQYHSSPSWTFG 
               
               
                   
                   
                 QGTRLEIK 
               
               
                   
               
               
                 BCMA_EB 
                 1552 
                 CAAGTGCAGCTCGTGGAATCGGGTGGCGGACTGGTGCAGCCGGGGGGC 
               
               
                 B-C1979-C1- 
                   
                 TCACTTAGACTGTCCTGCGCGGCCAGCGGATTCACTTTCTCCTCCTAC 
               
               
                 nt 
                   
                 GCCATGTCCTGGGTCAGACAGGCCCCTGGAAAGGGCCTGGAATGGGTG 
               
               
                 ScFv 
                   
                 TCCGCAATCAGCGGCAGCGGCGGCTCGACCTATTACGCGGATTCAGTG 
               
               
                 domain 
                   
                 AAGGGCAGATTCACCATTTCCCGGGACAACGCCAAGAACTCCTTGTAC 
               
               
                   
                   
                 CTTCAAATGAACTCCCTCCGCGCGGAAGATACCGCAATCTACTACTGC 
               
               
                   
                   
                 GCTCGGGCCACTTACAAGAGGGAACTGCGCTACTACTACGGGATGGAC 
               
               
                   
                   
                 GTCTGGGGCCAGGGAACCATGGTCACCGTGTCCAGCGGAGGAGGAGGA 
               
               
                   
                   
                 TCGGGAGGAGGCGGTAGCGGGGGTGGAGGGTCGGAGATCGTGATGACC 
               
               
                   
                   
                 CAGTCCCCCGGCACTGTGTCGCTGTCCCCCGGCGAACGGGCCACCCTG 
               
               
                   
                   
                 TCATGTCGGGCCAGCCAGTCAGTGTCGTCAAGCTTCCTCGCCTGGTAC 
               
               
                   
                   
                 CAGCAGAAACCGGGACAAGCTCCCCGCCTGCTGATCTACGGAGCCAGC 
               
               
                   
                   
                 AGCCGGGCCACCGGTATTCCTGACCGGTTCTCCGGTTCGGGGTCCGGG 
               
               
                   
                   
                 ACCGACTTTACTCTGACTATCTCTCGCCTCGAGCCAGAGGACTCCGCC 
               
               
                   
                   
                 GTGTATTACTGCCAGCAGTACCACTCCTCCCCGTCCTGGACGTTCGGA 
               
               
                   
                   
                 CAGGGCACAAGGCTGGAGATTAAG 
               
               
                   
               
               
                 BCMA_EB 
                 1553 
                 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1979-C1- 
                   
                 SAISGSGGSTYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAIYYC 
               
               
                 aa 
                   
                 ARATYKRELRYYYGMDVWGQGTMVTVSS 
               
               
                 VH 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1554 
                 EIVMTQSPGTVSLSPGERATLSCRASQSVSSSFLAWYQQKPGQAPRLL 
               
               
                 B-C1979-C1- 
                   
                 IYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDSAVYYCQQYHSSP 
               
               
                 aa 
                   
                 SWTFGQGTRLEIK 
               
               
                 VL 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1555 
                 MALPVTALLLPLALLLHAARPQVQLVESGGGLVQPGGSLRLSCAASGF 
               
               
                 B-C1979-C1- 
                   
                 TFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNA 
               
               
                 aa 
                   
                 KNSLYLQMNSLRAEDTAIYYCARATYKRELRYYYGMDVWGQGTMVTVS 
               
               
                 Full CART 
                   
                 SGGGGSGGGGSGGGGSEIVMTQSPGTVSLSPGERATLSCRASQSVSSS 
               
               
                   
                   
                 FLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLE 
               
               
                   
                   
                 PEDSAVYYCQQYHSSPSWTFGQGTRLEIKTTTPAPRPPTPAPTIASQP 
               
               
                   
                   
                 LSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITL 
               
               
                   
                   
                 YCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKF 
               
               
                   
                   
                 SRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRK 
               
               
                   
                   
                 NPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDT 
               
               
                   
                   
                 YDALHMQALPPR 
               
               
                   
               
               
                 BCMA_EB 
                 1556 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 B-C1979-C1- 
                   
                 CACGCCGCTCGGCCCCAAGTGCAGCTCGTGGAATCGGGTGGCGGACTG 
               
               
                 nt 
                   
                 GTGCAGCCGGGGGGCTCACTTAGACTGTCCTGCGCGGCCAGCGGATTC 
               
               
                 Full CART 
                   
                 ACTTTCTCCTCCTACGCCATGTCCTGGGTCAGACAGGCCCCTGGAAAG 
               
               
                   
                   
                 GGCCTGGAATGGGTGTCCGCAATCAGCGGCAGCGGCGGCTCGACCTAT 
               
               
                   
                   
                 TACGCGGATTCAGTGAAGGGCAGATTCACCATTTCCCGGGACAACGCC 
               
               
                   
                   
                 AAGAACTCCTTGTACCTTCAAATGAACTCCCTCCGCGCGGAAGATACC 
               
               
                   
                   
                 GCAATCTACTACTGCGCTCGGGCCACTTACAAGAGGGAACTGCGCTAC 
               
               
                   
                   
                 TACTACGGGATGGACGTCTGGGGCCAGGGAACCATGGTCACCGTGTCC 
               
               
                   
                   
                 AGCGGAGGAGGAGGATCGGGAGGAGGCGGTAGCGGGGGTGGAGGGTCG 
               
               
                   
                   
                 GAGATCGTGATGACCCAGTCCCCCGGCACTGTGTCGCTGTCCCCCGGC 
               
               
                   
                   
                 GAACGGGCCACCCTGTCATGTCGGGCCAGCCAGTCAGTGTCGTCAAGC 
               
               
                   
                   
                 TTCCTCGCCTGGTACCAGCAGAAACCGGGACAAGCTCCCCGCCTGCTG 
               
               
                   
                   
                 ATCTACGGAGCCAGCAGCCGGGCCACCGGTATTCCTGACCGGTTCTCC 
               
               
                   
                   
                 GGTTCGGGGTCCGGGACCGACTTTACTCTGACTATCTCTCGCCTCGAG 
               
               
                   
                   
                 CCAGAGGACTCCGCCGTGTATTACTGCCAGCAGTACCACTCCTCCCCG 
               
               
                   
                   
                 TCCTGGACGTTCGGACAGGGCACAAGGCTGGAGATTAAGACCACTACC 
               
               
                   
                   
                 CCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCT 
               
               
                   
                   
                 CTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTG 
               
               
                   
                   
                 CATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCT 
               
               
                   
                   
                 CTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTT 
               
               
                   
                   
                 TACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCC 
               
               
                   
                   
                 TTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGC 
               
               
                   
                   
                 CGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTC 
               
               
                   
                   
                 AGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTC 
               
               
                   
                   
                 TACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGAC 
               
               
                   
                   
                 AAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAG 
               
               
                   
                   
                 AATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCA 
               
               
                   
                   
                 GAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAA 
               
               
                   
                   
                 GGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACC 
               
               
                   
                   
                 TATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-C7 
               
            
           
           
               
               
               
            
               
                 BCMA_EB 
                 1557 
                 EVQLVETGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1978-C7- 
                   
                 SAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNTLKAEDTAVYYC 
               
               
                 aa 
                   
                 ARATYKRELRYYYGMDVWGQGTTVTVSSGGGGSGGGGSGGGGSEIVLT 
               
               
                 ScFv 
                   
                 QSPSTLSLSPGESATLSCRASQSVSTTFLAWYQQKPGQAPRLLIYGSS 
               
               
                 domain 
                   
                 NRATGIPDRFSGSGSGTDFTLTIRRLEPEDFAVYYCQQYHSSPSWTFG 
               
               
                   
                   
                 QGTKVEIK 
               
               
                   
               
               
                 BCMA_EB 
                 1558 
                 GAGGTGCAGCTTGTGGAAACCGGTGGCGGACTGGTGCAGCCCGGAGGA 
               
               
                 B-C1978-C7- 
                   
                 AGCCTCAGGCTGTCCTGCGCCGCGTCCGGCTTCACCTTCTCCTCGTAC 
               
               
                 nt 
                   
                 GCCATGTCCTGGGTCCGCCAGGCCCCCGGAAAGGGCCTGGAATGGGTG 
               
               
                 ScFv 
                   
                 TCCGCCATCTCTGGAAGCGGAGGTTCCACGTACTACGCGGACAGCGTC 
               
               
                 domain 
                   
                 AAGGGAAGGTTCACAATCTCCCGCGATAATTCGAAGAACACTCTGTAC 
               
               
                   
                   
                 CTTCAAATGAACACCCTGAAGGCCGAGGACACTGCTGTGTACTACTGC 
               
               
                   
                   
                 GCACGGGCCACCTACAAGAGAGAGCTCCGGTACTACTACGGAATGGAC 
               
               
                   
                   
                 GTCTGGGGCCAGGGAACTACTGTGACCGTGTCCTCGGGAGGGGGTGGC 
               
               
                   
                   
                 TCCGGGGGGGGCGGCTCCGGCGGAGGCGGTTCCGAGATTGTGCTGACC 
               
               
                   
                   
                 CAGTCACCTTCAACTCTGTCGCTGTCCCCGGGAGAGAGCGCTACTCTG 
               
               
                   
                   
                 AGCTGCCGGGCCAGCCAGTCCGTGTCCACCACCTTCCTCGCCTGGTAT 
               
               
                   
                   
                 CAGCAGAAGCCGGGGCAGGCACCACGGCTCTTGATCTACGGGTCAAGC 
               
               
                   
                   
                 AACAGAGCGACCGGAATTCCTGACCGCTTCTCGGGGAGCGGTTCAGGC 
               
               
                   
                   
                 ACCGACTTCACCCTGACTATCCGGCGCCTGGAACCCGAAGATTTCGCC 
               
               
                   
                   
                 GTGTATTACTGTCAACAGTACCACTCCTCGCCGTCCTGGACCTTTGGC 
               
               
                   
                   
                 CAAGGAACCAAAGTGGAAATCAAG 
               
               
                   
               
               
                 BCMA_EB 
                 1559 
                 EVQLVETGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1978-C7- 
                   
                 SAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNTLKAEDTAVYYC 
               
               
                 aa 
                   
                 ARATYKRELRYYYGMDVWGQGTTVTVSS 
               
               
                 VH 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1560 
                 EIVLTQSPSTLSLSPGESATLSCRASQSVSTTFLAWYQQKPGQAPRLL 
               
               
                 B-C1978-C7- 
                   
                 IYGSSNRATGIPDRFSGSGSGTDFTLTIRRLEPEDFAVYYCQQYHSSP 
               
               
                 aa 
                   
                 SWTFGQGTKVEIK 
               
               
                 VL 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1561 
                 MALPVTALLLPLALLLHAARPEVQLVETGGGLVQPGGSLRLSCAASGF 
               
               
                 B-C1978-C7- 
                   
                 TFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNS 
               
               
                 aa 
                   
                 KNTLYLQMNTLKAEDTAVYYCARATYKRELRYYYGMDVWGQGTTVTVS 
               
               
                 Full CART 
                   
                 SGGGGSGGGGSGGGGSEIVLTQSPSTLSLSPGESATLSCRASQSVSTT 
               
               
                   
                   
                 FLAWYQQKPGQAPRLLIYGSSNRATGIPDRFSGSGSGTDFTLTIRRLE 
               
               
                   
                   
                 PEDFAVYYCQQYHSSPSWTFGQGTKVEIKTTTPAPRPPTPAPTIASQP 
               
               
                   
                   
                 LSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITL 
               
               
                   
                   
                 YCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKF 
               
               
                   
                   
                 SRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRK 
               
               
                   
                   
                 NPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDT 
               
               
                   
                   
                 YDALHMQALPPR 
               
               
                   
               
               
                 BCMA_EB 
                 1562 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 B-C1978-C7- 
                   
                 CACGCCGCTCGGCCCGAGGTGCAGCTTGTGGAAACCGGTGGCGGACTG 
               
               
                 nt 
                   
                 GTGCAGCCCGGAGGAAGCCTCAGGCTGTCCTGCGCCGCGTCCGGCTTC 
               
               
                 Full CART 
                   
                 ACCTTCTCCTCGTACGCCATGTCCTGGGTCCGCCAGGCCCCCGGAAAG 
               
               
                   
                   
                 GGCCTGGAATGGGTGTCCGCCATCTCTGGAAGCGGAGGTTCCACGTAC 
               
               
                   
                   
                 TACGCGGACAGCGTCAAGGGAAGGTTCACAATCTCCCGCGATAATTCG 
               
               
                   
                   
                 AAGAACACTCTGTACCTTCAAATGAACACCCTGAAGGCCGAGGACACT 
               
               
                   
                   
                 GCTGTGTACTACTGCGCACGGGCCACCTACAAGAGAGAGCTCCGGTAC 
               
               
                   
                   
                 TACTACGGAATGGACGTCTGGGGCCAGGGAACTACTGTGACCGTGTCC 
               
               
                   
                   
                 TCGGGAGGGGGTGGCTCCGGGGGGGGCGGCTCCGGCGGAGGCGGTTCC 
               
               
                   
                   
                 GAGATTGTGCTGACCCAGTCACCTTCAACTCTGTCGCTGTCCCCGGGA 
               
               
                   
                   
                 GAGAGCGCTACTCTGAGCTGCCGGGCCAGCCAGTCCGTGTCCACCACC 
               
               
                   
                   
                 TTCCTCGCCTGGTATCAGCAGAAGCCGGGGCAGGCACCACGGCTCTTG 
               
               
                   
                   
                 ATCTACGGGTCAAGCAACAGAGCGACCGGAATTCCTGACCGCTTCTCG 
               
               
                   
                   
                 GGGAGCGGTTCAGGCACCGACTTCACCCTGACTATCCGGCGCCTGGAA 
               
               
                   
                   
                 CCCGAAGATTTCGCCGTGTATTACTGTCAACAGTACCACTCCTCGCCG 
               
               
                   
                   
                 TCCTGGACCTTTGGCCAAGGAACCAAAGTGGAAATCAAGACCACTACC 
               
               
                   
                   
                 CCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCT 
               
               
                   
                   
                 CTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTG 
               
               
                   
                   
                 CATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCT 
               
               
                   
                   
                 CTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTT 
               
               
                   
                   
                 TACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCC 
               
               
                   
                   
                 TTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGC 
               
               
                   
                   
                 CGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTC 
               
               
                   
                   
                 AGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTC 
               
               
                   
                   
                 TACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGAC 
               
               
                   
                   
                 AAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAG 
               
               
                   
                   
                 AATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCA 
               
               
                   
                   
                 GAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAA 
               
               
                   
                   
                 GGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACC 
               
               
                   
                   
                 TATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-D10 
               
            
           
           
               
               
               
            
               
                 BCMA_EB 
                 1563 
                 EVQLVETGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWV 
               
               
                 B-C1978- 
                   
                 SGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRDEDTAVYYC 
               
               
                 D10-aa 
                   
                 ARVGKAVPDVWGQGTTVTVSSGGGGSGGGGSGGGGSDIVMTQTPSSLS 
               
               
                 ScFv 
                   
                 ASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPS 
               
               
                 domain 
                   
                 RFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPYSFGQGTRLEIK 
               
               
                   
               
               
                 BCMA_EB 
                 1564 
                 GAAGTGCAGCTCGTGGAAACTGGAGGTGGACTCGTGCAGCCTGGACGG 
               
               
                 B-C1978- 
                   
                 TCGCTGCGGCTGAGCTGCGCTGCATCCGGCTTCACCTTCGACGATTAT 
               
               
                 D10-nt 
                   
                 GCCATGCACTGGGTCAGACAGGCGCCAGGGAAGGGACTTGAGTGGGTG 
               
               
                 ScFv 
                   
                 TCCGGTATCAGCTGGAATAGCGGCTCAATCGGATACGCGGACTCCGTG 
               
               
                 domain 
                   
                 AAGGGAAGGTTCACCATTTCCCGCGACAACGCCAAGAACTCCCTGTAC 
               
               
                   
                   
                 TTGCAAATGAACAGCCTCCGGGATGAGGACACTGCCGTGTACTACTGC 
               
               
                   
                   
                 GCCCGCGTCGGAAAAGCTGTGCCCGACGTCTGGGGCCAGGGAACCACT 
               
               
                   
                   
                 GTGACCGTGTCCAGCGGCGGGGGTGGATCGGGCGGTGGAGGGTCCGGT 
               
               
                   
                   
                 GGAGGGGGCTCAGATATTGTGATGACCCAGACCCCCTCGTCCCTGTCC 
               
               
                   
                   
                 GCCTCGGTCGGCGACCGCGTGACTATCACATGTAGAGCCTCGCAGAGC 
               
               
                   
                   
                 ATCTCCAGCTACCTGAACTGGTATCAGCAGAAGCCGGGGAAGGCCCCG 
               
               
                   
                   
                 AAGCTCCTGATCTACGCGGCATCATCACTGCAATCGGGAGTGCCGAGC 
               
               
                   
                   
                 CGGTTTTCCGGGTCCGGCTCCGGCACCGACTTCACGCTGACCATTTCT 
               
               
                   
                   
                 TCCCTGCAACCCGAGGACTTCGCCACTTACTACTGCCAGCAGTCCTAC 
               
               
                   
                   
                 TCCACCCCTTACTCCTTCGGCCAAGGAACCAGGCTGGAAATCAAG 
               
               
                   
               
               
                 BCMA_EB 
                 1565 
                 EVQLVETGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWV 
               
               
                 B-C1978- 
                   
                 SGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRDEDTAVYYC 
               
               
                 D10-aa 
                   
                 ARVGKAVPDVWGQGTTVTVSS 
               
               
                 VH 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1566 
                 DIVMTQTPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLI 
               
               
                 B-C1978- 
                   
                 YAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPY 
               
               
                 D10-aa 
                   
                 SFGQGTRLEIK 
               
               
                 VL 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1567 
                 MALPVTALLLPLALLLHAARPEVQLVETGGGLVQPGRSLRLSCAASGF 
               
               
                 B-C1978- 
                   
                 TFDDYAMHWVRQAPGKGLEWVSGISWNSGSIGYADSVKGRFTISRDNA 
               
               
                 D10-aa 
                   
                 KNSLYLQMNSLRDEDTAVYYCARVGKAVPDVWGQGTTVTVSSGGGGSG 
               
               
                 Full CART 
                   
                 GGGSGGGGSDIVMTQTPSSLSASVGDRVTITCRASQSISSYLNWYQQK 
               
               
                   
                   
                 PGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
               
               
                   
                   
                 CQQSYSTPYSFGQGTRLEIKTTTPAPRPPTPAPTIASQPLSLRPEACR 
               
               
                   
                   
                 PAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKL 
               
               
                   
                   
                 LYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAY 
               
               
                   
                   
                 KQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNE 
               
               
                   
                   
                 LQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQAL 
               
               
                   
                   
                 PPR 
               
               
                   
               
               
                 BCMA_EB 
                 1568 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 B-C1978- 
                   
                 CACGCCGCTCGGCCCGAAGTGCAGCTCGTGGAAACTGGAGGTGGACTC 
               
               
                 D10-nt 
                   
                 GTGCAGCCTGGACGGTCGCTGCGGCTGAGCTGCGCTGCATCCGGCTTC 
               
               
                 Full CART 
                   
                 ACCTTCGACGATTATGCCATGCACTGGGTCAGACAGGCGCCAGGGAAG 
               
               
                   
                   
                 GGACTTGAGTGGGTGTCCGGTATCAGCTGGAATAGCGGCTCAATCGGA 
               
               
                   
                   
                 TACGCGGACTCCGTGAAGGGAAGGTTCACCATTTCCCGCGACAACGCC 
               
               
                   
                   
                 AAGAACTCCCTGTACTTGCAAATGAACAGCCTCCGGGATGAGGACACT 
               
               
                   
                   
                 GCCGTGTACTACTGCGCCCGCGTCGGAAAAGCTGTGCCCGACGTCTGG 
               
               
                   
                   
                 GGCCAGGGAACCACTGTGACCGTGTCCAGCGGCGGGGGTGGATCGGGC 
               
               
                   
                   
                 GGTGGAGGGTCCGGTGGAGGGGGCTCAGATATTGTGATGACCCAGACC 
               
               
                   
                   
                 CCCTCGTCCCTGTCCGCCTCGGTCGGCGACCGCGTGACTATCACATGT 
               
               
                   
                   
                 AGAGCCTCGCAGAGCATCTCCAGCTACCTGAACTGGTATCAGCAGAAG 
               
               
                   
                   
                 CCGGGGAAGGCCCCGAAGCTCCTGATCTACGCGGCATCATCACTGCAA 
               
               
                   
                   
                 TCGGGAGTGCCGAGCCGGTTTTCCGGGTCCGGCTCCGGCACCGACTTC 
               
               
                   
                   
                 ACGCTGACCATTTCTTCCCTGCAACCCGAGGACTTCGCCACTTACTAC 
               
               
                   
                   
                 TGCCAGCAGTCCTACTCCACCCCTTACTCCTTCGGCCAAGGAACCAGG 
               
               
                   
                   
                 CTGGAAATCAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCT 
               
               
                   
                   
                 CCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGA 
               
               
                   
                   
                 CCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGC 
               
               
                   
                   
                 GATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTG 
               
               
                   
                   
                 CTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTG 
               
               
                   
                   
                 CTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAA 
               
               
                   
                   
                 GAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGC 
               
               
                   
                   
                 TGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTAC 
               
               
                   
                   
                 AAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGA 
               
               
                   
                   
                 GAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATG 
               
               
                   
                   
                 GGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAG 
               
               
                   
                   
                 CTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAA 
               
               
                   
                   
                 GGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTC 
               
               
                   
                   
                 AGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTG 
               
               
                   
                   
                 CCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1979-C12 
               
            
           
           
               
               
               
            
               
                 BCMA_EB 
                 1569 
                 EVQLVESGGGLVQPGRSLRLSCTASGFTFDDYAMHWVRQRPGKGLEWV 
               
               
                 B-C1979- 
                   
                 ASINWKGNSLAYGDSVKGRFAISRDNAKNTVFLQMNSLRTEDTAVYYC 
               
               
                 C12-aa 
                   
                 ASHQGVAYYNYAMDVWGRGTLVTVSSGGGGSGGGGSGGGGSEIVLTQS 
               
               
                 ScFv 
                   
                 PGTLSLSPGERATLSCRATQSIGSSFLAWYQQRPGQAPRLLIYGASQR 
               
               
                 domain 
                   
                 ATGIPDRFSGRGSGTDFTLTISRVEPEDSAVYYCQHYESSPSWTFGQG 
               
               
                   
                   
                 TKVEIK 
               
               
                   
               
               
                 BCMA_EB 
                 1570 
                 GAAGTGCAGCTCGTGGAGAGCGGGGGAGGATTGGTGCAGCCCGGAAGG 
               
               
                 B-C1979- 
                   
                 TCCCTGCGGCTCTCCTGCACTGCGTCTGGCTTCACCTTCGACGACTAC 
               
               
                 C12-nt 
                   
                 GCGATGCACTGGGTCAGACAGCGCCCGGGAAAGGGCCTGGAATGGGTC 
               
               
                 ScFv 
                   
                 GCCTCAATCAACTGGAAGGGAAACTCCCTGGCCTATGGCGACAGCGTG 
               
               
                 domain 
                   
                 AAGGGCCGCTTCGCCATTTCGCGCGACAACGCCAAGAACACCGTGTTT 
               
               
                   
                   
                 CTGCAAATGAATTCCCTGCGGACCGAGGATACCGCTGTGTACTACTGC 
               
               
                   
                   
                 GCCAGCCACCAGGGCGTGGCATACTATAACTACGCCATGGACGTGTGG 
               
               
                   
                   
                 GGAAGAGGGACGCTCGTCACCGTGTCCTCCGGGGGCGGTGGATCGGGT 
               
               
                   
                   
                 GGAGGAGGAAGCGGTGGCGGGGGCAGCGAAATCGTGCTGACTCAGAGC 
               
               
                   
                   
                 CCGGGAACTCTTTCACTGTCCCCGGGAGAACGGGCCACTCTCTCGTGC 
               
               
                   
                   
                 CGGGCCACCCAGTCCATCGGCTCCTCCTTCCTTGCCTGGTACCAGCAG 
               
               
                   
                   
                 AGGCCAGGACAGGCGCCCCGCCTGCTGATCTACGGTGCTTCCCAACGC 
               
               
                   
                   
                 GCCACTGGCATTCCTGACCGGTTCAGCGGCAGAGGGTCGGGAACCGAT 
               
               
                   
                   
                 TTCACACTGACCATTTCCCGGGTGGAGCCCGAAGATTCGGCAGTCTAC 
               
               
                   
                   
                 TACTGTCAGCATTACGAGTCCTCCCCTTCATGGACCTTCGGTCAAGGG 
               
               
                   
                   
                 ACCAAAGTGGAGATCAAG 
               
               
                   
               
               
                 BCMA_EB 
                 1571 
                 EVQLVESGGGLVQPGRSLRLSCTASGFTFDDYAMHWVRQRPGKGLEWV 
               
               
                 B-C1979- 
                   
                 ASINWKGNSLAYGDSVKGRFAISRDNAKNTVFLQMNSLRTEDTAVYYC 
               
               
                 C12-aa 
                   
                 ASHQGVAYYNYAMDVWGRGTLVTVSS 
               
               
                 VH 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1572 
                 EIVLTQSPGTLSLSPGERATLSCRATQSIGSSFLAWYQQRPGQAPRLL 
               
               
                 B-C1979- 
                   
                 IYGASQRATGIPDRFSGRGSGTDFTLTISRVEPEDSAVYYCQHYESSP 
               
               
                 C12-aa 
                   
                 SWTFGQGTKVEIK 
               
               
                 VL 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1573 
                 MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGF 
               
               
                 B-C1979- 
                   
                 TFDDYAMHWVRQRPGKGLEWVASINWKGNSLAYGDSVKGRFAISRDNA 
               
               
                 C12-aa 
                   
                 KNTVFLQMNSLRTEDTAVYYCASHQGVAYYNYAMDVWGRGTLVTVSSG 
               
               
                 Full CART 
                   
                 GGGSGGGGSGGGGSEIVLTQSPGTLSLSPGERATLSCRATQSIGSSFL 
               
               
                   
                   
                 AWYQQRPGQAPRLLIYGASQRATGIPDRFSGRGSGTDFTLTISRVEPE 
               
               
                   
                   
                 DSAVYYCQHYESSPSWTFGQGTKVEIKTTTPAPRPPTPAPTIASQPLS 
               
               
                   
                   
                 LRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYC 
               
               
                   
                   
                 KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSR 
               
               
                   
                   
                 SADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNP 
               
               
                   
                   
                 QEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYD 
               
               
                   
                   
                 ALHMQALPPR 
               
               
                   
               
               
                 BCMA_EB 
                 1574 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 B-C1979- 
                   
                 CACGCCGCTCGGCCCGAAGTGCAGCTCGTGGAGAGCGGGGGAGGATTG 
               
               
                 C12-nt 
                   
                 GTGCAGCCCGGAAGGTCCCTGCGGCTCTCCTGCACTGCGTCTGGCTTC 
               
               
                 Full CART 
                   
                 ACCTTCGACGACTACGCGATGCACTGGGTCAGACAGCGCCCGGGAAAG 
               
               
                   
                   
                 GGCCTGGAATGGGTCGCCTCAATCAACTGGAAGGGAAACTCCCTGGCC 
               
               
                   
                   
                 TATGGCGACAGCGTGAAGGGCCGCTTCGCCATTTCGCGCGACAACGCC 
               
               
                   
                   
                 AAGAACACCGTGTTTCTGCAAATGAATTCCCTGCGGACCGAGGATACC 
               
               
                   
                   
                 GCTGTGTACTACTGCGCCAGCCACCAGGGCGTGGCATACTATAACTAC 
               
               
                   
                   
                 GCCATGGACGTGTGGGGAAGAGGGACGCTCGTCACCGTGTCCTCCGGG 
               
               
                   
                   
                 GGCGGTGGATCGGGTGGAGGAGGAAGCGGTGGCGGGGGCAGCGAAATC 
               
               
                   
                   
                 GTGCTGACTCAGAGCCCGGGAACTCTTTCACTGTCCCCGGGAGAACGG 
               
               
                   
                   
                 GCCACTCTCTCGTGCCGGGCCACCCAGTCCATCGGCTCCTCCTTCCTT 
               
               
                   
                   
                 GCCTGGTACCAGCAGAGGCCAGGACAGGCGCCCCGCCTGCTGATCTAC 
               
               
                   
                   
                 GGTGCTTCCCAACGCGCCACTGGCATTCCTGACCGGTTCAGCGGCAGA 
               
               
                   
                   
                 GGGTCGGGAACCGATTTCACACTGACCATTTCCCGGGTGGAGCCCGAA 
               
               
                   
                   
                 GATTCGGCAGTCTACTACTGTCAGCATTACGAGTCCTCCCCTTCATGG 
               
               
                   
                   
                 ACCTTCGGTCAAGGGACCAAAGTGGAGATCAAGACCACTACCCCAGCA 
               
               
                   
                   
                 CCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCC 
               
               
                   
                   
                 CTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACC 
               
               
                   
                   
                 CGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCT 
               
               
                   
                   
                 GGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGT 
               
               
                   
                   
                 AAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATG 
               
               
                   
                   
                 AGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTC 
               
               
                   
                   
                 CCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGC 
               
               
                   
                   
                 AGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAAC 
               
               
                   
                   
                 GAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGG 
               
               
                   
                   
                 AGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCC 
               
               
                   
                   
                 CAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCC 
               
               
                   
                   
                 TATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCAC 
               
               
                   
                   
                 GACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGAC 
               
               
                   
                   
                 GCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1980-G4 
               
            
           
           
               
               
               
            
               
                 BCMA EB 
                 1575 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1980- 
                   
                 SAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC 
               
               
                 G4-aa 
                   
                 AKVVRDGMDVWGQGTTVTVSSGGGGSGGGGSGGGGSEIVLTQSPATLS 
               
               
                 ScFv 
                   
                 LSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIP 
               
               
                 domain 
                   
                 DRFSGNGSGTDFTLTISRLEPEDFAVYYCQQYGSPPRFTFGPGTKVDI 
               
               
                   
                   
                 K 
               
               
                   
               
               
                 BCMA_EB 
                 1576 
                 GAGGTGCAGTTGGTCGAAAGCGGGGGCGGGCTTGTGCAGCCTGGCGGA 
               
               
                 B-C1980- 
                   
                 TCACTGCGGCTGTCCTGCGCGGCATCAGGCTTCACGTTTTCTTCCTAC 
               
               
                 G4-nt 
                   
                 GCCATGTCCTGGGTGCGCCAGGCCCCTGGAAAGGGACTGGAATGGGTG 
               
               
                 ScFv 
                   
                 TCCGCGATTTCGGGGTCCGGCGGGAGCACCTACTACGCCGATTCCGTG 
               
               
                 domain 
                   
                 AAGGGCCGCTTCACTATCTCGCGGGACAACTCCAAGAACACCCTCTAC 
               
               
                   
                   
                 CTCCAAATGAATAGCCTGCGGGCCGAGGATACCGCCGTCTACTATTGC 
               
               
                   
                   
                 GCTAAGGTCGTGCGCGACGGAATGGACGTGTGGGGACAGGGTACCACC 
               
               
                   
                   
                 GTGACAGTGTCCTCGGGGGGAGGCGGTAGCGGCGGAGGAGGAAGCGGT 
               
               
                   
                   
                 GGTGGAGGTTCCGAGATTGTGCTGACTCAATCACCCGCGACCCTGAGC 
               
               
                   
                   
                 CTGTCCCCCGGCGAAAGGGCCACTCTGTCCTGTCGGGCCAGCCAATCA 
               
               
                   
                   
                 GTCTCCTCCTCGTACCTGGCCTGGTACCAGCAGAAGCCAGGACAGGCT 
               
               
                   
                   
                 CCGAGACTCCTTATCTATGGCGCATCCTCCCGCGCCACCGGAATCCCG 
               
               
                   
                   
                 GATAGGTTCTCGGGAAACGGATCGGGGACCGACTTCACTCTCACCATC 
               
               
                   
                   
                 TCCCGGCTGGAACCGGAGGACTTCGCCGTGTACTACTGCCAGCAGTAC 
               
               
                   
                   
                 GGCAGCCCGCCTAGATTCACTTTCGGCCCCGGCACCAAAGTGGACATC 
               
               
                   
                   
                 AAG 
               
               
                   
               
               
                 BCMA_EB 
                 1577 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1980- 
                   
                 SAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC 
               
               
                 G4-aa 
                   
                 AKVVRDGMDVWGQGTTVTVSS 
               
               
                 VH 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1578 
                 EIVLTQSPATLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLL 
               
               
                 B-C1980- 
                   
                 IYGASSRATGIPDRFSGNGSGTDFTLTISRLEPEDFAVYYCQQYGSPP 
               
               
                 G4-aa 
                   
                 RFTFGPGTKVDIK 
               
               
                 VL 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1579 
                 MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGF 
               
               
                 B-C1980- 
                   
                 TFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNS 
               
               
                 G4-aa 
                   
                 KNTLYLQMNSLRAEDTAVYYCAKVVRDGMDVWGQGTTVTVSSGGGGSG 
               
               
                 Full CART 
                   
                 GGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSSYLAWYQQ 
               
               
                   
                   
                 KPGQAPRLLIYGASSRATGIPDRFSGNGSGTDFTLTISRLEPEDFAVY 
               
               
                   
                   
                 YCQQYGSPPRFTFGPGTKVDIKTTTPAPRPPTPAPTIASQPLSLRPEA 
               
               
                   
                   
                 CRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRK 
               
               
                   
                   
                 KLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAP 
               
               
                   
                   
                 AYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLY 
               
               
                   
                   
                 NELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQ 
               
               
                   
                   
                 ALPPR 
               
               
                   
               
               
                 BCMA_EB 
                 1580 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 B-C1980- 
                   
                 CACGCCGCTCGGCCCGAGGTGCAGTTGGTCGAAAGCGGGGGCGGGCTT 
               
               
                 G4-nt 
                   
                 GTGCAGCCTGGCGGATCACTGCGGCTGTCCTGCGCGGCATCAGGCTTC 
               
               
                 Full CART 
                   
                 ACGTTTTCTTCCTACGCCATGTCCTGGGTGCGCCAGGCCCCTGGAAAG 
               
               
                   
                   
                 GGACTGGAATGGGTGTCCGCGATTTCGGGGTCCGGCGGGAGCACCTAC 
               
               
                   
                   
                 TACGCCGATTCCGTGAAGGGCCGCTTCACTATCTCGCGGGACAACTCC 
               
               
                   
                   
                 AAGAACACCCTCTACCTCCAAATGAATAGCCTGCGGGCCGAGGATACC 
               
               
                   
                   
                 GCCGTCTACTATTGCGCTAAGGTCGTGCGCGACGGAATGGACGTGTGG 
               
               
                   
                   
                 GGACAGGGTACCACCGTGACAGTGTCCTCGGGGGGAGGCGGTAGCGGC 
               
               
                   
                   
                 GGAGGAGGAAGCGGTGGTGGAGGTTCCGAGATTGTGCTGACTCAATCA 
               
               
                   
                   
                 CCCGCGACCCTGAGCCTGTCCCCCGGCGAAAGGGCCACTCTGTCCTGT 
               
               
                   
                   
                 CGGGCCAGCCAATCAGTCTCCTCCTCGTACCTGGCCTGGTACCAGCAG 
               
               
                   
                   
                 AAGCCAGGACAGGCTCCGAGACTCCTTATCTATGGCGCATCCTCCCGC 
               
               
                   
                   
                 GCCACCGGAATCCCGGATAGGTTCTCGGGAAACGGATCGGGGACCGAC 
               
               
                   
                   
                 TTCACTCTCACCATCTCCCGGCTGGAACCGGAGGACTTCGCCGTGTAC 
               
               
                   
                   
                 TACTGCCAGCAGTACGGCAGCCCGCCTAGATTCACTTTCGGCCCCGGC 
               
               
                   
                   
                 ACCAAAGTGGACATCAAGACCACTACCCCAGCACCGAGGCCACCCACC 
               
               
                   
                   
                 CCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCA 
               
               
                   
                   
                 TGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTC 
               
               
                   
                   
                 GCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTC 
               
               
                   
                   
                 CTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAG 
               
               
                   
                   
                 AAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACT 
               
               
                   
                   
                 ACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAA 
               
               
                   
                   
                 GGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCA 
               
               
                   
                   
                 GCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGT 
               
               
                   
                   
                 CGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCA 
               
               
                   
                   
                 GAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTAC 
               
               
                   
                   
                 AACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGT 
               
               
                   
                   
                 ATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAG 
               
               
                   
                   
                 GGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAG 
               
               
                   
                   
                 GCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1980-D2 
               
            
           
           
               
               
               
            
               
                 BCMA_EB 
                 1581 
                 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1980- 
                   
                 SAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC 
               
               
                 D2-aa 
                   
                 AKIPQTGTFDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVLTQSPGTL 
               
               
                 ScFv 
                   
                 SLSPGERATLSCRASQSVSSSYLAWYQQRPGQAPRLLIYGASSRATGI 
               
               
                 domain 
                   
                 PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQHYGSSPSWTFGQGTRLE 
               
               
                   
                   
                 IK 
               
               
                   
               
               
                 BCMA_EB 
                 1582 
                 GAAGTGCAGCTGCTGGAGTCCGGCGGTGGATTGGTGCAACCGGGGGGA 
               
               
                 B-C1980- 
                   
                 TCGCTCAGACTGTCCTGTGCGGCGTCAGGCTTCACCTTCTCGAGCTAC 
               
               
                 D2-nt 
                   
                 GCCATGTCATGGGTCAGACAGGCCCCTGGAAAGGGTCTGGAATGGGTG 
               
               
                 ScFv 
                   
                 TCCGCCATTTCCGGGAGCGGGGGATCTACATACTACGCCGATAGCGTG 
               
               
                 domain 
                   
                 AAGGGCCGCTTCACCATTTCCCGGGACAACTCCAAGAACACTCTCTAT 
               
               
                   
                   
                 CTGCAAATGAACTCCCTCCGCGCTGAGGACACTGCCGTGTACTACTGC 
               
               
                   
                   
                 GCCAAAATCCCTCAGACCGGCACCTTCGACTACTGGGGACAGGGGACT 
               
               
                   
                   
                 CTGGTCACCGTCAGCAGCGGTGGCGGAGGTTCGGGGGGAGGAGGAAGC 
               
               
                   
                   
                 GGCGGCGGAGGGTCCGAGATTGTGCTGACCCAGTCACCCGGCACTTTG 
               
               
                   
                   
                 TCCCTGTCGCCTGGAGAAAGGGCCACCCTTTCCTGCCGGGCATCCCAA 
               
               
                   
                   
                 TCCGTGTCCTCCTCGTACCTGGCCTGGTACCAGCAGAGGCCCGGACAG 
               
               
                   
                   
                 GCCCCACGGCTTCTGATCTACGGAGCAAGCAGCCGCGCGACCGGTATC 
               
               
                   
                   
                 CCGGACCGGTTTTCGGGCTCGGGCTCAGGAACTGACTTCACCCTCACC 
               
               
                   
                   
                 ATCTCCCGCCTGGAACCCGAAGATTTCGCTGTGTATTACTGCCAGCAC 
               
               
                   
                   
                 TACGGCAGCTCCCCGTCCTGGACGTTCGGCCAGGGAACTCGGCTGGAG 
               
               
                   
                   
                 ATCAAG 
               
               
                   
               
               
                 BCMA_EB 
                 1583 
                 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1980- 
                   
                 SAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC 
               
               
                 D2-aa 
                   
                 AKIPQTGTFDYWGQGTLVTVSS 
               
               
                 VH 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1584 
                 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQRPGQAPRLL 
               
               
                 B-C1980- 
                   
                 IYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQHYGSSP 
               
               
                 D2-aa 
                   
                 SWTFGQGTRLEIK 
               
               
                 VL 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1585 
                 MALPVTALLLPLALLLHAARPEVQLLESGGGLVQPGGSLRLSCAASGF 
               
               
                 B-C1980- 
                   
                 TESSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRETISRDNS 
               
               
                 D2-aa 
                   
                 KNTLYLQMNSLRAEDTAVYYCAKIPQTGTFDYWGQGTLVTVSSGGGGS 
               
               
                 Full CART 
                   
                 GGGGSGGGGSEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQ 
               
               
                   
                   
                 QRPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAV 
               
               
                   
                   
                 YYCQHYGSSPSWTFGQGTRLEIKTTTPAPRPPTPAPTIASQPLSLRPE 
               
               
                   
                   
                 ACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGR 
               
               
                   
                   
                 KKLLYIFKQPFMRPVQTTQEEDGCSCREPEEEEGGCELRVKFSRSADA 
               
               
                   
                   
                 PAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGL 
               
               
                   
                   
                 YNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHM 
               
               
                   
                   
                 QALPPR 
               
               
                   
               
               
                 BCMA_EB 
                 1586 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 B-C1980- 
                   
                 CACGCCGCTCGGCCCGAAGTGCAGCTGCTGGAGTCCGGCGGTGGATTG 
               
               
                 D2-nt 
                   
                 GTGCAACCGGGGGGATCGCTCAGACTGTCCTGTGCGGCGTCAGGCTTC 
               
               
                 Full CART 
                   
                 ACCTTCTCGAGCTACGCCATGTCATGGGTCAGACAGGCCCCTGGAAAG 
               
               
                   
                   
                 GGTCTGGAATGGGTGTCCGCCATTTCCGGGAGCGGGGGATCTACATAC 
               
               
                   
                   
                 TACGCCGATAGCGTGAAGGGCCGCTTCACCATTTCCCGGGACAACTCC 
               
               
                   
                   
                 AAGAACACTCTCTATCTGCAAATGAACTCCCTCCGCGCTGAGGACACT 
               
               
                   
                   
                 GCCGTGTACTACTGCGCCAAAATCCCTCAGACCGGCACCTTCGACTAC 
               
               
                   
                   
                 TGGGGACAGGGGACTCTGGTCACCGTCAGCAGCGGTGGCGGAGGTTCG 
               
               
                   
                   
                 GGGGGAGGAGGAAGCGGCGGCGGAGGGTCCGAGATTGTGCTGACCCAG 
               
               
                   
                   
                 TCACCCGGCACTTTGTCCCTGTCGCCTGGAGAAAGGGCCACCCTTTCC 
               
               
                   
                   
                 TGCCGGGCATCCCAATCCGTGTCCTCCTCGTACCTGGCCTGGTACCAG 
               
               
                   
                   
                 CAGAGGCCCGGACAGGCCCCACGGCTTCTGATCTACGGAGCAAGCAGC 
               
               
                   
                   
                 CGCGCGACCGGTATCCCGGACCGGTTTTCGGGCTCGGGCTCAGGAACT 
               
               
                   
                   
                 GACTTCACCCTCACCATCTCCCGCCTGGAACCCGAAGATTTCGCTGTG 
               
               
                   
                   
                 TATTACTGCCAGCACTACGGCAGCTCCCCGTCCTGGACGTTCGGCCAG 
               
               
                   
                   
                 GGAACTCGGCTGGAGATCAAGACCACTACCCCAGCACCGAGGCCACCC 
               
               
                   
                   
                 ACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAG 
               
               
                   
                   
                 GCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGAC 
               
               
                   
                   
                 TTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGG 
               
               
                   
                   
                 GTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGG 
               
               
                   
                   
                 AAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAG 
               
               
                   
                   
                 ACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAG 
               
               
                   
                   
                 GAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCT 
               
               
                   
                   
                 CCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTT 
               
               
                   
                   
                 GGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGAC 
               
               
                   
                   
                 CCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTG 
               
               
                   
                   
                 TACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATT 
               
               
                   
                   
                 GGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTAC 
               
               
                   
                   
                 CAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATG 
               
               
                   
                   
                 CAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-A10 
               
            
           
           
               
               
               
            
               
                 BCMA_EB 
                 1587 
                 EVQLVETGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1978- 
                   
                 SAISGSGGSTYYADSVKGRFTMSRENDKNSVFLQMNSLRVEDTGVYYC 
               
               
                 A10-aa 
                   
                 ARANYKRELRYYYGMDVWGQGTMVTVSSGGGGSGGGGSGGGGSEIVMT 
               
               
                 ScFv 
                   
                 QSPGTLSLSPGESATLSCRASQRVASNYLAWYQHKPGQAPSLLISGAS 
               
               
                 domain 
                   
                 SRATGVPDRFSGSGSGTDFTLAISRLEPEDSAVYYCQHYDSSPSWTFG 
               
               
                   
                   
                 QGTKVEIK 
               
               
                   
               
               
                 BCMA_EB 
                 1588 
                 GAAGTGCAACTGGTGGAAACCGGTGGAGGACTCGTGCAGCCTGGCGGC 
               
               
                 B-C1978- 
                   
                 AGCCTCCGGCTGAGCTGCGCCGCTTCGGGATTCACCTTTTCCTCCTAC 
               
               
                 A10-nt 
                   
                 GCGATGTCTTGGGTCAGACAGGCCCCCGGAAAGGGGCTGGAATGGGTG 
               
               
                 ScFv 
                   
                 TCAGCCATCTCCGGCTCCGGCGGATCAACGTACTACGCCGACTCCGTG 
               
               
                 domain 
                   
                 AAAGGCCGGTTCACCATGTCGCGCGAGAATGACAAGAACTCCGTGTTC 
               
               
                   
                   
                 CTGCAAATGAACTCCCTGAGGGTGGAGGACACCGGAGTGTACTATTGT 
               
               
                   
                   
                 GCGCGCGCCAACTACAAGAGAGAGCTGCGGTACTACTACGGAATGGAC 
               
               
                   
                   
                 GTCTGGGGACAGGGAACTATGGTGACCGTGTCATCCGGTGGAGGGGGA 
               
               
                   
                   
                 AGCGGCGGTGGAGGCAGCGGGGGCGGGGGTTCAGAAATTGTCATGACC 
               
               
                   
                   
                 CAGTCCCCGGGAACTCTTTCCCTCTCCCCCGGGGAATCCGCGACTTTG 
               
               
                   
                   
                 TCCTGCCGGGCCAGCCAGCGCGTGGCCTCGAACTACCTCGCATGGTAC 
               
               
                   
                   
                 CAGCATAAGCCAGGCCAAGCCCCTTCCCTGCTGATTTCCGGGGCTAGC 
               
               
                   
                   
                 AGCCGCGCCACTGGCGTGCCGGATAGGTTCTCGGGAAGCGGCTCGGGT 
               
               
                   
                   
                 ACCGATTTCACCCTGGCAATCTCGCGGCTGGAACCGGAGGATTCGGCC 
               
               
                   
                   
                 GTGTACTACTGCCAGCACTATGACTCATCCCCCTCCTGGACATTCGGA 
               
               
                   
                   
                 CAGGGCACCAAGGTCGAGATCAAG 
               
               
                   
               
               
                 BCMA_EB 
                 1589 
                 EVQLVETGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1978- 
                   
                 SAISGSGGSTYYADSVKGRFTMSRENDKNSVFLQMNSLRVEDTGVYYC 
               
               
                 A10-aa 
                   
                 ARANYKRELRYYYGMDVWGQGTMVTVSS 
               
               
                 VH 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1590 
                 EIVMTQSPGTLSLSPGESATLSCRASQRVASNYLAWYQHKPGQAPSLL 
               
               
                 B-C1978- 
                   
                 ISGASSRATGVPDRFSGSGSGTDFTLAISRLEPEDSAVYYCQHYDSSP 
               
               
                 A10-aa 
                   
                 SWTFGQGTKVEIK 
               
               
                 VL 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1591 
                 MALPVTALLLPLALLLHAARPEVQLVETGGGLVQPGGSLRLSCAASGF 
               
               
                 B-C1978- 
                   
                 TFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTMSREND 
               
               
                 A10-aa 
                   
                 KNSVFLQMNSLRVEDTGVYYCARANYKRELRYYYGMDVWGQGTMVTVS 
               
               
                 Full CART 
                   
                 SGGGGSGGGGSGGGGSEIVMTQSPGTLSLSPGESATLSCRASQRVASN 
               
               
                   
                   
                 YLAWYQHKPGQAPSLLISGASSRATGVPDRFSGSGSGTDFTLAISRLE 
               
               
                   
                   
                 PEDSAVYYCQHYDSSPSWTFGQGTKVEIKTTTPAPRPPTPAPTIASQP 
               
               
                   
                   
                 LSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITL 
               
               
                   
                   
                 YCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKF 
               
               
                   
                   
                 SRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRK 
               
               
                   
                   
                 NPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDT 
               
               
                   
                   
                 YDALHMQALPPR 
               
               
                   
               
               
                 BCMA_EB 
                 1592 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 B-C1978- 
                   
                 CACGCCGCTCGGCCCGAAGTGCAACTGGTGGAAACCGGTGGAGGACTC 
               
               
                 A10-nt 
                   
                 GTGCAGCCTGGCGGCAGCCTCCGGCTGAGCTGCGCCGCTTCGGGATTC 
               
               
                 Full CART 
                   
                 ACCTTTTCCTCCTACGCGATGTCTTGGGTCAGACAGGCCCCCGGAAAG 
               
               
                   
                   
                 GGGCTGGAATGGGTGTCAGCCATCTCCGGCTCCGGCGGATCAACGTAC 
               
               
                   
                   
                 TACGCCGACTCCGTGAAAGGCCGGTTCACCATGTCGCGCGAGAATGAC 
               
               
                   
                   
                 AAGAACTCCGTGTTCCTGCAAATGAACTCCCTGAGGGTGGAGGACACC 
               
               
                   
                   
                 GGAGTGTACTATTGTGCGCGCGCCAACTACAAGAGAGAGCTGCGGTAC 
               
               
                   
                   
                 TACTACGGAATGGACGTCTGGGGACAGGGAACTATGGTGACCGTGTCA 
               
               
                   
                   
                 TCCGGTGGAGGGGGAAGCGGCGGTGGAGGCAGCGGGGGCGGGGGTTCA 
               
               
                   
                   
                 GAAATTGTCATGACCCAGTCCCCGGGAACTCTTTCCCTCTCCCCCGGG 
               
               
                   
                   
                 GAATCCGCGACTTTGTCCTGCCGGGCCAGCCAGCGCGTGGCCTCGAAC 
               
               
                   
                   
                 TACCTCGCATGGTACCAGCATAAGCCAGGCCAAGCCCCTTCCCTGCTG 
               
               
                   
                   
                 ATTTCCGGGGCTAGCAGCCGCGCCACTGGCGTGCCGGATAGGTTCTCG 
               
               
                   
                   
                 GGAAGCGGCTCGGGTACCGATTTCACCCTGGCAATCTCGCGGCTGGAA 
               
               
                   
                   
                 CCGGAGGATTCGGCCGTGTACTACTGCCAGCACTATGACTCATCCCCC 
               
               
                   
                   
                 TCCTGGACATTCGGACAGGGCACCAAGGTCGAGATCAAGACCACTACC 
               
               
                   
                   
                 CCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCT 
               
               
                   
                   
                 CTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTG 
               
               
                   
                   
                 CATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCT 
               
               
                   
                   
                 CTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTT 
               
               
                   
                   
                 TACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCC 
               
               
                   
                   
                 TTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGC 
               
               
                   
                   
                 CGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTC 
               
               
                   
                   
                 AGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTC 
               
               
                   
                   
                 TACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGAC 
               
               
                   
                   
                 AAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAG 
               
               
                   
                   
                 AATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCA 
               
               
                   
                   
                 GAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAA 
               
               
                   
                   
                 GGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACC 
               
               
                   
                   
                 TATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-D4 
               
            
           
           
               
               
               
            
               
                 BCMA_EB 
                 1593 
                 EVQLLETGGGLVQPGGSLRLSCAASGFSFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1978- 
                   
                 SAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC 
               
               
                 D4-aa 
                   
                 AKALVGATGAFDIWGQGTLVTVSSGGGGSGGGGSGGGGSEIVLTQSPG 
               
               
                 ScFv 
                   
                 TLSLSPGERATLSCRASQSLSSNFLAWYQQKPGQAPGLLIYGASNWAT 
               
               
                 domain 
                   
                 GTPDRFSGSGSGTDFTLTITRLEPEDFAVYYCQYYGTSPMYTFGQGTK 
               
               
                   
                   
                 VEIK 
               
               
                   
               
               
                 BCMA_EB 
                 1594 
                 GAAGTGCAGCTGCTCGAAACCGGTGGAGGGCTGGTGCAGCCAGGGGGC 
               
               
                 B-C1978- 
                   
                 TCCCTGAGGCTTTCATGCGCCGCTAGCGGATTCTCCTTCTCCTCTTAC 
               
               
                 D4-nt 
                   
                 GCCATGTCGTGGGTCCGCCAAGCCCCTGGAAAAGGCCTGGAATGGGTG 
               
               
                 ScFv 
                   
                 TCCGCGATTTCCGGGAGCGGAGGTTCGACCTATTACGCCGACTCCGTG 
               
               
                 domain 
                   
                 AAGGGCCGCTTTACCATCTCCCGGGATAACTCCAAGAACACTCTGTAC 
               
               
                   
                   
                 CTCCAAATGAACTCGCTGAGAGCCGAGGACACCGCCGTGTATTACTGC 
               
               
                   
                   
                 GCGAAGGCGCTGGTCGGCGCGACTGGGGCATTCGACATCTGGGGACAG 
               
               
                   
                   
                 GGAACTCTTGTGACCGTGTCGAGCGGAGGCGGCGGCTCCGGCGGAGGA 
               
               
                   
                   
                 GGGAGCGGGGGCGGTGGTTCCGAAATCGTGTTGACTCAGTCCCCGGGA 
               
               
                   
                   
                 ACCCTGAGCTTGTCACCCGGGGAGCGGGCCACTCTCTCCTGTCGCGCC 
               
               
                   
                   
                 TCCCAATCGCTCTCATCCAATTTCCTGGCCTGGTACCAGCAGAAGCCC 
               
               
                   
                   
                 GGACAGGCCCCGGGCCTGCTCATCTACGGCGCTTCAAACTGGGCAACG 
               
               
                   
                   
                 GGAACCCCTGATCGGTTCAGCGGAAGCGGATCGGGTACTGACTTTACC 
               
               
                   
                   
                 CTGACCATCACCAGACTGGAACCGGAGGACTTCGCCGTGTACTACTGC 
               
               
                   
                   
                 CAGTACTACGGCACCTCCCCCATGTACACATTCGGACAGGGTACCAAG 
               
               
                   
                   
                 GTCGAGATTAAG 
               
               
                   
               
               
                 BCMA_EB 
                 1595 
                 EVQLLETGGGLVQPGGSLRLSCAASGFSFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1978- 
                   
                 SAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC 
               
               
                 D4-aa 
                   
                 AKALVGATGAFDIWGQGTLVTVSS 
               
               
                 VH 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1596 
                 EIVLTQSPGTLSLSPGERATLSCRASQSLSSNFLAWYQQKPGQAPGLL 
               
               
                 B-C1978- 
                   
                 IYGASNWATGTPDRFSGSGSGTDFTLTITRLEPEDFAVYYCQYYGTSP 
               
               
                 D4-aa 
                   
                 MYTFGQGTKVEIK 
               
               
                 VL 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1597 
                 MALPVTALLLPLALLLHAARPEVQLLETGGGLVQPGGSLRLSCAASGF 
               
               
                 B-C1978- 
                   
                 SFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNS 
               
               
                 D4-aa 
                   
                 KNTLYLQMNSLRAEDTAVYYCAKALVGATGAFDIWGQGTLVTVSSGGG 
               
               
                 Full CART 
                   
                 GSGGGGSGGGGSEIVLTQSPGTLSLSPGERATLSCRASQSLSSNFLAW 
               
               
                   
                   
                 YQQKPGQAPGLLIYGASNWATGTPDRFSGSGSGTDFTLTITRLEPEDF 
               
               
                   
                   
                 AVYYCQYYGTSPMYTFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLR 
               
               
                   
                   
                 PEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKR 
               
               
                   
                   
                 GRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSA 
               
               
                   
                   
                 DAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQE 
               
               
                   
                   
                 GLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDAL 
               
               
                   
                   
                 HMQALPPR 
               
               
                   
               
               
                 BCMA_EB 
                 1598 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 B-C1978- 
                   
                 CACGCCGCTCGGCCCGAAGTGCAGCTGCTCGAAACCGGTGGAGGGCTG 
               
               
                 D4-nt 
                   
                 GTGCAGCCAGGGGGCTCCCTGAGGCTTTCATGCGCCGCTAGCGGATTC 
               
               
                 Full CART 
                   
                 TCCTTCTCCTCTTACGCCATGTCGTGGGTCCGCCAAGCCCCTGGAAAA 
               
               
                   
                   
                 GGCCTGGAATGGGTGTCCGCGATTTCCGGGAGCGGAGGTTCGACCTAT 
               
               
                   
                   
                 TACGCCGACTCCGTGAAGGGCCGCTTTACCATCTCCCGGGATAACTCC 
               
               
                   
                   
                 AAGAACACTCTGTACCTCCAAATGAACTCGCTGAGAGCCGAGGACACC 
               
               
                   
                   
                 GCCGTGTATTACTGCGCGAAGGCGCTGGTCGGCGCGACTGGGGCATTC 
               
               
                   
                   
                 GACATCTGGGGACAGGGAACTCTTGTGACCGTGTCGAGCGGAGGCGGC 
               
               
                   
                   
                 GGCTCCGGCGGAGGAGGGAGCGGGGGCGGTGGTTCCGAAATCGTGTTG 
               
               
                   
                   
                 ACTCAGTCCCCGGGAACCCTGAGCTTGTCACCCGGGGAGCGGGCCACT 
               
               
                   
                   
                 CTCTCCTGTCGCGCCTCCCAATCGCTCTCATCCAATTTCCTGGCCTGG 
               
               
                   
                   
                 TACCAGCAGAAGCCCGGACAGGCCCCGGGCCTGCTCATCTACGGCGCT 
               
               
                   
                   
                 TCAAACTGGGCAACGGGAACCCCTGATCGGTTCAGCGGAAGCGGATCG 
               
               
                   
                   
                 GGTACTGACTTTACCCTGACCATCACCAGACTGGAACCGGAGGACTTC 
               
               
                   
                   
                 GCCGTGTACTACTGCCAGTACTACGGCACCTCCCCCATGTACACATTC 
               
               
                   
                   
                 GGACAGGGTACCAAGGTCGAGATTAAGACCACTACCCCAGCACCGAGG 
               
               
                   
                   
                 CCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGT 
               
               
                   
                   
                 CCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGT 
               
               
                   
                   
                 CTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACT 
               
               
                   
                   
                 TGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGC 
               
               
                   
                   
                 GGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCT 
               
               
                   
                   
                 GTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAG 
               
               
                   
                   
                 GAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCA 
               
               
                   
                   
                 GATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTC 
               
               
                   
                   
                 AATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGA 
               
               
                   
                   
                 CGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAG 
               
               
                   
                   
                 GGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGC 
               
               
                   
                   
                 GAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGA 
               
               
                   
                   
                 CTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTT 
               
               
                   
                   
                 CACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1980-A2 
               
            
           
           
               
               
               
            
               
                 BCMA_EB 
                 1599 
                 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1980- 
                   
                 SAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC 
               
               
                 A2-aa 
                   
                 VLWFGEGFDPWGQGTLVTVSSGGGGSGGGGSGGGGSDIVLTQSPLSLP 
               
               
                 ScFv 
                   
                 VTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRA 
               
               
                 domain 
                   
                 SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPLTFGGGTK 
               
               
                   
                   
                 VDIK 
               
               
                   
               
               
                 BCMA_EB 
                 1600 
                 GAAGTGCAGCTGCTTGAGAGCGGTGGAGGTCTGGTGCAGCCCGGGGGA 
               
               
                 B-C1980- 
                   
                 TCACTGCGCCTGTCCTGTGCCGCGTCCGGTTTCACTTTCTCCTCGTAC 
               
               
                 A2-nt 
                   
                 GCCATGTCGTGGGTCAGACAGGCACCGGGAAAGGGACTGGAATGGGTG 
               
               
                 ScFv 
                   
                 TCAGCCATTTCGGGTTCGGGGGGCAGCACCTACTACGCTGACTCCGTG 
               
               
                 domain 
                   
                 AAGGGCCGGTTCACCATTTCCCGCGACAACTCCAAGAACACCTTGTAC 
               
               
                   
                   
                 CTCCAAATGAACTCCCTGCGGGCCGAAGATACCGCCGTGTATTACTGC 
               
               
                   
                   
                 GTGCTGTGGTTCGGAGAGGGATTCGACCCGTGGGGACAAGGAACACTC 
               
               
                   
                   
                 GTGACTGTGTCATCCGGCGGAGGCGGCAGCGGTGGCGGCGGTTCCGGC 
               
               
                   
                   
                 GGCGGCGGATCTGACATCGTGTTGACCCAGTCCCCTCTGAGCCTGCCG 
               
               
                   
                   
                 GTCACTCCTGGCGAACCAGCCAGCATCTCCTGCCGGTCGAGCCAGTCC 
               
               
                   
                   
                 CTCCTGCACTCCAATGGGTACAACTACCTCGATTGGTATCTGCAAAAG 
               
               
                   
                   
                 CCGGGCCAGAGCCCCCAGCTGCTGATCTACCTTGGGTCAAACCGCGCT 
               
               
                   
                   
                 TCCGGGGTGCCTGATAGATTCTCCGGGTCCGGGAGCGGAACCGACTTT 
               
               
                   
                   
                 ACCCTGAAAATCTCGAGGGTGGAGGCCGAGGACGTCGGAGTGTACTAC 
               
               
                   
                   
                 TGCATGCAGGCGCTCCAGACTCCCCTGACCTTCGGAGGAGGAACGAAG 
               
               
                   
                   
                 GTCGACATCAAGA 
               
               
                   
               
               
                 BCMA_EB 
                 1601 
                 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1980- 
                   
                 SAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC 
               
               
                 A2-aa 
                   
                 VLWFGEGFDPWGQGTLVTVSS 
               
               
                 VH 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1602 
                 DIVLTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQS 
               
               
                 B-C1980- 
                   
                 PQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQA 
               
               
                 A2-aa 
                   
                 LQTPLTFGGGTKVDIK 
               
               
                 VL 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1603 
                 MALPVTALLLPLALLLHAARPEVQLLESGGGLVQPGGSLRLSCAASGF 
               
               
                 B-C1980- 
                   
                 TFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNS 
               
               
                 A2-aa 
                   
                 KNTLYLQMNSLRAEDTAVYYCVLWFGEGFDPWGQGTLVTVSSGGGGSG 
               
               
                 Full CART 
                   
                 GGGSGGGGSDIVLTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLD 
               
               
                   
                   
                 WYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAED 
               
               
                   
                   
                 VGVYYCMQALQTPLTFGGGTKVDIKTTTPAPRPPTPAPTIASQPLSLR 
               
               
                   
                   
                 PEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKR 
               
               
                   
                   
                 GRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSA 
               
               
                   
                   
                 DAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQE 
               
               
                   
                   
                 GLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDAL 
               
               
                   
                   
                 HMQALPPR 
               
               
                   
               
               
                 BCMA_EB 
                 1604 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 B-C1980- 
                   
                 CACGCCGCTCGGCCCGAAGTGCAGCTGCTTGAGAGCGGTGGAGGTCTG 
               
               
                 A2-nt 
                   
                 GTGCAGCCCGGGGGATCACTGCGCCTGTCCTGTGCCGCGTCCGGTTTC 
               
               
                 Full CART 
                   
                 ACTTTCTCCTCGTACGCCATGTCGTGGGTCAGACAGGCACCGGGAAAG 
               
               
                   
                   
                 GGACTGGAATGGGTGTCAGCCATTTCGGGTTCGGGGGGCAGCACCTAC 
               
               
                   
                   
                 TACGCTGACTCCGTGAAGGGCCGGTTCACCATTTCCCGCGACAACTCC 
               
               
                   
                   
                 AAGAACACCTTGTACCTCCAAATGAACTCCCTGCGGGCCGAAGATACC 
               
               
                   
                   
                 GCCGTGTATTACTGCGTGCTGTGGTTCGGAGAGGGATTCGACCCGTGG 
               
               
                   
                   
                 GGACAAGGAACACTCGTGACTGTGTCATCCGGCGGAGGCGGCAGCGGT 
               
               
                   
                   
                 GGCGGCGGTTCCGGCGGCGGCGGATCTGACATCGTGTTGACCCAGTCC 
               
               
                   
                   
                 CCTCTGAGCCTGCCGGTCACTCCTGGCGAACCAGCCAGCATCTCCTGC 
               
               
                   
                   
                 CGGTCGAGCCAGTCCCTCCTGCACTCCAATGGGTACAACTACCTCGAT 
               
               
                   
                   
                 TGGTATCTGCAAAAGCCGGGCCAGAGCCCCCAGCTGCTGATCTACCTT 
               
               
                   
                   
                 GGGTCAAACCGCGCTTCCGGGGTGCCTGATAGATTCTCCGGGTCCGGG 
               
               
                   
                   
                 AGCGGAACCGACTTTACCCTGAAAATCTCGAGGGTGGAGGCCGAGGAC 
               
               
                   
                   
                 GTCGGAGTGTACTACTGCATGCAGGCGCTCCAGACTCCCCTGACCTTC 
               
               
                   
                   
                 GGAGGAGGAACGAAGGTCGACATCAAGACCACTACCCCAGCACCGAGG 
               
               
                   
                   
                 CCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGT 
               
               
                   
                   
                 CCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGT 
               
               
                   
                   
                 CTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACT 
               
               
                   
                   
                 TGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGC 
               
               
                   
                   
                 GGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCT 
               
               
                   
                   
                 GTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAG 
               
               
                   
                   
                 GAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCA 
               
               
                   
                   
                 GATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTC 
               
               
                   
                   
                 AATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGA 
               
               
                   
                   
                 CGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAG 
               
               
                   
                   
                 GGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGC 
               
               
                   
                   
                 GAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGA 
               
               
                   
                   
                 CTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTT 
               
               
                   
                   
                 CACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1981-C3 
               
            
           
           
               
               
               
            
               
                 BCMA_EB 
                 1605 
                 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1981- 
                   
                 SAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC 
               
               
                 C3-aa 
                   
                 AKVGYDSSGYYRDYYGMDVWGQGTTVTVSSGGGGSGGGGSGGGGSEIV 
               
               
                 ScFv 
                   
                 LTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYG 
               
               
                 domain 
                   
                 TSSRATGISDRFSGSGSGTDFTLTISRLEPEDFAVYYCQHYGNSPPKF 
               
               
                   
                   
                 TFGPGTKLEIK 
               
               
                   
               
               
                 BCMA_EB 
                 1606 
                 CAAGTGCAGCTCGTGGAGTCAGGCGGAGGACTGGTGCAGCCCGGGGGC 
               
               
                 B-C1981- 
                   
                 TCCCTGAGACTTTCCTGCGCGGCATCGGGTTTTACCTTCTCCTCCTAT 
               
               
                 C3-nt 
                   
                 GCTATGTCCTGGGTGCGCCAGGCCCCGGGAAAGGGACTGGAATGGGTG 
               
               
                 ScFv 
                   
                 TCCGCAATCAGCGGTAGCGGGGGCTCAACATACTACGCCGACTCCGTC 
               
               
                 domain 
                   
                 AAGGGTCGCTTCACTATTTCCCGGGACAACTCCAAGAATACCCTGTAC 
               
               
                   
                   
                 CTCCAAATGAACAGCCTCAGGGCCGAGGATACTGCCGTGTACTACTGC 
               
               
                   
                   
                 GCCAAAGTCGGATACGATAGCTCCGGTTACTACCGGGACTACTACGGA 
               
               
                   
                   
                 ATGGACGTGTGGGGACAGGGCACCACCGTGACCGTGTCAAGCGGCGGA 
               
               
                   
                   
                 GGCGGTTCAGGAGGGGGAGGCTCCGGCGGTGGAGGGTCCGAAATCGTC 
               
               
                   
                   
                 CTGACTCAGTCGCCTGGCACTCTGTCGTTGTCCCCGGGGGAGCGCGCT 
               
               
                   
                   
                 ACCCTGTCGTGTCGGGCGTCGCAGTCCGTGTCGAGCTCCTACCTCGCG 
               
               
                   
                   
                 TGGTACCAGCAGAAGCCCGGACAGGCCCCTAGACTTCTGATCTACGGC 
               
               
                   
                   
                 ACTTCTTCACGCGCCACCGGGATCAGCGACAGGTTCAGCGGCTCCGGC 
               
               
                   
                   
                 TCCGGGACCGACTTCACCCTGACCATTAGCCGGCTGGAGCCTGAAGAT 
               
               
                   
                   
                 TTCGCCGTGTATTACTGCCAACACTACGGAAACTCGCCGCCAAAGTTC 
               
               
                   
                   
                 ACGTTCGGACCCGGAACCAAGCTGGAAATCAAG 
               
               
                   
               
               
                 BCMA_EB 
                 1607 
                 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1981- 
                   
                 SAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC 
               
               
                 C3-aa 
                   
                 AKVGYDSSGYYRDYYGMDVWGQGTTVTVSS 
               
               
                 VH 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1608 
                 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLL 
               
               
                 B-C1981- 
                   
                 IYGTSSRATGISDRFSGSGSGTDFTLTISRLEPEDFAVYYCQHYGNSP 
               
               
                 C3-aa 
                   
                 PKFTFGPGTKLEIK 
               
               
                 VL 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1609 
                 MALPVTALLLPLALLLHAARPQVQLVESGGGLVQPGGSLRLSCAASGF 
               
               
                 B-C1981- 
                   
                 TFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNS 
               
               
                 C3-aa 
                   
                 KNTLYLQMNSLRAEDTAVYYCAKVGYDSSGYYRDYYGMDVWGQGTTVT 
               
               
                 Full CART 
                   
                 VSSGGGGSGGGGSGGGGSEIVLTQSPGTLSLSPGERATLSCRASQSVS 
               
               
                   
                   
                 SSYLAWYQQKPGQAPRLLIYGTSSRATGISDRFSGSGSGTDFTLTISR 
               
               
                   
                   
                 LEPEDFAVYYCQHYGNSPPKFTFGPGTKLEIKTTTPAPRPPTPAPTIA 
               
               
                   
                   
                 SQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLV 
               
               
                   
                   
                 ITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELR 
               
               
                   
                   
                 VKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKP 
               
               
                   
                   
                 RRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTAT 
               
               
                   
                   
                 KDTYDALHMQALPPR 
               
               
                   
               
               
                 BCMA_EB 
                 1610 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 B-C1981- 
                   
                 CACGCCGCTCGGCCCCAAGTGCAGCTCGTGGAGTCAGGCGGAGGACTG 
               
               
                 C3-nt 
                   
                 GTGCAGCCCGGGGGCTCCCTGAGACTTTCCTGCGCGGCATCGGGTTTT 
               
               
                 Full CART 
                   
                 ACCTTCTCCTCCTATGCTATGTCCTGGGTGCGCCAGGCCCCGGGAAAG 
               
               
                   
                   
                 GGACTGGAATGGGTGTCCGCAATCAGCGGTAGCGGGGGCTCAACATAC 
               
               
                   
                   
                 TACGCCGACTCCGTCAAGGGTCGCTTCACTATTTCCCGGGACAACTCC 
               
               
                   
                   
                 AAGAATACCCTGTACCTCCAAATGAACAGCCTCAGGGCCGAGGATACT 
               
               
                   
                   
                 GCCGTGTACTACTGCGCCAAAGTCGGATACGATAGCTCCGGTTACTAC 
               
               
                   
                   
                 CGGGACTACTACGGAATGGACGTGTGGGGACAGGGCACCACCGTGACC 
               
               
                   
                   
                 GTGTCAAGCGGCGGAGGCGGTTCAGGAGGGGGAGGCTCCGGCGGTGGA 
               
               
                   
                   
                 GGGTCCGAAATCGTCCTGACTCAGTCGCCTGGCACTCTGTCGTTGTCC 
               
               
                   
                   
                 CCGGGGGAGCGCGCTACCCTGTCGTGTCGGGCGTCGCAGTCCGTGTCG 
               
               
                   
                   
                 AGCTCCTACCTCGCGTGGTACCAGCAGAAGCCCGGACAGGCCCCTAGA 
               
               
                   
                   
                 CTTCTGATCTACGGCACTTCTTCACGCGCCACCGGGATCAGCGACAGG 
               
               
                   
                   
                 TTCAGCGGCTCCGGCTCCGGGACCGACTTCACCCTGACCATTAGCCGG 
               
               
                   
                   
                 CTGGAGCCTGAAGATTTCGCCGTGTATTACTGCCAACACTACGGAAAC 
               
               
                   
                   
                 TCGCCGCCAAAGTTCACGTTCGGACCCGGAACCAAGCTGGAAATCAAG 
               
               
                   
                   
                 ACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCC 
               
               
                   
                   
                 TCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGT 
               
               
                   
                   
                 GGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATT 
               
               
                   
                   
                 TGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTG 
               
               
                   
                   
                 ATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTT 
               
               
                   
                   
                 AAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGC 
               
               
                   
                   
                 TGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGC 
               
               
                   
                   
                 GTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAG 
               
               
                   
                   
                 AACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGAC 
               
               
                   
                   
                 GTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCG 
               
               
                   
                   
                 CGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGAT 
               
               
                   
                   
                 AAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGA 
               
               
                   
                   
                 AGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACC 
               
               
                   
                   
                 AAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-G4 
               
            
           
           
               
               
               
            
               
                 BCMA_EB 
                 1611 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1978- 
                   
                 SAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC 
               
               
                 G4-aa 
                   
                 AKMGWSSGYLGAFDIWGQGTTVTVSSGGGGSGGGGSGGGGSEIVLTQS 
               
               
                 ScFv 
                   
                 PGTLSLSPGERATLSCRASQSVASSFLAWYQQKPGQAPRLLIYGASGR 
               
               
                 domain 
                   
                 ATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQHYGGSPRLTFGGG 
               
               
                   
                   
                 TKVDIK 
               
               
                   
               
               
                 BCMA_EB 
                 1612 
                 GAAGTCCAACTGGTGGAGTCCGGGGGAGGGCTCGTGCAGCCCGGAGGC 
               
               
                 B-C1978- 
                   
                 AGCCTTCGGCTGTCGTGCGCCGCCTCCGGGTTCACGTTCTCATCCTAC 
               
               
                 G4-nt 
                   
                 GCGATGTCGTGGGTCAGACAGGCACCAGGAAAGGGACTGGAATGGGTG 
               
               
                 ScFv 
                   
                 TCCGCCATTAGCGGCTCCGGCGGTAGCACCTACTATGCCGACTCAGTG 
               
               
                 domain 
                   
                 AAGGGAAGGTTCACTATCTCCCGCGACAACAGCAAGAACACCCTGTAC 
               
               
                   
                   
                 CTCCAAATGAACTCTCTGCGGGCCGAGGATACCGCGGTGTACTATTGC 
               
               
                   
                   
                 GCCAAGATGGGTTGGTCCAGCGGATACTTGGGAGCCTTCGACATTTGG 
               
               
                   
                   
                 GGACAGGGCACTACTGTGACCGTGTCCTCCGGGGGTGGCGGATCGGGA 
               
               
                   
                   
                 GGCGGCGGCTCGGGTGGAGGGGGTTCCGAAATCGTGTTGACCCAGTCA 
               
               
                   
                   
                 CCGGGAACCCTCTCGCTGTCCCCGGGAGAACGGGCTACACTGTCATGT 
               
               
                   
                   
                 AGAGCGTCCCAGTCCGTGGCTTCCTCGTTCCTGGCCTGGTACCAGCAG 
               
               
                   
                   
                 AAGCCGGGACAGGCACCCCGCCTGCTCATCTACGGAGCCAGCGGCCGG 
               
               
                   
                   
                 GCGACCGGCATCCCTGACCGCTTCTCCGGTTCCGGCTCGGGCACCGAC 
               
               
                   
                   
                 TTTACTCTGACCATTAGCAGGCTTGAGCCCGAGGATTTTGCCGTGTAC 
               
               
                   
                   
                 TACTGCCAACACTACGGGGGGAGCCCTCGCCTGACCTTCGGAGGCGGA 
               
               
                   
                   
                 ACTAAGGTCGATATCAAAA 
               
               
                   
               
               
                 BCMA_EB 
                 1613 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWV 
               
               
                 B-C1978- 
                   
                 SAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC 
               
               
                 G4-aa 
                   
                 AKMGWSSGYLGAFDIWGQGTTVTVSS 
               
               
                 VH 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1614 
                 EIVLTQSPGTLSLSPGERATLSCRASQSVASSFLAWYQQKPGQAPRLL 
               
               
                 B-C1978- 
                   
                 IYGASGRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQHYGGSP 
               
               
                 G4-aa 
                   
                 RLTFGGGTKVDIK 
               
               
                 VL 
                   
                   
               
               
                   
               
               
                 BCMA_EB 
                 1615 
                 MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGF 
               
               
                 B-C1978- 
                   
                 TFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNS 
               
               
                 G4-aa 
                   
                 KNTLYLQMNSLRAEDTAVYYCAKMGWSSGYLGAFDIWGQGTTVTVSSG 
               
               
                 Full CART 
                   
                 GGGSGGGGSGGGGSEIVLTQSPGTLSLSPGERATLSCRASQSVASSFL 
               
               
                   
                   
                 AWYQQKPGQAPRLLIYGASGRATGIPDRFSGSGSGTDFTLTISRLEPE 
               
               
                   
                   
                 DFAVYYCQHYGGSPRLTFGGGTKVDIKTTTPAPRPPTPAPTIASQPLS 
               
               
                   
                   
                 LRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYC 
               
               
                   
                   
                 KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSR 
               
               
                   
                   
                 SADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNP 
               
               
                   
                   
                 QEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYD 
               
               
                   
                   
                 ALHMQALPPR 
               
               
                   
               
               
                 BCMA_EB 
                 1616 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTC 
               
               
                 B-C1978- 
                   
                 CACGCCGCTCGGCCCGAAGTCCAACTGGTGGAGTCCGGGGGAGGGCTC 
               
               
                 G4-nt 
                   
                 GTGCAGCCCGGAGGCAGCCTTCGGCTGTCGTGCGCCGCCTCCGGGTTC 
               
               
                 Full CART 
                   
                 ACGTTCTCATCCTACGCGATGTCGTGGGTCAGACAGGCACCAGGAAAG 
               
               
                   
                   
                 GGACTGGAATGGGTGTCCGCCATTAGCGGCTCCGGCGGTAGCACCTAC 
               
               
                   
                   
                 TATGCCGACTCAGTGAAGGGAAGGTTCACTATCTCCCGCGACAACAGC 
               
               
                   
                   
                 AAGAACACCCTGTACCTCCAAATGAACTCTCTGCGGGCCGAGGATACC 
               
               
                   
                   
                 GCGGTGTACTATTGCGCCAAGATGGGTTGGTCCAGCGGATACTTGGGA 
               
               
                   
                   
                 GCCTTCGACATTTGGGGACAGGGCACTACTGTGACCGTGTCCTCCGGG 
               
               
                   
                   
                 GGTGGCGGATCGGGAGGCGGCGGCTCGGGTGGAGGGGGTTCCGAAATC 
               
               
                   
                   
                 GTGTTGACCCAGTCACCGGGAACCCTCTCGCTGTCCCCGGGAGAACGG 
               
               
                   
                   
                 GCTACACTGTCATGTAGAGCGTCCCAGTCCGTGGCTTCCTCGTTCCTG 
               
               
                   
                   
                 GCCTGGTACCAGCAGAAGCCGGGACAGGCACCCCGCCTGCTCATCTAC 
               
               
                   
                   
                 GGAGCCAGCGGCCGGGCGACCGGCATCCCTGACCGCTTCTCCGGTTCC 
               
               
                   
                   
                 GGCTCGGGCACCGACTTTACTCTGACCATTAGCAGGCTTGAGCCCGAG 
               
               
                   
                   
                 GATTTTGCCGTGTACTACTGCCAACACTACGGGGGGAGCCCTCGCCTG 
               
               
                   
                   
                 ACCTTCGGAGGCGGAACTAAGGTCGATATCAAAACCACTACCCCAGCA 
               
               
                   
                   
                 CCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCC 
               
               
                   
                   
                 CTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACC 
               
               
                   
                   
                 CGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCT 
               
               
                   
                   
                 GGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGT 
               
               
                   
                   
                 AAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATG 
               
               
                   
                   
                 AGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTC 
               
               
                   
                   
                 CCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGC 
               
               
                   
                   
                 AGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAAC 
               
               
                   
                   
                 GAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGG 
               
               
                   
                   
                 AGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCC 
               
               
                   
                   
                 CAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCC 
               
               
                   
                   
                 TATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCAC 
               
               
                   
                   
                 GACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGAC 
               
               
                   
                   
                 GCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4E 
               
             
            
               
                   
               
               
                 Additional exemplary BCMA CAR sequences 
               
            
           
           
               
               
               
            
               
                   
                   
                 SEQ 
               
               
                 Name 
                 Sequence 
                 ID NO: 
               
               
                   
               
               
                 A7D12.2 
                 QIQLVQSGPDLKKPGETVKLSCKASGYTFTNFGMNWVKQAPGKGFKWMAWINTYTGES 
                 1617 
               
               
                 VH 
                 YFADDFKGRFAFSVETSATTAYLQINNLKTEDTATYFCARGEIYYGYDGGFAYWGQGT 
                   
               
               
                   
                 LVTVSA 
                   
               
               
                   
               
               
                 A7D12.2 
                 DVVMTQSHRFMSTSVGDRVSITCRASQDVNTAVSWYQQKPGQSPKLLIFSASYRYTGV 
                 1618 
               
               
                 VL 
                 PDRFTGSGSGADFTLTISSVQAEDLAVYYCQQHYSTPWTFGGGTKLDIK 
                   
               
               
                   
               
               
                 A7D12.2 
                 QIQLVQSGPDLKKPGETVKLSCKASGYTFTNFGMNWVKQAPGKGFKWMAWINTYTGES 
                 1619 
               
               
                 scFv 
                 YFADDFKGRFAFSVETSATTAYLQINNLKTEDTATYFCARGEIYYGYDGGFAYWGQGT 
                   
               
               
                 domain 
                 LVTVSAGGGGSGGGGSGGGGSDVVMTQSHRFMSTSVGDRVSITCRASQDVNTAVSWYQ 
                   
               
               
                   
                 QKPGQSPKLLIFSASYRYTGVPDRFTGSGSGADFTLTISSVQAEDLAVYYCQQHYSTP 
                   
               
               
                   
                 WTFGGGTKLDIK 
                   
               
               
                   
               
               
                 A7D12.2 
                 QIQLVQSGPDLKKPGETVKLSCKASGYTFTNFGMNWVKQAPGKGFKWMAWINTYTGES 
                 1620 
               
               
                 Full 
                 YFADDFKGRFAFSVETSATTAYLQINNLKTEDTATYFCARGEIYYGYDGGFAYWGQGT 
                   
               
               
                 CART 
                 LVTVSAGGGGSGGGGSGGGGSDVVMTQSHRFMSTSVGDRVSITCRASQDVNTAVSWYQ 
                   
               
               
                   
                 QKPGQSPKLLIFSASYRYTGVPDRFTGSGSGADFTLTISSVQAEDLAVYYCQQHYSTP 
                   
               
               
                   
                 WTFGGGTKLDIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI 
                   
               
               
                   
                 YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEE 
                   
               
               
                   
                 EEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRR 
                   
               
               
                   
                 KNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQAL 
                   
               
               
                   
                 PPR 
                   
               
               
                   
               
               
                 C11D5.3 
                 QIQLVQSGPELKKPGETVKISCKASGYTFTDYSINWVKRAPGKGLKWMGWINTETREP 
                 1621 
               
               
                 VH 
                 AYAYDFRGRFAFSLETSASTAYLQINNLKYEDTATYFCALDYSYAMDYWGQGTSVTVS 
                   
               
               
                   
                 S 
                   
               
               
                   
               
               
                 C11D5.3 
                 DIVLTQSPASLAMSLGKRATISCRASESVSVIGAHLIHWYQQKPGQPPKLLIYLASNL 
                 1622 
               
               
                 VL 
                 ETGVPARFSGSGSGTDFTLTIDPVEEDDVAIYSCLQSRIFPRTFGGGTKLEIK 
                   
               
               
                   
               
               
                 C11D5.3 
                 QIQLVQSGPELKKPGETVKISCKASGYTFTDYSINWVKRAPGKGLKWMGWINTETREP 
                 1623 
               
               
                 scFv 
                 AYAYDFRGRFAFSLETSASTAYLQINNLKYEDTATYFCALDYSYAMDYWGQGTSVTVS 
                   
               
               
                 domain 
                 SGGGGSGGGGSGGGGSQIQLVQSGPELKKPGETVKISCKASGYTFTDYSINWVKRAPG 
                   
               
               
                   
                 KGLKWMGWINTETREPAYAYDFRGRFAFSLETSASTAYLQINNLKYEDTATYFCALDY 
                   
               
               
                   
                 SYAMDYWGQGTSVTVSS 
                   
               
               
                   
               
               
                 C11D5.3 
                 QIQLVQSGPELKKPGETVKISCKASGYTFTDYSINWVKRAPGKGLKWMGWINTETREP 
                 1624 
               
               
                 Full 
                 AYAYDFRGRFAFSLETSASTAYLQINNLKYEDTATYFCALDYSYAMDYWGQGTSVTVS 
                   
               
               
                 CART 
                 SGGGGSGGGGSGGGGSQIQLVQSGPELKKPGETVKISCKASGYTFTDYSINWVKRAPG 
                   
               
               
                   
                 KGLKWMGWINTETREPAYAYDFRGRFAFSLETSASTAYLQINNLKYEDTATYFCALDY 
                   
               
               
                   
                 SYAMDYWGQGTSVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLD 
                   
               
               
                   
                 FACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC 
                   
               
               
                   
                 RFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMG 
                   
               
               
                   
                 GKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDAL 
                   
               
               
                   
                 HMQALPPR 
                   
               
               
                   
               
               
                 C12A3.2 
                 QIQLVQSGPELKKPGETVKISCKASGYTFRHYSMNWVKQAPGKGLKWMGRINTESGVP 
                 1625 
               
               
                 VH 
                 IYADDFKGRFAFSVETSASTAYLVINNLKDEDTASYFCSNDYLYSLDFWGQGTALTVS 
                   
               
               
                   
                 S 
                   
               
               
                   
               
               
                 C12A3.2 
                 DIVLTQSPPSLAMSLGKRATISCRASESVTILGSHLIYWYQQKPGQPPTLLIQLASNV 
                 1626 
               
               
                 VL 
                 QTGVPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPRTFGGGTKLEIK 
                   
               
               
                   
               
               
                 C12A3.2 
                 QIQLVQSGPELKKPGETVKISCKASGYTFRHYSMNWVKQAPGKGLKWMGRINTESGVP 
                 1627 
               
               
                 scFv 
                 IYADDFKGRFAFSVETSASTAYLVINNLKDEDTASYFCSNDYLYSLDFWGQGTALTVS 
                   
               
               
                 domain 
                 SGGGGSGGGGSGGGGSDIVLTQSPPSLAMSLGKRATISCRASESVTILGSHLIYWYQQ 
                   
               
               
                   
                 KPGQPPTLLIQLASNVQTGVPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPR 
                   
               
               
                   
                 TFGGGTKLEIK 
                   
               
               
                   
               
               
                 C12A3.2 
                 QIQLVQSGPELKKPGETVKISCKASGYTFRHYSMNWVKQAPGKGLKWMGRINTESGVP 
                 1628 
               
               
                 Full 
                 IYADDFKGRFAFSVETSASTAYLVINNLKDEDTASYFCSNDYLYSLDFWGQGTALTVS 
                   
               
               
                 CART 
                 SGGGGSGGGGSGGGGSDIVLTQSPPSLAMSLGKRATISCRASESVTILGSHLIYWYQQ 
                   
               
               
                   
                 KPGQPPTLLIQLASNVQTGVPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPR 
                   
               
               
                   
                 TFGGGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY 
                   
               
               
                   
                 IWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEE 
                   
               
               
                   
                 EGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRK 
                   
               
               
                   
                 NPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALP 
                   
               
               
                   
                 PR 
                   
               
               
                   
               
               
                 C13F12.1 
                 QIQLVQSGPELKKPGETVKISCKASGYTFTHYSMNWVKQAPGKGLKWMGRINTETGEP 
                 1629 
               
               
                 VH 
                 LYADDFKGRFAFSLETSASTAYLVINNLKNEDTATFFCSNDYLYSCDYWGQGTTLTVS 
                   
               
               
                   
                 S 
                   
               
               
                   
               
               
                 C13F12.1 
                 DIVLTQSPPSLAMSLGKRATISCRASESVTILGSHLIYWYQQKPGQPPTLLIQLASNV 
                 1630 
               
               
                 VL 
                 QTGVPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPRTFGGGTKLEIK 
                   
               
               
                   
               
               
                 C13F12.1 
                 QIQLVQSGPELKKPGETVKISCKASGYTFTHYSMNWVKQAPGKGLKWMGRINTETGEP 
                 1631 
               
               
                 scFv 
                 LYADDFKGRFAFSLETSASTAYLVINNLKNEDTATFFCSNDYLYSCDYWGQGTTLTVS 
                   
               
               
                 domain 
                 SGGGGSGGGGSGGGGSDIVLTQSPPSLAMSLGKRATISCRASESVTILGSHLIYWYQQ 
                   
               
               
                   
                 KPGQPPTLLIQLASNVQTGVPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPR 
                   
               
               
                   
                 TFGGGTKLEIK 
                   
               
               
                   
               
               
                 C13F12.1 
                 QIQLVQSGPELKKPGETVKISCKASGYTFTHYSMNWVKQAPGKGLKWMGRINTETGEP 
                 1632 
               
               
                 Full 
                 LYADDFKGRFAFSLETSASTAYLVINNLKNEDTATFFCSNDYLYSCDYWGQGTTLTVS 
                   
               
               
                 CART 
                 SGGGGSGGGGSGGGGSDIVLTQSPPSLAMSLGKRATISCRASESVTILGSHLIYWYQQ 
                   
               
               
                   
                 KPGQPPTLLIQLASNVQTGVPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPR 
                   
               
               
                   
                 TFGGGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY 
                   
               
               
                   
                 IWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEE 
                   
               
               
                   
                 EGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRK 
                   
               
               
                   
                 NPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALP 
                   
               
               
                   
                 PR 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4F 
               
               
                   
               
               
                 Amino acid sequences of exemplary BCMA binding domains 
               
               
                   
               
             
            
               
                 ER26 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 J6M0 VH 
                 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQ 
               
               
                 1635 
                   
                 GLEWMGATYRGHSDTYYNQKFKGRVTITADKSTSTAYMELSSLRS 
               
               
                   
                   
                 EDTAVYYCARGAIYDGYDVLDNWGQGTLVTVSS 
               
               
                 SEQ ID NO: 
                 J6M0 VL 
                 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKL 
               
               
                 1636 
                   
                 LIYYTSNLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYRK 
               
               
                   
                   
                 LPWTFGQGTKLEIKR 
               
               
                 SEQ ID NO: 
                 Anti-BCMA 
                 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQ 
               
               
                 1637 
                 heavy chain of 
                 GLEWMGATYRGHSDTYYNQKFKGRVTITADKSTSTAYMELSSLRS 
               
               
                   
                 ER26 
                 EDTAVYYCARGAIYNGYDVLDNWGQGTLVTVSSASTKGPSVFPLA 
               
               
                   
                   
                 PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ 
               
               
                   
                   
                 SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD 
               
               
                   
                   
                 KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSH 
               
               
                   
                   
                 EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD 
               
               
                   
                   
                 WLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVCTLPPSREEM 
               
               
                   
                   
                 TKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF 
               
               
                   
                   
                 FLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGX, 
               
               
                   
                   
                 wherein X is K or absent 
               
               
                 SEQ ID NO: 
                 Anti-BCMA 
                 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKL 
               
               
                 1638 
                 light chain of 
                 LIYYTSNLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYRK 
               
               
                   
                 ER26 
                 LPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY 
               
               
                   
                   
                 PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD 
               
               
                   
                   
                 YEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
            
           
           
               
            
               
                 BQ76 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 17A5 VH 
                 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 1639 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT 
               
               
                   
                   
                 AVYYCAKVAPYFAPFDYWGQGTLVTVSS 
               
               
                 SEQ ID NO: 
                 17A5 VL 
                 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRL 
               
               
                 1640 
                   
                 LIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGN 
               
               
                   
                   
                 PPLYTFGQGTKVEIK 
               
               
                 SEQ ID NO: 
                 Anti-BCMA 
                 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 1641 
                 heavy chain of 
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT 
               
               
                   
                 BQ76 
                 AVYYCAKVAPYFAPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKST 
               
               
                   
                   
                 SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY 
               
               
                   
                   
                 SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTC 
               
               
                   
                   
                 PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 
               
               
                   
                   
                 KFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNG 
               
               
                   
                   
                 KEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQ 
               
               
                   
                   
                 VSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVS 
               
               
                   
                   
                 KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGX, wherein 
               
               
                   
                   
                 X is K or absent 
               
               
                 SEQ ID NO: 
                 Anti-BCMA 
                 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRL 
               
               
                 1642 
                 light chain of 
                 LIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGN 
               
               
                   
                 BQ76 
                 PPLYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF 
               
               
                   
                   
                 YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 
               
               
                   
                   
                 DYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
            
           
           
               
            
               
                 BU76 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 C11D5 VH 
                 QIQLVQSGPELKKPGETVKISCKASGYTFTDYSINWVKRAPGKGLK 
               
               
                 1643 
                   
                 WMGWINTETREPAYAYDFRGRFAFSLETSASTAYLQINNLKYEDT 
               
               
                   
                   
                 ATYFCALDYSYAMDYWGQGTSVTVSS 
               
               
                 SEQ ID NO: 
                 C11D5 VL 
                 DIVLTQSPPSLAMSLGKRATISCRASESVTILGSHLIHWYQQKPGQP 
               
               
                 1644 
                   
                 PTLLIQLASNVQTGVPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQ 
               
               
                   
                   
                 SRTIPRTFGGGTKLEIK 
               
               
                 SEQ ID NO: 
                 Anti-BCMA 
                 QIQLVQSGPELKKPGETVKISCKASGYTFTDYSINWVKRAPGKGLK 
               
               
                 1645 
                 heavy chain of 
                 WMGWINTETREPAYAYDFRGRFAFSLETSASTAYLQINNLKYEDT 
               
               
                   
                 BU76 
                 ATYFCALDYSYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTS 
               
               
                   
                   
                 GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 
               
               
                   
                   
                 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP 
               
               
                   
                   
                 PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK 
               
               
                   
                   
                 FNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGK 
               
               
                   
                   
                 EYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQV 
               
               
                   
                   
                 SLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSK 
               
               
                   
                   
                 LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGX, wherein 
               
               
                   
                   
                 X is K or absent 
               
               
                 SEQ ID NO: 
                 Anti-BCMA 
                 DIVLTQSPASLAMSLGKRATISCRASESVSVIGAHLIHWYQQKPGQP 
               
               
                 1646 
                 light chain of 
                 PKLLIYLASNLETGVPARFSGSGSGTDFTLTIDPVEEDDVAIYSCLQS 
               
               
                   
                 BU76 
                 RIFPRTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF 
               
               
                   
                   
                 YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 
               
               
                   
                   
                 DYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
            
           
           
               
            
               
                 EE11 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 83A10 VH 
                 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 1647 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT 
               
               
                   
                   
                 AVYYCAKVLGWFDYWGQGTLVTVSS 
               
               
                 SEQ ID NO: 
                 83A10 VL 
                 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRL 
               
               
                 1648 
                   
                 LIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGY 
               
               
                   
                   
                 PPDFTFGQGTKVEIK 
               
               
                 SEQ ID NO: 
                 Anti-BCMA 
                 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 1649 
                 scFv-Fc of 
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDT 
               
               
                   
                 EE11 
                 AVYYCAKVLGWFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGG 
               
               
                   
                   
                 GSEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAP 
               
               
                   
                   
                 RLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQY 
               
               
                   
                   
                 GYPPDFTFGQGTKVEIKGGGGSDKTHTCPPCPAPELLGGPSVFLFPP 
               
               
                   
                   
                 KPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEK 
               
               
                   
                   
                 TISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVE 
               
               
                   
                   
                 WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPGX, wherein X is K or absent 
               
               
                   
               
            
           
           
               
            
               
                 EM90 
               
            
           
           
               
               
               
            
               
                 SEQ ID NO: 
                 Comment light 
                 QAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQEKPGQA 
               
               
                 1650 
                 chain of EM90 
                 FRGLIGGTNKRAPGTPARFSGSLLGGKAALTLSGAQPEDEAEYYCA 
               
               
                   
                   
                 LWYSNLWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLV 
               
               
                   
                   
                 CLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLS 
               
               
                   
                   
                 LTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 
               
               
                 SEQ ID NO: 
                 Anti-BCMA 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSNSGMIWVRQAPGKGL 
               
               
                 1651 
                 heavy chain of 
                 EWVGHIRSKTDGGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKT 
               
               
                   
                 EM90 
                 EDTAVYYCTTGGSGSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS 
               
               
                   
                   
                 TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL 
               
               
                   
                   
                 YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT 
               
               
                   
                   
                 CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE 
               
               
                   
                   
                 VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN 
               
               
                   
                   
                 GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKN 
               
               
                   
                   
                 QVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLV 
               
               
                   
                   
                 SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGX, 
               
               
                   
                   
                 wherein X is K or absent 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4G 
               
             
            
               
                   
               
               
                 Heavy Chain Variable Domain CDRs according to the Kabat numbering scheme 
               
               
                 (Kabat et al. (1991), ″Sequences of Proteins of Immunological Interest,″ 5th Ed. 
               
               
                 Public Health Service, National Institutes of Health, Bethesda, MD) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Candidate 
                 HCDR1 
                 ID 
                 HCDR2 
                 ID 
                 HCDR3 
                 ID 
               
               
                   
               
               
                 139109 
                 NHGMS 
                 1652 
                 GIVYSGSTYYAASV 
                 1701 
                 HGGESDV 
                 1741 
               
               
                   
                   
                   
                 KG 
                   
                   
                   
               
               
                   
               
               
                 139103 
                 NYAMS 
                 1653 
                 GISRSGENTYYADS 
                 1702 
                 SPAHYYGGMDV 
                 1742 
               
               
                   
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 139105 
                 DYAMH 
                 1654 
                 GISWNSGSIGYADSV 
                 1703 
                 HSFLAY 
                 1743 
               
               
                   
                   
                   
                 KG 
                   
                   
                   
               
               
                   
               
               
                 139111 
                 NHGMS 
                 1655 
                 GIVYSGSTYYAASV 
                 1704 
                 HGGESDV 
                 1744 
               
               
                   
                   
                   
                 KG 
                   
                   
                   
               
               
                   
               
               
                 139100 
                 NFGIN 
                 1656 
                 WINPKNNNTNYAQ 
                 1705 
                 GPYYYQSYMDV 
                 1745 
               
               
                   
                   
                   
                 KFQG 
                   
                   
                   
               
               
                   
               
               
                 139101 
                 SDAMT 
                 1657 
                 VISGSGGTTYYADS 
                 1706 
                 LDSSGYYYARGPRY 
                 1746 
               
               
                   
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 139102 
                 NYGIT 
                 1658 
                 WISAYNGNTNYAQ 
                 1707 
                 GPYYYYMDV 
                 1747 
               
               
                   
                   
                   
                 KFQG 
                   
                   
                   
               
               
                   
               
               
                 139104 
                 NHGMS 
                 1659 
                 GIVYSGSTYYAASV 
                 1708 
                 HGGESDV 
                 1748 
               
               
                   
                   
                   
                 KG 
                   
                   
                   
               
               
                   
               
               
                 139106 
                 NHGMS 
                 1670 
                 GIVYSGSTYYAASV 
                 1709 
                 HGGESDV 
                 1749 
               
               
                   
                   
                   
                 KG 
                   
                   
                   
               
               
                   
               
               
                 139107 
                 NHGMS 
                 1671 
                 GIVYSGSTYYAASV 
                 1710 
                 HGGESDV 
                 1750 
               
               
                   
                   
                   
                 KG 
                   
                   
                   
               
               
                   
               
               
                 139108 
                 DYYMS 
                 1672 
                 YISSSGSTIYYADSV 
                 1711 
                 ESGDGMDV 
                 1751 
               
               
                   
                   
                   
                 KG 
                   
                   
                   
               
               
                   
               
               
                 139110 
                 DYYMS 
                 1672 
                 YISSSGNTIYYADSV 
                 1712 
                 STMVREDY 
                 1752 
               
               
                   
                   
                   
                 KG 
                   
                   
                   
               
               
                   
               
               
                 139112 
                 NHGMS 
                 1673 
                 GIVYSGSTYYAASV 
                 1713 
                 HGGESDV 
                 1753 
               
               
                   
                   
                   
                 KG 
                   
                   
                   
               
               
                   
               
               
                 139113 
                 NHGMS 
                 1674 
                 GIVYSGSTYYAASV 
                 1714 
                 HGGESDV 
                 1754 
               
               
                   
                   
                   
                 KG 
                   
                   
                   
               
               
                   
               
               
                 139114 
                 NHGMS 
                 1675 
                 GIVYSGSTYYAASV 
                 1715 
                 HGGESDV 
                 1755 
               
               
                   
                   
                   
                 KG 
                   
                   
                   
               
               
                   
               
               
                 149362 
                 SSYYYW 
                 1676 
                 SIYYSGSAYYNPSLK 
                 1716 
                 HWQEWPDAFDI 
                 1756 
               
               
                   
                 G 
                   
                 S 
                   
                   
                   
               
               
                   
               
               
                 149363 
                 TSGMCV 
                 1677 
                 RIDWDEDKFYSTSL 
                 1717 
                 SGAGGTSATAFDI 
                 1757 
               
               
                   
                 S 
                   
                 KT 
                   
                   
                   
               
               
                   
               
               
                 149364 
                 SYSMN 
                 1678 
                 SISSSSSYIYYADSVK 
                 1718 
                 TIAAVYAFDI 
                 1758 
               
               
                   
                   
                   
                 G 
                   
                   
                   
               
               
                   
               
               
                 149365 
                 DYYMS 
                 1679 
                 YISSSGSTIYYADSV 
                 1719 
                 DLRGAFDI 
                 1759 
               
               
                   
                   
                   
                 KG 
                   
                   
                   
               
               
                   
               
               
                 149366 
                 SHYIH 
                 1680 
                 MINPSGGVTAYSQT 
                 1720 
                 EGSGSGWYFDF 
                 1760 
               
               
                   
                   
                   
                 LQG 
                   
                   
                   
               
               
                   
               
               
                 149367 
                 SGGYY 
                 1681 
                 YIYYSGSTYYNPSLK 
                 1721 
                 AGIAARLRGAFDI 
                 1761 
               
               
                   
                 WS 
                   
                 S 
                   
                   
                   
               
               
                   
               
               
                 149368 
                 SYAIS 
                 1682 
                 GIIPIFGTANYAQKF 
                 1722 
                 RGGYQLLRWDVGLL 
                 1762 
               
               
                   
                   
                   
                 QG 
                   
                 RSAFDI 
                   
               
               
                   
               
               
                 149369 
                 SNSAAW 
                 1683 
                 RTYYRSKWYSFYAI 
                 1723 
                 SSPEGLFLYWFDP 
                 1763 
               
               
                   
                 N 
                   
                 SLKS 
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 SYAMS 
                 1684 
                 AISGSGGSTYYADS 
                 1724 
                 VEGSGSLDY 
                 1764 
               
               
                 C1978-A4 
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RYPMS 
                 1685 
                 GISDSGVSTYYADS 
                 1725 
                 RAGSEASDI 
                 1765 
               
               
                 C1978-G1 
                   
                   
                 AKG 
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 SYAMS 
                 1686 
                 AISGSGGSTYYADS 
                 1726 
                 ATYKRELRYYYGM 
                 1766 
               
               
                 C1979-C1 
                 VKG 
                   
                 DV 
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 SYAMS 
                 1687 
                 AISGSGGSTYYADS 
                 1727 
                 ATYKRELRYYYGM 
                 1767 
               
               
                 C1978-C7 
                   
                   
                 VKG 
                   
                 DV 
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 DYAMH 
                 1688 
                 GISWNSGSIGYADSV 
                 1728 
                 VGKAVPDV 
                 1768 
               
               
                 C1978-D10 
                   
                   
                 KG 
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 DYAMH 
                 1689 
                 SINWKGNSLAYGDS 
                 1729 
                 HQGVAYYNYAMDV 
                 1769 
               
               
                 C1979-C12 
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 SYAMS 
                 1690 
                 AISGSGGSTYYADS 
                 1730 
                 VVRDGMDV 
                 1770 
               
               
                 C1980-G4 
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 SYAMS 
                 1691 
                 AISGSGGSTYYADS 
                 1731 
                 IPQTGTFDY 
                 1771 
               
               
                 C1980-D2 
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 SYAMS 
                 1692 
                 AISGSGGSTYYADS 
                 1732 
                 ANYKRELRYYYGM 
                 1772 
               
               
                 C1978-A10 
                   
                   
                 VKG 
                   
                 DV 
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 SYAMS 
                 1693 
                 AISGSGGSTYYADS 
                 1733 
                 ALVGATGAFDI 
                 1773 
               
               
                 C1978-D4 
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 SYAMS 
                 1694 
                 AISGSGGSTYYADS 
                 1734 
                 WFGEGFDP 
                 1774 
               
               
                 C1980-A2 
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 SYAMS 
                 1695 
                 AISGSGGSTYYADS 
                 1735 
                 VGYDSSGYYRDYYG 
                 1775 
               
               
                 C1981-C3 
                   
                   
                 VKG 
                   
                 MDV 
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 SYAMS 
                 1696 
                 AISGSGGSTYYADS 
                 1736 
                 MGWSSGYLGAFDI 
                 1776 
               
               
                 C1978-G4 
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 A7D12.2 
                 NFGMN 
                 1697 
                 WINTYTGESYFADD 
                 1737 
                 GEIYYGYDGGFAY 
                 1777 
               
               
                   
                   
                   
                 FKG 
                   
                   
                   
               
               
                   
               
               
                 C11D5.3 
                 DYSIN 
                 1698 
                 WINTETREPAYAYD 
                 1738 
                 DYSYAMDY 
                 1778 
               
               
                   
                   
                   
                 FRG 
                   
                   
                   
               
               
                   
               
               
                 C12A3.2 
                 HYSMN 
                 1699 
                 RINTESGVPIYADDF 
                 1739 
                 DYLYSLDF 
                 1779 
               
               
                   
                   
                   
                 KG 
                   
                   
                   
               
               
                   
               
               
                 C13F12.1 
                 HYSMN 
                 1700 
                 RINTETGEPLYADDF 
                 1740 
                 DYLYSCDY 
                 1800 
               
               
                   
                   
                   
                 KG 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4H 
               
             
            
               
                   
               
               
                 Light Chain Variable Domain CDRs according to the Kabat numbering scheme 
               
               
                 (Kabat et al. (1991), ″Sequences of Proteins of Immunological Interest,″ 5th Ed. 
               
               
                 Public Health Service, National Institutes of Health, Bethesda, MD). 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Candidate 
                 LCDR1 
                 ID 
                 LCDR2 
                 ID 
                 LCDR3 
                 ID 
               
               
                   
               
               
                 139109 
                 RASQSISSYLN 
                 2514 
                 AASSLQS 
                 2554 
                 QQSYSTPYT 
                 2594 
               
               
                   
               
               
                 139103 
                 RASQSISSSFLA 
                 2504 
                 GASRRAT 
                 2544 
                 QQYHSSPSWT 
                 2584 
               
               
                   
               
               
                 139105 
                 RSSQSLLHSNGYN 
                 2505 
                 LGSNRAS 
                 2545 
                 mQALQTPYT 
                 2585 
               
               
                   
                 YLD 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 139111 
                 KSSQSLLRNDGKTP 
                 2506 
                 EVSNRFS 
                 2546 
                 MQNIQFPS 
                 2586 
               
               
                   
                 LY 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 139100 
                 RSSQSLLHSNGYN 
                 2507 
                 LGSKRAS 
                 2547 
                 MQALQTPYT 
                 2587 
               
               
                   
                 YLN 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 139101 
                 RASQSISSYLN 
                 2508 
                 GASTLAS 
                 2548 
                 QQSYKRAS 
                 2588 
               
               
                   
               
               
                 139102 
                 RSSQSLLYSNGYN 
                 2509 
                 LGSNRAS 
                 2549 
                 MQGRQFPYS 
                 2589 
               
               
                   
                 YVD 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 139104 
                 RASQSVSSNLA 
                 2510 
                 GASTRAS 
                 2550 
                 QQYGSSLT 
                 2590 
               
               
                   
               
               
                 139106 
                 RASQSVSSKLA 
                 2511 
                 GASIRAT 
                 2551 
                 QQYGSSSWT 
                 2591 
               
               
                   
               
               
                 139107 
                 RASQSVGSTNLA 
                 2512 
                 DASNRAT 
                 2552 
                 QQYGSSPPWT 
                 2592 
               
               
                   
               
               
                 139108 
                 RASQSISSYLN 
                 2513 
                 AASSLQS 
                 2553 
                 QQSYTLA 
                 2593 
               
               
                   
               
               
                 139110 
                 KSSESLVHNSGKTY 
                 2515 
                 EVSNRDS 
                 2555 
                 MQGTHWPGT 
                 2595 
               
               
                   
                 LN 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 139112 
                 QASEDINKFLN 
                 2516 
                 DASTLQT 
                 2556 
                 QQYESLPLT 
                 2596 
               
               
                   
               
               
                 139113 
                 RASQSVGSNLA 
                 2517 
                 GASTRAT 
                 2557 
                 QQYNDWLPV 
                 2597 
               
               
                   
                   
                   
                   
                   
                 T 
                   
               
               
                   
               
               
                 139114 
                 RASQSIGSSSLA 
                 2518 
                 GASSRAS 
                 2558 
                 QQYAGSPPFT 
                 2598 
               
               
                   
               
               
                 149362 
                 KASQDIDDAMN 
                 2519 
                 SATSPVP 
                 2559 
                 LQHDNFPLT 
                 2599 
               
               
                   
               
               
                 149363 
                 RASQDIYNNLA 
                 2520 
                 AANKSQS 
                 2560 
                 QHYYRFPYS 
                 2600 
               
               
                   
               
               
                 149364 
                 RSSQSLLHSNGYN 
                 2521 
                 LGSNRAS 
                 2561 
                 MQALQTPYT 
                 2601 
               
               
                   
                 YLD 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 149365 
                 GGNNIGTKSVH 
                 2522 
                 DDSVRPS 
                 2562 
                 QVWDSDSEH 
                 2602 
               
               
                   
                   
                   
                   
                   
                 VV 
                   
               
               
                   
               
               
                 149366 
                 SGDGLSKKYVS 
                 2523 
                 RDKERPS 
                 2563 
                 QAWDDTTVV 
                 2603 
               
               
                   
               
               
                 149367 
                 RASQGIRNWLA 
                 2524 
                 AASNLQS 
                 2564 
                 QKYNSAPFT 
                 2604 
               
               
                   
               
               
                 149368 
                 GGNNIGSKSVH 
                 2525 
                 GKNNRPS 
                 2565 
                 SSRDSSGDHL 
                 2605 
               
               
                   
                   
                   
                   
                   
                 RV 
                   
               
               
                   
               
               
                 149369 
                 QGDSLGNYYAT 
                 2526 
                 GTNNRPS 
                 2566 
                 NSRDSSGHHL 
                 2606 
               
               
                   
                   
                   
                   
                   
                 L 
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSVSSAYLA 
                 2527 
                 GASTRAT 
                 2567 
                 QHYGSSFNGS 
                 2607 
               
               
                 C1978-A4 
                   
                   
                   
                   
                 SLFT 
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSVSNSLA 
                 2528 
                 DASSRAT 
                 2568 
                 QQFGTSSGLT 
                 2608 
               
               
                 C1978-G1 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSVSSSFLA 
                 2529 
                 GASSRAT 
                 2569 
                 QQYHSSPSWT 
                 2609 
               
               
                 C1979-C1 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSVSTTFLA 
                 2530 
                 GSSNRAT 
                 2570 
                 QQYHSSPSWT 
                 2610 
               
               
                 C1978-C7 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSISSYLN 
                 2531 
                 AASSLQS 
                 2571 
                 QQSYSTPYS 
                 2611 
               
               
                 C1978-D10 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RATQSIGSSFLA 
                 2532 
                 GASQRAT 
                 2572 
                 QHYESSPSWT 
                 2612 
               
               
                 C1979-C12 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSVSSSYLA 
                 2533 
                 GASSRAT 
                 2573 
                 QQYGSPPRFT 
                 2613 
               
               
                 C1980-G4 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSVSSSYLA 
                 2534 
                 GASSRAT 
                 2574 
                 QHYGSSPSWT 
                 2614 
               
               
                 C1980-D2 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQRVASNYLA 
                 2535 
                 GASSRAT 
                 2575 
                 QHYDSSPSWT 
                 2615 
               
               
                 C1978-A10 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSLSSNFLA 
                 2536 
                 GASNWAT 
                 2576 
                 QYYGTSPMY 
                 2616 
               
               
                 C1978-D4 
                   
                   
                   
                   
                 T 
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RSSQSLLHSNGYN 
                 2537 
                 LGSNRAS 
                 2577 
                 MQALQTPLT 
                 2617 
               
               
                 C1980-A2 
                 YLD 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSVSSSYLA 
                 2538 
                 GTSSRAT 
                 2578 
                 QHYGNSPPKF 
                 2618 
               
               
                 C1981-C3 
                   
                   
                   
                   
                 T 
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSVASSFLA 
                 2539 
                 GASGRAT 
                 2579 
                 QHYGGSPRLT 
                 2619 
               
               
                 C1978-G4 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 A7D12.2 
                 RASQDVNTAVS 
                 2540 
                 SASYRYT 
                 2580 
                 QQHYSTPWT 
                 2620 
               
               
                   
               
               
                 C11D5.3 
                 RASESVSVIGAHLI 
                 2541 
                 LASNLET 
                 2581 
                 LQSRIFPRT 
                 2621 
               
               
                   
                 H 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 C12A3.2 
                 RASESVTILGSHLIY 
                 2542 
                 LASNVQT 
                 2582 
                 LQSRTIPRT 
                 2622 
               
               
                   
               
               
                 C13F12.1 
                 RASESVTILGSHLIY 
                 2543 
                 LASNVQT 
                 2583 
                 LQSRTIPRT 
                 2623 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4I 
               
             
            
               
                   
               
               
                 Heavy Chain Variable Domain CDRs according to a combination of the Kabat numbering 
               
               
                 scheme (Kabat et al. (1991), ″Sequences of Proteins of Immunological Interest,″ 5th 
               
               
                 Ed. Public Health Service, National Institutes of Health, Bethesda, MD) and the Chothia 
               
               
                 numbering scheme (A1-Lazikani et al., (1997) JMB 273,927-948). 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Candidate 
                 HCDR1 
                 ID 
                 HCDR2 
                 ID 
                 HCDR3 
                 ID 
               
               
                   
               
               
                 139109 
                 GFALSNHGMS 
                 2874 
                 GIVYSGSTYYAAS 
                 2914 
                 HGGESDV 
                 2954 
               
               
                   
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 139103 
                 GFTFSNYAMS 
                 2864 
                 GISRSGENTYYAD 
                 2904 
                 SPAHYYGGMDV 
                 2944 
               
               
                   
                   
                   
                 SVKG 
                   
                   
                   
               
               
                   
               
               
                 139105 
                 GFTFDDYAMH 
                 2865 
                 GISWNSGSIGYAD 
                 2905 
                 HSFLAY 
                 2945 
               
               
                   
                   
                   
                 SVKG 
                   
                   
                   
               
               
                   
               
               
                 139111 
                 GFALSNHGMS 
                 2866 
                 GIVYSGSTYYAAS 
                 2906 
                 HGGESDV 
                 2946 
               
               
                   
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 139100 
                 GYIFDNFGIN 
                 2867 
                 WINPKNNNTNYA 
                 2907 
                 GPYYYQSYMDV 
                 2947 
               
               
                   
                   
                   
                 QKFQG 
                   
                   
                   
               
               
                   
               
               
                 139101 
                 GFTFSSDAMT 
                 2868 
                 VISGSGGTTYYAD 
                 2908 
                 LDSSGYYYARGPR 
                 2948 
               
               
                   
                   
                   
                 SVKG 
                   
                 Y 
                   
               
               
                   
               
               
                 139102 
                 GYTFSNYGIT 
                 2869 
                 WISAYNGNTNYA 
                 2909 
                 GPYYYYMDV 
                 2949 
               
               
                   
                   
                   
                 QKFQG 
                   
                   
                   
               
               
                   
               
               
                 139104 
                 GFALSNHGMS 
                 2870 
                 GIVYSGSTYYAAS 
                 2910 
                 HGGESDV 
                 2950 
               
               
                   
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 139106 
                 GFALSNHGMS 
                 2871 
                 GIVYSGSTYYAAS 
                 2911 
                 HGGESDV 
                 2951 
               
               
                   
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 139107 
                 GFALSNHGMS 
                 2872 
                 GIVYSGSTYYAAS 
                 2912 
                 HGGESDV 
                 2952 
               
               
                   
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 139108 
                 GFTFSDYYMS 
                 2873 
                 YISSSGSTIYYADS 
                 2913 
                 ESGDGMDV 
                 2953 
               
               
                   
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 139110 
                 GFTFSDYYMS 
                 2875 
                 YISSSGNTIYYAD 
                 2915 
                 STMVREDY 
                 2955 
               
               
                   
                   
                   
                 SVKG 
                   
                   
                   
               
               
                   
               
               
                 139112 
                 GFALSNHGMS 
                 2876 
                 GIVYSGSTYYAAS 
                 2916 
                 HGGESDV 
                 2956 
               
               
                   
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 139113 
                 GFALSNHGMS 
                 2877 
                 GIVYSGSTYYAAS 
                 2917 
                 HGGESDV 
                 2957 
               
               
                   
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 139114 
                 GFALSNHGMS 
                 2878 
                 GIVYSGSTYYAAS 
                 2918 
                 HGGESDV 
                 2958 
               
               
                   
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 149362 
                 GGSISSSYYYW 
                 2879 
                 SIYYSGSAYYNPS 
                 2919 
                 HWQEWPDAFDI 
                 2959 
               
               
                   
                 G 
                   
                 LKS 
                   
                   
                   
               
               
                   
               
               
                 149363 
                 GFSLRTSGMC 
                 2880 
                 RIDWDEDKFYSTS 
                 2920 
                 SGAGGTSATAFDI 
                 2960 
               
               
                   
                 VS 
                   
                 LKT 
                   
                   
                   
               
               
                   
               
               
                 149364 
                 GFTFSSYSMN 
                 2881 
                 SISSSSSYIYYADS 
                 2921 
                 TIAAVYAFDI 
                 2961 
               
               
                   
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 149365 
                 GFTFSDYYMS 
                 2882 
                 YISSSGSTIYYADS 
                 2922 
                 DLRGAFDI 
                 2962 
               
               
                   
                   
                   
                 VKG 
                   
                   
                   
               
               
                   
               
               
                 149366 
                 GYTVTSHYIH 
                 2883 
                 MINPSGGVTAYS 
                 2923 
                 EGSGSGWYFDF 
                 2963 
               
               
                   
                   
                   
                 QTLQG 
                   
                   
                   
               
               
                   
               
               
                 149367 
                 GGSISSGGYY 
                 2884 
                 YIYYSGSTYYNPS 
                 2924 
                 AGIAARLRGAFDI 
                 2964 
               
               
                   
                 WS 
                   
                 LKS 
                   
                   
                   
               
               
                   
               
               
                 149368 
                 GGTFSSYAIS 
                 2885 
                 GIIPIFGTANYAQ 
                 2925 
                 RGGYQLLRWDVG 
                 2965 
               
               
                   
                   
                   
                 KFQG 
                   
                 LLRSAFDI 
                   
               
               
                   
               
               
                 149369 
                 GDSVSSNSAA 
                 2886 
                 RTYYRSKWYSFY 
                 2926 
                 SSPEGLFLYWFDP 
                 2966 
               
               
                   
                 WN 
                   
                 AISLKS 
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 GFTFSSYAMS 
                 2887 
                 AISGSGGSTYYAD 
                 2927 
                 VEGSGSLDY 
                 2967 
               
               
                 C1978-A4 
                   
                   
                 SVKG 
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 GITFSRYPMS 
                 2888 
                 GISDSGVSTYYAD 
                 2928 
                 RAGSEASDI 
                 2968 
               
               
                 C1978-G1 
                   
                   
                 SAKG 
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 GFTFSSYAMS 
                 2889 
                 AISGSGGSTYYAD 
                 2929 
                 ATYKRELRYYYG 
                 2969 
               
               
                 C1979-C1 
                   
                   
                 SVKG 
                   
                 MDV 
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 GFTFSSYAMS 
                 2890 
                 AISGSGGSTYYAD 
                 2930 
                 ATYKRELRYYYG 
                 2970 
               
               
                 C1978-C7 
                   
                   
                 SVKG 
                   
                 MDV 
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 GFTFDDYAMH 
                 2891 
                 GISWNSGSIGYAD 
                 2931 
                 VGKAVPDV 
                 2971 
               
               
                 C1978-D10 
                   
                   
                 SVKG 
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 GFTFDDYAMH 
                 2892 
                 SINWKGNSLAYG 
                 2932 
                 HQGVAYYNYAM 
                 2972 
               
               
                 C1979-C12 
                   
                   
                 DSVKG 
                   
                 DV 
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 GFTFSSYAMS 
                 2893 
                 AISGSGGSTYYAD 
                 2933 
                 VVRDGMDV 
                 2973 
               
               
                 C1980-G4 
                   
                   
                 SVKG 
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 GFTFSSYAMS 
                 2894 
                 AISGSGGSTYYAD 
                 2934 
                 IPQTGTFDY 
                 2974 
               
               
                 C1980-D2 
                   
                   
                 SVKG 
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 GFTFSSYAMS 
                 2895 
                 AISGSGGSTYYAD 
                 2935 
                 ANYKRELRYYYG 
                 2975 
               
               
                 C1978-A10 
                   
                   
                 SVKG 
                   
                 MDV 
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 GFSFSSYAMS 
                 2896 
                 AISGSGGSTYYAD 
                 2936 
                 ALVGATGAFDI 
                 2976 
               
               
                 C1978-D4 
                   
                   
                 SVKG 
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 GFTFSSYAMS 
                 2897 
                 AISGSGGSTYYAD 
                 2937 
                 WFGEGFDP 
                 2977 
               
               
                 C1980-A2 
                   
                   
                 SVKG 
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 GFTFSSYAMS 
                 2898 
                 AISGSGGSTYYAD 
                 2938 
                 VGYDSSGYYRDY 
                 2978 
               
               
                 C1981-C3 
                   
                   
                 SVKG 
                   
                 YGMDV 
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 GFTFSSYAMS 
                 2899 
                 AISGSGGSTYYAD 
                 2939 
                 MGWSSGYLGAFD 
                 2979 
               
               
                 C1978-G4 
                   
                   
                 SVKG 
                   
                 I 
                   
               
               
                   
               
               
                 A7D12.2 
                 GYTFTNFGMN 
                 2900 
                 WINTYTGESYFA 
                 2940 
                 GEIYYGYDGGFAY 
                 2980 
               
               
                   
                   
                   
                 DDFKG 
                   
                   
                   
               
               
                   
               
               
                 C11D5.3 
                 GYTFTDYSIN 
                 2901 
                 WINTETREPAYA 
                 2941 
                 DYSYAMDY 
                 2981 
               
               
                   
                   
                   
                 YDFRG 
                   
                   
                   
               
               
                   
               
               
                 C12A3.2 
                 GYTFRHYSMN 
                 2902 
                 RINTESGVPIYAD 
                 2942 
                 DYLYSLDF 
                 2982 
               
               
                   
                   
                   
                 DFKG 
                   
                   
                   
               
               
                   
               
               
                 C13F12.1 
                 GYTFTHYSMN 
                 2903 
                 RINTETGEPLYAD 
                 2943 
                 DYLYSCDY 
                 2983 
               
               
                   
                   
                   
                 DFKG 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4J 
               
             
            
               
                   
               
               
                 Light Chain Variable Domain CDRs according to a combination of the Kabat 
               
               
                 numbering scheme (Kabat et al. (1991), ″Sequences of Proteins of Immunological 
               
               
                 Interest,″ 5th Ed. Public Health Service, National Institutes of Health, 
               
               
                 Bethesda, MD) and the Chothia numbering scheme (A1-Lazikani et al., (1997) 
               
               
                 JMB 273,927-948). 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Candidate 
                 LCDR1 
                 ID 
                 LCDR2 
                 ID 
                 LCDR3 
                 ID 
               
               
                   
               
               
                 139109 
                 RASQSISSYLN 
                 3994 
                 AASSLQS 
                 1034 
                 QQSYSTPYT 
                 3074 
               
               
                   
               
               
                 139103 
                 RASQSISSSFLA 
                 3984 
                 GASRRAT 
                 3024 
                 QQYHSSPSWT 
                 3064 
               
               
                   
               
               
                 139105 
                 RSSQSLLHSNGYNYLD 
                 3985 
                 LGSNRAS 
                 3025 
                 MQALQTPYT 
                 3065 
               
               
                   
               
               
                 139111 
                 KSSQSLLRNDGKTPLY 
                 3986 
                 EVSNRFS 
                 3026 
                 MQNIQFPS 
                 3066 
               
               
                   
               
               
                 139100 
                 RSSQSLLHSNGYNYLN 
                 3987 
                 LGSKRAS 
                 3027 
                 MQALQTPYT 
                 3067 
               
               
                   
               
               
                 139101 
                 RASQSISSYLN 
                 3988 
                 GASTLAS 
                 3028 
                 QQSYKRAS 
                 3068 
               
               
                   
               
               
                 139102 
                 RSSQSLLYSNGYNYVD 
                 3989 
                 LGSNRAS 
                 3029 
                 MQGRQFPYS 
                 3069 
               
               
                   
               
               
                 139104 
                 RASQSVSSNLA 
                 3990 
                 GASTRAS 
                 3030 
                 QQYGSSLT 
                 3070 
               
               
                   
               
               
                 139106 
                 RASQSVSSKLA 
                 3991 
                 GASIRAT 
                 3031 
                 QQYGSSSWT 
                 3071 
               
               
                   
               
               
                 139107 
                 RASQSVGSTNLA 
                 3992 
                 DASNRAT 
                 3032 
                 QQYGSSPPWT 
                 3072 
               
               
                   
               
               
                 139108 
                 RASQSISSYLN 
                 3993 
                 AASSLQS 
                 3033 
                 QQSYTLA 
                 3073 
               
               
                   
               
               
                 139110 
                 KSSESLVHNSGKTYLN 
                 3995 
                 EVSNRDS 
                 3035 
                 MQGTHWPGT 
                 3075 
               
               
                   
               
               
                 139112 
                 QASEDINKFLN 
                 3996 
                 DASTLQT 
                 3036 
                 QQYESLPLT 
                 3076 
               
               
                   
               
               
                 139113 
                 RASQSVGSNLA 
                 3997 
                 GASTRAT 
                 3037 
                 QQYNDWLPV 
                 3077 
               
               
                   
                   
                   
                   
                   
                 T 
                   
               
               
                   
               
               
                 139114 
                 RASQSIGSSSLA 
                 3998 
                 GASSRAS 
                 3038 
                 QQYAGSPPFT 
                 3078 
               
               
                   
               
               
                 149362 
                 KASQDIDDAMN 
                 3999 
                 SATSPVP 
                 3039 
                 LQHDNFPLT 
                 3079 
               
               
                   
               
               
                 149363 
                 RASQDIYNNLA 
                 3000 
                 AANKSQS 
                 3040 
                 QHYYRFPYS 
                 3080 
               
               
                   
               
               
                 149364 
                 RSSQSLLHSNGYNYLD 
                 3001 
                 LGSNRAS 
                 3041 
                 MQALQTPYT 
                 3081 
               
               
                   
               
               
                 149365 
                 GGNNIGTKSVH 
                 3002 
                 DDSVRPS 
                 3042 
                 QVWDSDSEHV 
                 3082 
               
               
                   
                   
                   
                   
                   
                 V 
                   
               
               
                   
               
               
                 149366 
                 SGDGLSKKYVS 
                 3003 
                 RDKERPS 
                 3043 
                 QAWDDTTVV 
                 3083 
               
               
                   
               
               
                 149367 
                 RASQGIRNWLA 
                 3004 
                 AASNLQS 
                 3044 
                 QKYNSAPFT 
                 3084 
               
               
                   
               
               
                 149368 
                 GGNNIGSKSVH 
                 3005 
                 GKNNRPS 
                 3045 
                 SSRDSSGDHL 
                 3085 
               
               
                   
                   
                   
                   
                   
                 RV 
                   
               
               
                   
               
               
                 149369 
                 QGDSLGNYYAT 
                 3006 
                 GTNNRPS 
                 3046 
                 NSRDSSGHHL 
                 3086 
               
               
                   
                   
                   
                   
                   
                 L 
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSVSSAYLA 
                 3007 
                 GASTRAT 
                 3047 
                 QHYGSSFNGS 
                 3087 
               
               
                 C1978-A4 
                   
                   
                   
                   
                 SLFT 
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSVSNSLA 
                 3008 
                 DASSRAT 
                 3048 
                 QQFGTSSGLT 
                 3088 
               
               
                 C1978-G1 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSVSSSFLA 
                 3009 
                 GASSRAT 
                 3049 
                 QQYHSSPSWT 
                 3089 
               
               
                 C1979-C1 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSVSTTFLA 
                 3010 
                 GSSNRAT 
                 3050 
                 QQYHSSPSWT 
                 3090 
               
               
                 C1978-C7 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSISSYLN 
                 3011 
                 AASSLQS 
                 3051 
                 QQSYSTPYS 
                 3091 
               
               
                 C1978-D10 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RATQSIGSSFLA 
                 3012 
                 GASQRAT 
                 3052 
                 QHYESSPSWT 
                 3092 
               
               
                 C1979-C12 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSVSSSYLA 
                 3013 
                 GASSRAT 
                 3053 
                 QQYGSPPRFT 
                 3093 
               
               
                 C1980-G4 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSVSSSYLA 
                 3014 
                 GASSRAT 
                 3054 
                 QHYGSSPSWT 
                 3094 
               
               
                 C1980-D2 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQRVASNYLA 
                 3015 
                 GASSRAT 
                 3055 
                 QHYDSSPSWT 
                 3095 
               
               
                 C1978-A10 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSLSSNFLA 
                 3016 
                 GASNWAT 
                 3056 
                 QYYGTSPMYT 
                 3096 
               
               
                 C1978-D4 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RSSQSLLHSNGYNYLD 
                 3017 
                 LGSNRAS 
                 3057 
                 MQALQTPLT 
                 3097 
               
               
                 C1980-A2 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSVSSSYLA 
                 3018 
                 GTSSRAT 
                 3058 
                 QHYGNSPPKF 
                 3098 
               
               
                 C1981-C3 
                   
                   
                   
                   
                 T 
                   
               
               
                   
               
               
                 BCMA_EBB- 
                 RASQSVASSFLA 
                 3019 
                 GASGRAT 
                 3059 
                 QHYGGSPRLT 
                 3099 
               
               
                 C1978-G4 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 A7D12.2 
                 RASQDVNTAVS 
                 3020 
                 SASYRYT 
                 3060 
                 QQHYSTPWT 
                 3100 
               
               
                   
               
               
                 C11D5.3 
                 RASESVSVIGAHLIH 
                 3021 
                 LASNLET 
                 3061 
                 LQSRIFPRT 
                 3101 
               
               
                   
               
               
                 C12A3.2 
                 RASESVTILGSHLIY 
                 3022 
                 LASNVQT 
                 3062 
                 LQSRTIPRT 
                 3102 
               
               
                   
               
               
                 C13F12.1 
                 RASESVTILGSHLIY 
                 3023 
                 LASNVQT 
                 3063 
                 LQSRTIPRT 
                 3103 
               
               
                   
               
            
           
         
       
     
     Combination CARs 
     In some embodiments, the method comprises administering a Chimeric Antigen Receptor (CAR) molecule that binds CD19 in combination with a B-cell inhibitor, for example, one or more (e.g., one, two, three or more) B-cell inhibitors. In some embodiments, the B-cell inhibitor is chosen from an inhibitor of CD10, CD19, CD20, CD22, CD34, CD123, FLT-3, or ROR1, or a combination thereof. In some embodiments, the combination maintains or has better clinical effectiveness as compared to either therapy alone. In some embodiments, the methods herein involve the use of engineered cells, e.g., T cells, to express a CAR molecule that binds CD19, in combination with a B-cell inhibitor (e.g., an antibody (e.g., a mono- or bispecific antibody) to a second B target, e.g., CD10, CD19, CD20, CD22, CD34, CD123, FLT-3, or ROR1) or a CAR-expressing cell e.g., a CAR-expressing immune effector cell, that binds to the second B cell target, or a combination thereof) to treat the disorder associated with expression of CD19. The disclosure additionally features novel antigen binding domains and CAR molecules directed to CD20 and CD22, and uses, e.g., as monotherapies or in combination therapies. 
     Accordingly, in one aspect, the invention pertains to a method of treating a subject (e.g., a mammal) having a disease associated with expression of CD19. The method comprises administering to the subject a CD19 inhibitor, e.g., a CAR molecule that binds CD19 described herein, in combination with a B-cell inhibitor. For instance, the method comprises administering to the subject an effective number of one or more cells that express a CAR molecule that binds CD19, e.g., a CAR molecule that binds CD19 described herein (e.g., a wild-type or mutant CD19), in combination with a B-cell inhibitor. In certain embodiments, the B-cell inhibitor is chosen from a CD10 inhibitor, e.g., one or more CD10 inhibitors described herein; a CD20 inhibitor, e.g., one or more CD20 inhibitor described herein; a CD22 inhibitor, e.g., one or more CD22 inhibitors described herein; a CD34 inhibitor, e.g., one or more CD34 inhibitors described herein; a CD123 inhibitor, e.g., one or more CD123 inhibitor described herein; a FLT-3 inhibitor, e.g., one or more FLT-3 inhibitors described herein; an ROR1 inhibitor, e.g., one or more ROR1 inhibitor described herein; a CD79b inhibitor, e.g., one or more CD79b inhibitor described herein; a CD179b inhibitor, e.g., one or more CD179b inhibitor described herein; a CD79a inhibitor, e.g., one or more CD79a inhibitor described herein or any combination thereof. In certain aspects, a method of treating a subject having a B-cell leukemia or B-cell lymphoma, comprising administering to the subject an effective number of one or more cells that express a CAR molecule that binds CD19, in combination with one or more inhibitors of CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a is disclosed. 
     In a related aspect, the present disclosure provides a method of reducing the proliferation of CD19-expressing cells, e.g., by administering to a subject, e.g., a patient in need thereof, a combination therapy as described herein, e.g., a CD19 inhibitor in combination with a B-cell inhibitor, e.g., one or more B-cell inhibitors as described herein. In another aspect, the present disclosure provides a method of selectively killing CD19-expressing cells, e.g., by administering to a subject, e.g., a patient in need thereof, a combination therapy as described herein, e.g., a CD19 inhibitor in combination with a B-cell inhibitor, e.g., one or more B-cell inhibitors as described herein. In certain aspects, the disclosure provides a method of providing an anti-tumor immunity in a subject, e.g., a mammal, comprising administering to the mammal an effective amount of a combination (e.g., one or more CAR-expressing cells) as described herein. 
     In an aspect, the disclosure provides a method of preventing a CD19-negative relapse in a mammal, comprising administering to the mammal one or more B-cell inhibitors, wherein the B-cell inhibitor comprises an inhibitor of one or more of CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. 
     CD20 Inhibitors and Binding Domains 
     CD20 inhibitors and binding domains, exemplary CD20 inhibitors, and methods of using the same are described e.g., on pages 126-136 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     In one aspect the antigen-binding portion of the CAR recognizes and binds an antigen within the extracellular domain of the CD20 protein. In one aspect, the CD20 protein is expressed on a cancer cell. In some aspects, the present disclosure provides a CD20 inhibitor or binding domain, e.g., a CD20 inhibitor or binding domain as described herein. The composition may also comprise a second agent, e.g., an anti-CD19 CAR-expressing cell or a CD19 binding domain. 
     In one embodiment, the CD20 inhibitor is an anti-CD20 expressing cell, e.g., CD20 CART or CD20-expressing NK cell. 
     Design, function, and sequences of CD20 CAR-expressing cells, e.g., CD20 CARTs, and methods of using the same are described on pages 127-136 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. CD20 binding domains are described in Tables 11-15B on pages 422-454 of International Application WO 2016/164731. 
     CD22 Inhibitors and Binding Domains 
     CD22 inhibitors and binding domains, exemplary CD22 inhibitors, and methods of using the same are described e.g., on pages 136-146 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     In one aspect the antigen-binding portion of the CAR recognizes and binds an antigen within the extracellular domain of the CD22 protein. In one aspect, the CD22 protein is expressed on a cancer cell. In some aspects, the present disclosure provides a CD22 inhibitor or binding domain, e.g., a CD22 inhibitor or binding domain as described herein. The composition may also comprise a second agent, e.g., an anti-CD19 CAR-expressing cell or a CD19 binding domain. 
     In some aspects, a CD22 inhibitor or binding domain is administered as a monotherapy. In some aspects, the CD22 inhibitor or binding domain is administered in combination with a second agent such as an anti-CD19 CAR-expressing cell. In an embodiment, the CD22 inhibitor is administered in combination with a CD19 inhibitor, e.g., a CD19 CAR-expressing cell, e.g., a CAR-expressing cell described herein e.g., a cell expressing a CAR comprising an antibody binding domain that is murine, human, or humanized. 
     In one embodiment, the CD22 inhibitor is a CD22 CAR-expressing cell, e.g., a CD22-CAR that comprises a CD22 binding domain and is engineered into a cell (e.g., T cell or NK cell) for administration in combination with CD19 CAR-expressing cell, e.g., CART, and methods of their use for adoptive therapy. 
     Design, function, and sequences of CD22 CAR-expressing cells, e.g., CD22 CARTs, and methods of using the same are described on pages 137-143 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     In one embodiment, the CD22 inhibitor is a CD22 inhibitor described herein. The CD22 inhibitor can be, e.g., an anti-CD22 antibody (e.g., an anti-CD22 mono- or bispecific antibody), a small molecule, or a CD22 CART. In some embodiments the anti-CD22 antibody is conjugated or otherwise bound to a therapeutic agent. Exemplary therapeutic agents include, e.g., microtubule disrupting agents (e.g., monomethyl auristatin E) and toxins (e.g., diphtheria toxin or  Pseudomonas  exotoxin-A, ricin). In an embodiment, the CD22 inhibitor is administered in combination with a CD19 inhibitor, e.g., a CD19 CAR-expressing cell, e.g., a CAR-expressing cell described herein e.g., a cell expressing a CAR comprising an antibody binding domain that is murine, human, or humanized. 
     In one embodiment, the anti-CD22 antibody is selected from an anti-CD19/CD22 bispecific ligand-directed toxin (e.g., two scFv ligands, recognizing human CD19 and CD22, linked to the first 389 amino acids of diphtheria toxin (DT), DT 390, e.g., DT2219ARL); anti-CD22 monoclonal antibody-MMAE conjugate (e.g., DCDT2980S); scFv of an anti-CD22 antibody RF134 fused to a fragment of  Pseudomonas  exotoxin-A (e.g., BL22); deglycosylated ricin A chain-conjugated anti-CD19/anti-CD22 (e.g., Combotox); humanized anti-CD22 monoclonal antibody (e.g., epratuzumab); or the Fv portion of an anti-CD22 antibody covalently fused to a 38 KDa fragment of  Pseudomonas  exotoxin-A (e.g., moxetumomab pasudotox). 
     CD22 inhibitor dosing is described on pages 144-146 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     CDRs of a CD22 antibody molecule are described in Table 7A, 7B, 7C, 8A and/or 8B on pages 406-414 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     CD123 Inhibitors 
     CD123 inhibitors and binding domains, exemplary CD123 inhibitors, and methods of using the same are described e.g., on pages 53-56, and 149-151 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     In one aspect the antigen-binding portion of the CAR recognizes and binds an antigen within the extracellular domain of the CD123 protein. In one aspect, the CD123 protein is expressed on a cancer cell. In an embodiment, the CD123 inhibitor is administered in combination with a CD19 inhibitor, e.g., a CD19 CAR-expressing cell, e.g., a CAR-expressing cell described herein, e.g., a cell expressing a CAR comprising an antibody binding domain that is murine, human, or humanized. 
     Design, function, and sequences of CD123 CAR-expressing cells, e.g., CD123 CARTs, and methods of using the same are described on line 10-24 on page 151 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     In some embodiments, a CD123 inhibitor includes an anti-CD123 CAR-expressing cell, e.g., CART, e.g., a cell expressing an anti-CD123 CAR construct or encoded by a CD123 binding CAR comprising a scFv, CDRs, or VH and VL chains. In another aspect, provided herein is a population of CAR-expressing cells, e.g., CART cells, comprising a mixture of cells expressing CD19 CARs and CD123 CARs. 
     Other Inhibitors 
     ROR1 inhibitors, anti-ROR1 CAR-expressing cells, and methods of using the same are described on pages 51-53, and 146-149 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     CD10 inhibitors, anti-CD10 CAR-expressing cells, and methods of using the same are described on pages 56-57, and 151-154 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     CD34 inhibitors, anti-CD34 CAR-expressing cells, and methods of using the same are described on page 57, and 154-156 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     FLT3 inhibitors, anti-FLT3 CAR-expressing cells, and methods of using the same are described on page 57, and 156-161 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     CD79b inhibitors, anti-CD79b CAR-expressing cells, and methods of using the same are described on page 58, and 161-163 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     CD179b inhibitors, anti-CD179b CAR-expressing cells, and methods of using the same are described on page 58, and 163-165 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     CD79a inhibitors, anti-CD79a CAR-expressing cells, and methods of using the same are described on page 59, and 165-166 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     In an embodiment, the B-cell inhibitor comprises an inhibitor of one or more of CD10, CD19, CD20, CD22, CD34, FLT-3, or ROR1. In an embodiment, the B-cell inhibitor comprises an effective number of one or more cells that express a CAR molecule that binds one or more of CD10, CD20, CD22, CD34, FLT-3, ROR1, CD79b, CD179b, or CD79a. In an embodiment, the B-cell inhibitor comprises a CD123 CAR. In an embodiment, the B cell inhibitor comprises one or more cells that express a CAR molecule that binds CD123. In an embodiment, the disease is a CD19-negative cancer, e.g., a CD19-negative relapsed cancer. In an embodiment, the CD19 CAR-expressing cell is administered simultaneously with, before, or after the one or more B-cell inhibitor. 
     In some aspects, the disclosure provides a method of treating a patient who is a non-responder, partial responder, or relapser to a CD19 inhibitor, e.g., a CD19 CAR therapy, comprising administering to the patient a B-cell inhibitor, e.g., a B-cell inhibitor as described herein, e.g., an inhibitor of one or more of (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all of) CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. In embodiments, the B-cell inhibitor is a CAR-expressing cell (e.g., T cell or NK cell) that is an inhibitor of one or more of (e.g., 2, 3, 4, 5, 6, or all of) CD10, CD20, CD22, CD34, CD123, FLT-3, or ROR1. In embodiments, the patient has, or is identified as having, a CD19-negative cancer cell and a cancer cell that is positive for one or more of (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all of) CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. 
     In embodiments, the method further comprises administering to the patient a B-cell inhibitor for which the cancer cell is positive, e.g., an inhibitor of one or more of (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all of) the CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a for which the cancer cell is positive. In embodiments, the method further comprises one or both of a step of determining whether the patient comprises a CD19-negative cancer cell, and a step of determining whether the patient comprises a cancer cell that is positive for one or more of (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or all of) CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. In embodiments, the subject has or is identified as having a population of tumor or cancer cells that test negative for CD19 expression as measured by binding to an anti-CD19 antibody, e.g., an antibody with the same specificity as any of the CAR molecules in Table 2 or Table 3. 
     CAR Therapies 
     CAR antigen binding domains, nucleic acid constructs comprising CAR molecules, functional features thereof, and CAR-expressing cells are described in International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     The inhibitors herein, e.g., CAR-expressing cells directed against CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a, may comprise one or more of the compositions described herein, e.g., a transmembrane domain, intracellular signaling domain, costimulatory domain, leader sequence, or hinge. 
     In one aspect, the present invention encompasses a recombinant nucleic acid construct comprising a transgene encoding a CAR. In some embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an anti-CD19 binding domain selected from one or more of SEQ ID NOS:61-72, wherein the sequence is contiguous with and in the same reading frame as the nucleic acid sequence encoding an intracellular signaling domain. An exemplary intracellular signaling domain that can be used in the CAR includes, but is not limited to, one or more intracellular signaling domains of, e.g., CD3-zeta, CD28, 4-1BB, and the like. In some instances, the CAR can comprise any combination of CD3-zeta, CD28, 4-1BB, and the like. 
     In one aspect, the present invention contemplates modifications of the starting antibody or fragment (e.g., scFv) amino acid sequence that generate functionally equivalent molecules. For example, the VH or VL of an antigen binding domain, e.g., scFv, comprised in the CAR can be modified to retain at least about 70%, 71%. 72%. 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity of the starting VH or VL framework region of the antigen binding domain, e.g., scFv. The present invention contemplates modifications of the entire CAR construct, e.g., modifications in one or more amino acid sequences of the various domains of the CAR construct in order to generate functionally equivalent molecules. The CAR construct can be modified to retain at least about 70%, 71%. 72%. 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity of the starting CAR construct. The present invention also contemplates modifications of CDRs, e.g., modifications in one or more amino acid sequences of one or more CDRs of a CAR construct in order to generate functionally equivalent molecules. For instance, the CDR may have, e.g., up to and including 1, 2, 3, 4, 5, or 6 alterations (e.g., substitutions) relative to a CDR sequence provided herein. 
     The nucleic acid sequences coding for the desired molecules can be obtained using recombinant methods known in the art, such as, for example by screening libraries from cells expressing the gene, by deriving the gene from a vector known to include the same, or by isolating directly from cells and tissues containing the same, using standard techniques. Alternatively, the nucleic acid of interest can be produced synthetically, rather than cloned. 
     The present invention includes, among other things, retroviral and lentiviral vector constructs expressing a CAR that can be directly transduced into a cell. 
     The present invention also includes an RNA construct that can be directly transfected into a cell. A method for generating mRNA for use in transfection involves in vitro transcription (IVT) of a template with specially designed primers, followed by polyA addition, to produce a construct containing 3′ and 5′ untranslated sequence (“UTR”), a 5′ cap and/or Internal Ribosome Entry Site (IRES), the nucleic acid to be expressed, and a polyA tail, typically 50-2000 bases in length (SEQ ID NO:118). RNA so produced can efficiently transfect different kinds of cells. In one embodiment, the template includes sequences for the CAR. In an embodiment, an RNA CAR vector is transduced into a T cell by electroporation. 
     Antigen Binding Domain 
     In one aspect, the CAR of the invention comprises a target-specific binding element otherwise referred to as an antigen binding domain. The choice of moiety depends upon the type and number of ligands that define the surface of a target cell. For example, the antigen binding domain may be chosen to recognize a ligand that acts as a cell surface marker on target cells associated with a particular disease state. Thus examples of cell surface markers that may act as ligands for the antigen binding domain in a CAR of the invention include those associated with viral, bacterial and parasitic infections, autoimmune disease and cancer cells. The antigen-binding domain can bind, e.g., one or more of CD19 or BCMA. 
     In one aspect, the CAR-mediated T-cell response can be directed to an antigen of interest by way of engineering an antigen binding domain that specifically binds a desired antigen into the CAR. 
     The antigen binding domain (e.g., an antigen-binding domain that binds one or more of CD19 or BCMA) can be any domain that binds to the antigen including but not limited to a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a murine antibody, a human antibody, a humanized antibody, and a functional fragment thereof, including but not limited to a single-domain antibody such as a heavy chain variable domain (VH), a light chain variable domain (VL) and a variable domain (VHH) of camelid derived nanobody, and to an alternative scaffold known in the art to function as antigen binding domain, such as a recombinant fibronectin domain, and the like. 
     In some instances, it is beneficial for the antigen binding domain to be derived from the same species in which the CAR will ultimately be used in. For example, for use in humans, it may be beneficial for the antigen binding domain of the CAR to comprise human or humanized residues for the antigen binding domain of an antibody or antibody fragment. 
     A humanized antibody can be produced using a variety of techniques known in the art, including but not limited to, CDR-grafting (see, e.g., European Patent No. EP 239,400; International Publication No. WO 91/09967; and U.S. Pat. Nos. 5,225,539, 5,530,101, and 5,585,089, each of which is incorporated herein in its entirety by reference), veneering or resurfacing (see, e.g., European Patent Nos. EP 592,106 and EP 519,596; Padlan, 1991, Molecular Immunology, 28(4/5):489-498; Studnicka et al., 1994, Protein Engineering, 7(6):805-814; and Roguska et al., 1994, PNAS, 91:969-973, each of which is incorporated herein by its entirety by reference), chain shuffling (see, e.g., U.S. Pat. No. 5,565,332, which is incorporated herein in its entirety by reference), and techniques disclosed in, e.g., U.S. Patent Application Publication No. US2005/0042664, U.S. Patent Application Publication No. US2005/0048617, U.S. Pat. Nos. 6,407,213, 5,766,886, International Publication No. WO 9317105, Tan et al., J. Immunol., 169:1119-25 (2002), Caldas et al., Protein Eng., 13(5):353-60 (2000), Morea et al., Methods, 20(3):267-79 (2000), Baca et al., J. Biol. Chem., 272(16):10678-84 (1997), Roguska et al., Protein Eng., 9(10):895-904 (1996), Couto et al., Cancer Res., 55 (23 Supp):5973s-5977s (1995), Couto et al., Cancer Res., 55(8):1717-22 (1995), Sandhu J S, Gene, 150(2):409-10 (1994), and Pedersen et al., J. Mol. Biol., 235(3):959-73 (1994), each of which is incorporated herein in its entirety by reference. 
     A humanized antibody or antibody fragment has one or more amino acid residues remaining in it from a source which is nonhuman. These nonhuman amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain. As provided herein, humanized antibodies or antibody fragments comprise one or more CDRs from nonhuman immunoglobulin molecules and framework regions wherein the amino acid residues comprising the framework are derived completely or mostly from human germline. Multiple techniques for humanization of antibodies or antibody fragments are well-known in the art and can essentially be performed following the method of Winter and co-workers (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody, i.e., CDR-grafting (EP 239,400; PCT Publication No. WO 91/09967; and U.S. Pat. Nos. 4,816,567; 6,331,415; 5,225,539; 5,530,101; 5,585,089; 6,548,640, the contents of which are incorporated herein by reference herein in their entirety). In such humanized antibodies and antibody fragments, substantially less than an intact human variable domain has been substituted by the corresponding sequence from a nonhuman species. Humanized antibodies are often human antibodies in which some CDR residues and possibly some framework (FR) residues are substituted by residues from analogous sites in rodent antibodies. Humanization of antibodies and antibody fragments can also be achieved by veneering or resurfacing (EP 592,106; EP 519,596; Padlan, 1991, Molecular Immunology, 28(4/5):489-498; Studnicka et al., Protein Engineering, 7(6):805-814 (1994); and Roguska et al., PNAS, 91:969-973 (1994)) or chain shuffling (U.S. Pat. No. 5,565,332), the contents of which are incorporated herein by reference herein in their entirety. 
     The choice of human variable domains, both light and heavy, to be used in making the humanized antibodies is to reduce antigenicity. According to the so-called “best-fit” method, the sequence of the variable domain of a rodent antibody is screened against the entire library of known human variable-domain sequences. The human sequence which is closest to that of the rodent is then accepted as the human framework (FR) for the humanized antibody (Sims et al., J. Immunol., 151:2296 (1993); Chothia et al., J. Mol. Biol., 196:901 (1987), the contents of which are incorporated herein by reference herein in their entirety). Another method uses a particular framework derived from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains. The same framework may be used for several different humanized antibodies (see, e.g., Nicholson et al. Mol. Immun. 34 (16-17): 1157-1165 (1997); Carter et al., Proc. Natl. Acad. Sci. USA, 89:4285 (1992); Presta et al., J. Immunol., 151:2623 (1993), the contents of which are incorporated herein by reference herein in their entirety). In some embodiments, the framework region, e.g., all four framework regions, of the heavy chain variable region are derived from a VH4_4-59 germline sequence. In one embodiment, the framework region can comprise, one, two, three, four or five modifications, e.g., substitutions, e.g., from the amino acid at the corresponding murine sequence (e.g., of SEQ ID NO:59). In one embodiment, the framework region, e.g., all four framework regions of the light chain variable region are derived from a VK3_1.25 germline sequence. In one embodiment, the framework region can comprise, one, two, three, four or five modifications, e.g., substitutions, e.g., from the amino acid at the corresponding murine sequence (e.g., of SEQ ID NO:59). 
     In some aspects, the portion of a CAR composition of the invention that comprises an antibody fragment is humanized with retention of high affinity for the target antigen and other favorable biological properties. According to one aspect of the invention, humanized antibodies and antibody fragments are prepared by a process of analysis of the parental sequences and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, e.g., the analysis of residues that influence the ability of the candidate immunoglobulin to bind the target antigen. In this way, FR residues can be selected and combined from the recipient and import sequences so that the desired antibody or antibody fragment characteristic, such as increased affinity for the target antigen, is achieved. In general, the CDR residues are directly and most substantially involved in influencing antigen binding. 
     A humanized antibody or antibody fragment may retain a similar antigenic specificity as the original antibody, e.g., in the present invention, the ability to bind human CD19, CD20, or CD22. In some embodiments, a humanized antibody or antibody fragment may have improved affinity and/or specificity of binding to human CD19, CD20, or CD22. 
     In one aspect, the binding domain (e.g., an antigen-binding domain that binds one or more of CD10, CD19, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, CD79a, or BCMA) is a fragment, e.g., a single chain variable fragment (scFv). In one aspect, the binding domain is a Fv, a Fab, a (Fab′)2, or a bi-functional (e.g. bi-specific) hybrid antibody (e.g., Lanzavecchia et al., Eur. J. Immunol. 17, 105 (1987)). In one aspect, the antibodies and fragments thereof of the invention binds a CD19, CD20, or CD22 protein with wild-type or enhanced affinity. 
     In some instances, scFvs can be prepared according to method known in the art (see, for example, Bird et al., (1988) Science 242:423-426 and Huston et al., (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). ScFv molecules can be produced by linking VH and VL regions together using flexible polypeptide linkers. The scFv molecules comprise a linker (e.g., a Ser-Gly linker) with an optimized length and/or amino acid composition. The linker length can greatly affect how the variable regions of a scFv fold and interact. In fact, if a short polypeptide linker is employed (e.g., between 5-10 amino acids) intrachain folding is prevented. Interchain folding is also required to bring the two variable regions together to form a functional epitope binding site. For examples of linker orientation and size see, e.g., Hollinger et al. 1993 Proc Natl Acad. Sci. U.S.A. 90:6444-6448, U.S. Patent Application Publication Nos. 2005/0100543, 2005/0175606, 2007/0014794, and PCT publication Nos. WO2006/020258 and WO2007/024715, is incorporated herein by reference. 
     An scFv can comprise a linker of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, or more amino acid residues between its VL and VH regions. The linker sequence may comprise any naturally occurring amino acid. In some embodiments, the linker sequence comprises amino acids glycine and serine. In another embodiment, the linker sequence comprises sets of glycine and serine repeats such as (Gly 4 Ser)n, where n is a positive integer equal to or greater than 1 (SEQ ID NO:18). In one embodiment, the linker can be (Gly 4 Ser) 4  (SEQ ID NO:106) or (Gly 4 Ser) 3 (SEQ ID NO:107). Variation in the linker length may retain or enhance activity, giving rise to superior efficacy in activity studies. 
     In some embodiments, the amino acid sequence of the antigen binding domain (e.g., an antigen-binding domain that binds one or more of CD10, CD19, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a) or other portions or the entire CAR) can be modified, e.g., an amino acid sequence described herein can be modified, e.g., by a conservative substitution. Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). 
     Percent identity in the context of two or more nucleic acids or polypeptide sequences, refers to two or more sequences that are the same. Two sequences are “substantially identical” if two sequences have a specified percentage of amino acid residues or nucleotides that are the same (e.g., 60% identity, optionally 70%, 71%. 72%. 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity over a specified region, or, when not specified, over the entire sequence), when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection. Optionally, the identity exists over a region that is at least about 50 nucleotides (or 10 amino acids) in length, or over a region that is 100 to 500 or 1000 or more nucleotides (or 20, 50, 200 or more amino acids) in length. 
     For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters. Methods of alignment of sequences for comparison are well known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman, (1970) Adv. Appl. Math. 2:482c, by the homology alignment algorithm of Needleman and Wunsch, (1970) J. Mol. Biol. 48:443, by the search for similarity method of Pearson and Lipman, (1988) Proc. Nat&#39;l. Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by manual alignment and visual inspection (see, e.g., Brent et al., (2003) Current Protocols in Molecular Biology). 
     Two examples of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al., (1977) Nuc. Acids Res. 25:3389-3402; and Altschul et al., (1990) J. Mol. Biol. 215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information. 
     The percent identity between two amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller, (1988) Comput. Appl. Biosci. 4:11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (1970) J. Mol. Biol. 48:444-453) algorithm which has been incorporated into the GAP program in the GCG software package (available at www.gcg.com), using either a Blossom 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. 
     In one aspect, the present invention contemplates modifications of the starting antibody or fragment (e.g., scFv) amino acid sequence that generate functionally equivalent molecules. For example, the VH or VL of a binding domain (e.g., an antigen-binding domain that binds one or more of CD10, CD19, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a), e.g., scFv, comprised in the CAR can be modified to retain at least about 70%, 71%. 72%. 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity of the starting VH or VL framework region of the anti-CD19 binding domain, e.g., scFv. More broadly, the VH or VL of a B-cell antigen binding domain, to CD10, CD20, CD22, CD34, CD123, FLT-3, or ROR1, e.g., scFv, comprised in the CAR can be modified to retain at least about 70%, 71%. 72%. 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity of the starting VH or VL framework region of the antigen binding domain, e.g., scFv. The present invention contemplates modifications of the entire CAR construct, e.g., modifications in one or more amino acid sequences of the various domains of the CAR construct in order to generate functionally equivalent molecules. The CAR construct can be modified to retain at least about 70%, 71%. 72%. 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity of the starting CAR construct. 
     Bispecific CARs 
     In an embodiment a multispecific antibody molecule is a bispecific antibody molecule. A bispecific antibody has specificity for no more than two antigens. A bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence which has binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope. In an embodiment the first and second epitopes are on the same antigen, e.g., the same protein (or subunit of a multimeric protein). In an embodiment the first and second epitopes overlap. In an embodiment the first and second epitopes do not overlap. In an embodiment the first and second epitopes are on different antigens, e.g., different proteins (or different subunits of a multimeric protein). In an embodiment a bispecific antibody molecule comprises a heavy chain variable domain sequence and a light chain variable domain sequence which have binding specificity for a first epitope and a heavy chain variable domain sequence and a light chain variable domain sequence which have binding specificity for a second epitope. In an embodiment a bispecific antibody molecule comprises a half antibody having binding specificity for a first epitope and a half antibody having binding specificity for a second epitope. In an embodiment a bispecific antibody molecule comprises a half antibody, or fragment thereof, having binding specificity for a first epitope and a half antibody, or fragment thereof, having binding specificity for a second epitope. In an embodiment a bispecific antibody molecule comprises a scFv, or fragment thereof, have binding specificity for a first epitope and a scFv, or fragment thereof, have binding specificity for a second epitope. In an embodiment the first epitope is located on CD19 and the second epitope is located on a second B cell antigen, e.g., CD10, CD20, CD22, CD34, CD123, FLT-3, or ROR1. 
     A bispecific antibody molecule (which can be, e.g., administered alone or as a portion of a CAR) can comprise two VH regions and two VL regions. In some embodiments, the upstream antibody or portion thereof (e.g. scFv) is arranged with its VH (VH 1 ) upstream of its VL (VL 1 ) and the downstream antibody or portion thereof (e.g. scFv) is arranged with its VL (VL 2 ) upstream of its VH (VH 2 ), such that the overall bispecific antibody molecule has the arrangement VH 1 -VL 1 -VL 2 -VH 2 . In other embodiments, the upstream antibody or portion thereof (e.g. scFv) is arranged with its VL (VL 1 ) upstream of its VH (VH 1 ) and the downstream antibody or portion thereof (e.g. scFv) is arranged with its VH (VH 2 ) upstream of its VL (VL 2 ), such that the overall bispecific antibody molecule has the arrangement VL 1 -VH 1 -VH 2 -VL 2 . 
     In certain embodiments, the antibody molecule is a multi-specific (e.g., a bispecific or a trispecific) antibody molecule. Protocols for generating bispecific or heterodimeric antibody molecules are known in the art; including but not limited to, for example, the “knob in a hole” approach described in, e.g., U.S. Pat. No. 5,731,168; the electrostatic steering Fc pairing as described in, e.g., WO 09/089004, WO 06/106905 and WO 2010/129304; Strand Exchange Engineered Domains (SEED) heterodimer formation as described in, e.g., WO 07/110205; Fab arm exchange as described in, e.g., WO 08/119353, WO 2011/131746, and WO 2013/060867; double antibody conjugate, e.g., by antibody cross-linking to generate a bi-specific structure using a heterobifunctional reagent having an amine-reactive group and a sulfhydryl reactive group as described in, e.g., U.S. Pat. No. 4,433,059; bispecific antibody determinants generated by recombining half antibodies (heavy-light chain pairs or Fabs) from different antibodies through cycle of reduction and oxidation of disulfide bonds between the two heavy chains, as described in, e.g., U.S. Pat. No. 4,444,878; trifunctional antibodies, e.g., three Fab′ fragments cross-linked through sulfhdryl reactive groups, as described in, e.g., U.S. Pat. No. 5,273,743; biosynthetic binding proteins, e.g., pair of scFvs cross-linked through C-terminal tails preferably through disulfide or amine-reactive chemical cross-linking, as described in, e.g., U.S. Pat. No. 5,534,254; bifunctional antibodies, e.g., Fab fragments with different binding specificities dimerized through leucine zippers (e.g., c-fos and c-jun) that have replaced the constant domain, as described in, e.g., U.S. Pat. No. 5,582,996; bispecific and oligospecific mono- and oligovalent receptors, e.g., VH-CH1 regions of two antibodies (two Fab fragments) linked through a polypeptide spacer between the CH1 region of one antibody and the VH region of the other antibody typically with associated light chains, as described in, e.g., U.S. Pat. No. 5,591,828; bispecific DNA-antibody conjugates, e.g., crosslinking of antibodies or Fab fragments through a double stranded piece of DNA, as described in, e.g., U.S. Pat. No. 5,635,602; bispecific fusion proteins, e.g., an expression construct containing two scFvs with a hydrophilic helical peptide linker between them and a full constant region, as described in, e.g., U.S. Pat. No. 5,637,481; multivalent and multispecific binding proteins, e.g., dimer of polypeptides having first domain with binding region of Ig heavy chain variable region, and second domain with binding region of Ig light chain variable region, generally termed diabodies (higher order structures are also encompassed creating for bispecific, trispecific, or tetraspecific molecules, as described in, e.g., U.S. Pat. No. 5,837,242; minibody constructs with linked VL and VH chains further connected with peptide spacers to an antibody hinge region and CH3 region, which can be dimerized to form bispecific/multivalent molecules, as described in, e.g., U.S. Pat. No. 5,837,821; VH and VL domains linked with a short peptide linker (e.g., 5 or 10 amino acids) or no linker at all in either orientation, which can form dimers to form bispecific diabodies; trimers and tetramers, as described in, e.g., U.S. Pat. No. 5,844,094; String of VH domains (or VL domains in family members) connected by peptide linkages with crosslinkable groups at the C-terminus further associated with VL domains to form a series of FVs (or scFvs), as described in, e.g., U.S. Pat. No. 5,864,019; and single chain binding polypeptides with both a VH and a VL domain linked through a peptide linker are combined into multivalent structures through non-covalent or chemical crosslinking to form, e.g., homobivalent, heterobivalent, trivalent, and tetravalent structures using both scFV or diabody type format, as described in, e.g., U.S. Pat. No. 5,869,620. Additional exemplary multispecific and bispecific molecules and methods of making the same are found, for example, in U.S. Pat. Nos. 5,910,573, 5,932,448, 5,959,083, 5,989,830, 6,005,079, 6,239,259, 6,294,353, 6,333,396, 6,476,198, 6,511,663, 6,670,453, 6,743,896, 6,809,185, 6,833,441, 7,129,330, 7,183,076, 7,521,056, 7,527,787, 7,534,866, 7,612,181, US2002004587A1, US2002076406A1, US2002103345A1, US2003207346A1, US2003211078A1, US2004219643A1, US2004220388A1, US2004242847A1, US2005003403A1, US2005004352A1, US2005069552A1, US2005079170A1, US2005100543A1, US2005136049A1, US2005136051A1, US2005163782A1, US2005266425A1, US2006083747A1, US2006120960A1, US2006204493A1, US2006263367A1, US2007004909A1, US2007087381A1, US2007128150A1, US2007141049A1, US2007154901A1, US2007274985A1, US2008050370A1, US2008069820A1, US2008152645A1, US2008171855A1, US2008241884A1, US2008254512A1, US2008260738A1, US2009130106A1, US2009148905A1, US2009155275A1, US2009162359A1, US2009162360A1, US2009175851A1, US2009175867A1, US2009232811A1, US2009234105A1, US2009263392A1, US2009274649A1, EP346087A2, WO0006605A2, WO02072635A2, WO04081051A1, WO06020258A2, WO2007044887A2, WO2007095338A2, WO2007137760A2, WO2008119353A1, WO2009021754A2, WO2009068630A1, WO9103493A1, WO9323537A1, WO9409131A1, WO9412625A2, WO9509917A1, WO9637621A2, WO9964460A1. The contents of the above-referenced applications are incorporated herein by reference in their entireties. 
     Within each antibody or antibody fragment (e.g., scFv) of a bispecific antibody molecule, the VH can be upstream or downstream of the VL. In some embodiments, the upstream antibody or antibody fragment (e.g., scFv) is arranged with its VH (VH1) upstream of its VL (VL1) and the downstream antibody or antibody fragment (e.g., scFv) is arranged with its VL (VL 2 ) upstream of its VH (VH 2 ), such that the overall bispecific antibody molecule has the arrangement VH 1 -VL 1 -VL 2 -VH 2 . In other embodiments, the upstream antibody or antibody fragment (e.g., scFv) is arranged with its VL (VL1) upstream of its VH (VH1) and the downstream antibody or antibody fragment (e.g., scFv) is arranged with its VH (VH 2 ) upstream of its VL (VL 2 ), such that the overall bispecific antibody molecule has the arrangement VL 1 -VH 1 -VH 2 -VL 2 . Optionally, a linker is disposed between the two antibodies or antibody fragments (e.g., scFvs), e.g., between VL 1  and VL 2  if the construct is arranged as VH 1 -VL 1 -VL 2 -VH 2 , or between VH 1  and VH 2  if the construct is arranged as VL 1 -VH 1 -VH 2 -VL 2 . The linker may be a linker as described herein, e.g., a (Gly 4 -Ser)n linker, wherein n is 1, 2, 3, 4, 5, or 6, e.g., 4 (SEQ ID NO: 53). In general, the linker between the two scFvs should be long enough to avoid mispairing between the domains of the two scFvs. Optionally, a linker is disposed between the VL and VH of the first scFv. Optionally, a linker is disposed between the VL and VH of the second scFv. In constructs that have multiple linkers, any two or more of the linkers can be the same or different. Accordingly, in some embodiments, a bispecific CAR comprises VLs, VHs, and optionally one or more linkers in an arrangement as described herein. 
     In certain embodiments the antibody molecule is a bispecific antibody molecule having a first binding specificity for a first B-cell epitope and a second binding specificity for another B-cell antigen. For instance, in some embodiments the bispecific antibody molecule has a first binding specificity for CD19 and a second binding specificity for one or more of CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. In some embodiments the bispecific antibody molecule has a first binding specificity for CD19 and a second binding specificity for CD22. Exemplary bispecific CAR19/CAR22 antibody molecules and sequences thereof, are described on page 62 and pages 501-506 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     CAR Compositions 
     Compositions comprising cells that express a CAR molecule, e.g., a composition comprising: (i) one or more cells that express a CAR molecule that binds CD19, e.g., a CAR molecule that binds CD19 described herein, e.g., a CD19 CAR, and (ii) a B-cell inhibitor, e.g., one or more inhibitors of CD10, CD20, CD22, CD34, CD123, FLT-3, or ROR1, are described on pages 15-17 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     In one embodiment, a method of administration of a composition described herein includes administering a population of cells, a plurality of which comprise a CAR molecule described herein. In some embodiments, the population of CAR-expressing cells comprises a mixture of cells expressing different CARs. For example, in one embodiment, the population of CAR-expressing cells can include a first cell expressing a CAR having an anti-CD19 binding domain described herein, and a second cell expressing a CAR having a different B-cell antigen binding domain. In embodiments, the first and second cell populations are T cells. In embodiments, the first and second populations of T cells are the same isotype, e.g., are both CD4+ T cells, or are both CD8+ T cells. In other embodiments, the first and second populations of T cells are different isotypes, e.g., the first population comprises CD4+ T cells and the second population comprises CD8+ T cells. In embodiments, the first and second populations of T cells are cell types described in WO2012/129514, which is herein incorporated by reference in its entirety. 
     As another example, a population of cells can comprise a single cell type that expresses both a CAR having an anti-CD19 binding domain described herein and a CAR having a different B-cell antigen binding domain. As another example, a population of cells can comprise a single cell type that expresses a CAR having two or more (e.g., 2, 3, 4, or 5) B-cell antigen binding domains, e.g., is a bispecific CAR, e.g., as described herein. 
     In an embodiment, when the first B-cell inhibitor is a CD19 CAR-expressing cell and the second B-cell inhibitor is a CD10 CAR-expressing cell, the first CAR and second CAR may be expressed by the same cell type or different types. In another embodiment, when the first B-cell inhibitor is a CD19 CAR-expressing cell and the second B-cell inhibitor is a CD20 CAR-expressing cell, the first CAR and second CAR may be expressed by the same cell type or different types. In yet another embodiment, when the first B-cell inhibitor is a CD19 CAR-expressing cell and the second B-cell inhibitor is a CD22 CAR-expressing cell, the first CAR and second CAR may be expressed by the same cell type or different types. 
     In an embodiment, when the first B-cell inhibitor is a CD19 CAR-expressing cell and the second B-cell inhibitor is a CD34 CAR-expressing cell, the first CAR and second CAR may be expressed by the same cell type or different types. In another embodiment, when the first B-cell inhibitor is a CD19 CAR-expressing cell and the second B-cell inhibitor is a CD123 CAR-expressing cell, the first CAR and second CAR may be expressed by the same cell type or different types. In yet another embodiment, when the first B-cell inhibitor is a CD19 CAR-expressing cell and the second B-cell inhibitor is a FLT-3 CAR-expressing cell, the first CAR and second CAR may be expressed by the same cell type or different types. In an embodiment, when the first B-cell inhibitor is a CD19 CAR-expressing cell and the second B-cell inhibitor is a ROR1 CAR-expressing cell, the first CAR and second CAR may be expressed by the same cell type or different types. 
     More generally, when the first B-cell inhibitor comprises a CD19 CAR and there is a second B-cell inhibitor e.g., which comprises a second CAR, the first CAR and the second B-cell inhibitor may be expressed by the same cell type or different types. Exemplary cell populations comprising cells expressing different CAR molecules, and methods of using the same are described on pages 23-32 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     In embodiments, the cell expresses an inhibitory molecule that comprises a first polypeptide that comprises at least a portion of an inhibitory molecule, associated with a second polypeptide that comprises a positive signal from an intracellular signaling domain. In embodiments, the inhibitory molecule comprise first polypeptide that comprises at least a portion of PD1 and a second polypeptide comprising a costimulatory domain and primary signaling domain. 
     Chimeric TCR 
     In one aspect, the antibodies and antibody fragments disclosed herein (e.g., those directed against CD10, CD19, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a) can be grafted to one or more constant domain of a T cell receptor (“TCR”) chain, for example, a TCR alpha or TCR beta chain, to create an chimeric TCR that binds specifically to a cancer associated antigen. Without being bound by theory, it is believed that chimeric TCRs will signal through the TCR complex upon antigen binding. For example, an scFv as disclosed herein, can be grafted to the constant domain, e.g., at least a portion of the extracellular constant domain, the transmembrane domain and the cytoplasmic domain, of a TCR chain, for example, the TCR alpha chain and/or the TCR beta chain. As another example, an antibody fragment, for example a VL domain as described herein, can be grafted to the constant domain of a TCR alpha chain, and an antibody fragment, for example a VH domain as described herein, can be grafted to the constant domain of a TCR beta chain (or alternatively, a VL domain may be grafted to the constant domain of the TCR beta chain and a VH domain may be grafted to a TCR alpha chain). As another example, the CDRs of an antibody or antibody fragment, e.g., the CDRs of an antibody or antibody fragment as described in any of the Tables herein may be grafted into a TCR alpha and/or beta chain to create a chimeric TCR that binds specifically to a cancer associated antigen. For example, the LC CDRs disclosed herein may be grafted into the variable domain of a TCR alpha chain and the HC CDRs disclosed herein may be grafted to the variable domain of a TCR beta chain, or vice versa. Such chimeric TCRs may be produced by any appropriate method (For example, Willemsen R A et al, Gene Therapy 2000; 7: 1369-1377; Zhang T et al, Cancer Gene Ther 2004; 11: 487-496; Aggen et al, Gene Ther. 2012 April; 19(4):365-74). 
     Non-Antibody Scaffolds 
     In embodiments, the antigen binding domain comprises a non antibody scaffold, e.g., a fibronectin, ankyrin, domain antibody, lipocalin, small modular immuno-pharmaceutical, maxybody, Protein A, or affilin. In embodiments, the antigen binding domain is a polypeptide or fragment thereof of a naturally occurring protein expressed on a cell. In some embodiments, the antigen binding domain comprises a non-antibody scaffold. 
     Non-antibody scaffolds include: fibronectin (Novartis, Mass.), ankyrin (Molecular Partners AG, Zurich, Switzerland), domain antibodies (Domantis, Ltd., Cambridge, Mass., and Ablynx nv, Zwijnaarde, Belgium), lipocalin (Pieris Proteolab AG, Freising, Germany), small modular immuno-pharmaceuticals (Trubion Pharmaceuticals Inc., Seattle, Wash.), maxybodies (Avidia, Inc., Mountain View, Calif.), Protein A (Affibody AG, Sweden), and affilin (gamma-crystallin or ubiquitin) (Scil Proteins GmbH, Halle, Germany). 
     Additional and exemplary non-antibody scaffolds are described on pages 179-181 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     Transmembrane Domain 
     With respect to the transmembrane domain, in various embodiments, a CAR can be designed to comprise a transmembrane domain that is attached to the extracellular domain of the CAR. A transmembrane domain can include one or more additional amino acids adjacent to the transmembrane region, e.g., one or more amino acid associated with the extracellular region of the protein from which the transmembrane was derived (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 up to 15 amino acids of the extracellular region) and/or one or more additional amino acids associated with the intracellular region of the protein from which the transmembrane protein is derived (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 up to 15 amino acids of the intracellular region). In one aspect, the transmembrane domain is one that is associated with one of the other domains of the CAR, e.g., in one embodiment, the transmembrane domain may be from the same protein that the signaling domain, costimulatory domain or the hinge domain is derived from. In another aspect, the transmembrane domain is not derived from the same protein that any other domain of the CAR is derived from. In some instances, the transmembrane domain can be selected or modified by amino acid substitution to avoid binding of such domains to the transmembrane domains of the same or different surface membrane proteins, e.g., to minimize interactions with other members of the receptor complex. In one aspect, the transmembrane domain is capable of homodimerization with another CAR on the cell surface of a CAR-expressing cell. In a different aspect the amino acid sequence of the transmembrane domain may be modified or substituted so as to minimize interactions with the binding domains of the native binding partner present in the same CAR-expressing cell. 
     The transmembrane domain may be derived either from a natural or from a recombinant source. Where the source is natural, the domain may be derived from any membrane-bound or transmembrane protein. In one aspect the transmembrane domain is capable of signaling to the intracellular domain(s) whenever the CAR has bound to a target. A transmembrane domain of particular use in this invention may include at least the transmembrane region(s) of e.g., the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154. In some embodiments, a transmembrane domain may include at least the transmembrane region(s) of, e.g., KIRDS2, OX40, CD2, CD27, LFA-1 (CD11a, CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD160, CD19, IL2R beta, IL2R gamma, IL7R α, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, PAG/Cbp, NKG2D, NKG2C, or CD19. 
     In some instances, the transmembrane domain can be attached to the extracellular region of the CAR, e.g., the antigen binding domain of the CAR, via a hinge, e.g., a hinge from a human protein. For example, in one embodiment, the hinge can be a human Ig (immunoglobulin) hinge, e.g., an IgG4 hinge, an IgD hinge, a GS linker (e.g., a GS linker described herein), a KIR2DS2 hinge, or a CD8a hinge. In one embodiment, the hinge or spacer comprises (e.g., consists of) the amino acid sequence of SEQ ID NO:14. In one aspect, the transmembrane domain comprises (e.g., consists of) a transmembrane domain of SEQ ID NO: 15. 
     In one aspect, the hinge or spacer comprises an IgG4 hinge. For example, in one embodiment, the hinge or spacer comprises a hinge of the amino acid sequence 
                    (SEQ ID NO: 46)       GAGAGCAAGTACGGCCCTCCCTGCCCCCCTTGCCCTGCCCCCGAGTTCC               TGGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCT               GATGATCAGCCGGACCCCCGAGGTGACCTGTGTGGTGGTGGACGTGTCC               CAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGG               TGCACAACGCCAAGACCAAGCCCCGGGAGGAGCAGTTCAATAGCACCTA               CCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGC               AAGGAATACAAGTGTAAGGTGTCCAACAAGGGCCTGCCCAGCAGCATCG               AGAAAACCATCAGCAAGGCCAAGGGCCAGCCTCGGGAGCCCCAGGTGTA               CACCCTGCCCCCTAGCCAAGAGGAGATGACCAAGAACCAGGTGTCCCTG               ACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGG               AGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCT               GGACAGCGACGGCAGCTTCTTCCTGTACAGCCGGCTGACCGTGGACAAG               AGCCGGTGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGG               CCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGCAA               GATG.            
In some embodiments, the hinge or spacer comprises a hinge encoded by a nucleotide sequence of
 
     
       
         
           
               
            
               
                 (SEQ ID NO: 45) 
               
               
                 ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS 
               
               
                   
               
               
                 QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNG 
               
               
                   
               
               
                 KEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSL 
               
               
                   
               
               
                 TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK 
               
               
                   
               
               
                 SRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKM. 
               
            
           
         
       
     
     In one aspect, the hinge or spacer comprises an IgD hinge. For example, in one embodiment, the hinge or spacer comprises a hinge of the amino acid sequence 
                    (SEQ ID NO: 47)       RWPESPKAQASSVPTAQPQAEGSLAKATTAPATTRNTGRGGEEKKKEKE               KEEQEERETKTPECPSHTQPLGVYLLTPAVQDLWLRDKATFTCFVVGSD               LKDAHLTWEVAGKVPTGGVEEGLLERHSNGSQSQHSRLTLPRSLWNAGT               SVTCTLNHPSLPPQRLMALREPAAQAPVKLSLNLLASSDPPEAASWLLC               EVSGFSPPNILLMWLEDQREVNTSGFAPARPPPQPGSTTFWAWSVLRVP               APPSPQPATYTCVVSHEDSRTLLNASRSLEVSYVTDH.            
In some embodiments, the hinge or spacer comprises a hinge encoded by a nucleotide sequence of
 
     
       
         
           
               
            
               
                 (SEQ ID NO: 48) 
               
               
                 AGGTGGCCCGAAAGTCCCAAGGCCCAGGCATCTAGTGTTCCTACTGCAC 
               
               
                   
               
               
                 AGCCCCAGGCAGAAGGCAGCCTAGCCAAAGCTACTACTGCACCTGCCAC 
               
               
                   
               
               
                 TACGCGCAATACTGGCCGTGGCGGGGAGGAGAAGAAAAAGGAGAAAGAG 
               
               
                   
               
               
                 AAAGAAGAACAGGAAGAGAGGGAGACCAAGACCCCTGAATGTCCATCCC 
               
               
                   
               
               
                 ATACCCAGCCGCTGGGCGTCTATCTCTTGACTCCCGCAGTACAGGACTT 
               
               
                   
               
               
                 GTGGCTTAGAGATAAGGCCACCTTTACATGTTTCGTCGTGGGCTCTGAC 
               
               
                   
               
               
                 CTGAAGGATGCCCATTTGACTTGGGAGGTTGCCGGAAAGGTACCCACAG 
               
               
                   
               
               
                 GGGGGGTTGAGGAAGGGTTGCTGGAGCGCCATTCCAATGGCTCTCAGAG 
               
               
                   
               
               
                 CCAGCACTCAAGACTCACCCTTCCGAGATCCCTGTGGAACGCCGGGACC 
               
               
                   
               
               
                 TCTGTCACATGTACTCTAAATCATCCTAGCCTGCCCCCACAGCGTCTGA 
               
               
                   
               
               
                 TGGCCCTTAGAGAGCCAGCCGCCCAGGCACCAGTTAAGCTTAGCCTGAA 
               
               
                   
               
               
                 TCTGCTCGCCAGTAGTGATCCCCCAGAGGCCGCCAGCTGGCTCTTATGC 
               
               
                   
               
               
                 GAAGTGTCCGGCTTTAGCCCGCCCAACATCTTGCTCATGTGGCTGGAGG 
               
               
                   
               
               
                 ACCAGCGAGAAGTGAACACCAGCGGCTTCGCTCCAGCCCGGCCCCCACC 
               
               
                   
               
               
                 CCAGCCGGGTTCTACCACATTCTGGGCCTGGAGTGTCTTAAGGGTCCCA 
               
               
                   
               
               
                 GCACCACCTAGCCCCCAGCCAGCCACATACACCTGTGTTGTGTCCCATG 
               
               
                   
               
               
                 AAGATAGCAGGACCCTGCTAAATGCTTCTAGGAGTCTGGAGGTTTCCTA 
               
               
                   
               
               
                 CGTGACTGACCATT. 
               
            
           
         
       
     
     In one aspect, the transmembrane domain may be recombinant, in which case it will comprise predominantly hydrophobic residues such as leucine and valine. In one aspect a triplet of phenylalanine, tryptophan and valine can be found at each end of a recombinant transmembrane domain. 
     Optionally, a short oligo- or polypeptide linker, between 2 and 10 amino acids in length may form the linkage between the transmembrane domain and the cytoplasmic region of the CAR. A glycine-serine doublet provides a particularly suitable linker. For example, in one aspect, the linker comprises the amino acid sequence of GGGGSGGGGS (SEQ ID NO:49). In some embodiments, the linker is encoded by a nucleotide sequence of 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 50) 
               
               
                   
                 GGTGGCGGAGGTTCTGGAGGTGGAGGTTCC. 
               
            
           
         
       
     
     In one aspect, the hinge or spacer comprises a KIR2DS2 hinge. 
     Cytoplasmic Domain 
     The cytoplasmic domain or region of the CAR includes an intracellular signaling domain. An intracellular signaling domain is generally responsible for activation of at least one of the normal effector functions of the immune cell in which the CAR has been introduced. 
     Examples of intracellular signaling domains for use in the CAR of the invention include the cytoplasmic sequences of the T cell receptor (TCR) and co-receptors that act in concert to initiate signal transduction following antigen receptor engagement, as well as any derivative or variant of these sequences and any recombinant sequence that has the same functional capability. 
     It is known that signals generated through the TCR alone are insufficient for full activation of the T cell and that a secondary and/or costimulatory signal is also required. Thus, T cell activation can be said to be mediated by two distinct classes of cytoplasmic signaling sequences: those that initiate antigen-dependent primary activation through the TCR (primary intracellular signaling domains) and those that act in an antigen-independent manner to provide a secondary or costimulatory signal (secondary cytoplasmic domain, e.g., a costimulatory domain). 
     A primary signaling domain regulates primary activation of the TCR complex either in a stimulatory way, or in an inhibitory way. Primary intracellular signaling domains that act in a stimulatory manner may contain signaling motifs which are known as immunoreceptor tyrosine-based activation motifs or ITAMs. 
     Examples of ITAM containing primary intracellular signaling domains that are of particular use in the invention include those of CD3 zeta, common FcR gamma (FCER1G), Fc gamma RIIa, FcR beta (Fc Epsilon Rib), CD3 gamma, CD3 delta, CD3 epsilon, CD79a, CD79b, CD278 (also known as “ICOS”), FcεRI, DAP10, DAP12, and CD66d. In one embodiment, a CAR of the invention comprises an intracellular signaling domain, e.g., a primary signaling domain of CD3-zeta. 
     In one embodiment, a primary signaling domain comprises a modified ITAM domain, e.g., a mutated ITAM domain which has altered (e.g., increased or decreased) activity as compared to the native ITAM domain. In one embodiment, a primary signaling domain comprises a modified ITAM-containing primary intracellular signaling domain, e.g., an optimized and/or truncated ITAM-containing primary intracellular signaling domain. In an embodiment, a primary signaling domain comprises one, two, three, four or more ITAM motifs. 
     Further examples of molecules containing a primary intracellular signaling domain that are of particular use in the invention include those of DAP10, DAP12, and CD32. 
     Costimulatory Signaling Domain 
     The intracellular signalling domain of the CAR can comprise the CD3-zeta signaling domain by itself or it can be combined with any other desired intracellular signaling domain(s) useful in the context of a CAR of the invention. For example, the intracellular signaling domain of the CAR can comprise a CD3 zeta chain portion and a costimulatory signaling domain. The costimulatory signaling domain refers to a portion of the CAR comprising the intracellular domain of a costimulatory molecule. In one embodiment, the intracellular domain is designed to comprise the signaling domain of CD3-zeta and the signaling domain of CD28. In one aspect, the intracellular domain is designed to comprise the signaling domain of CD3-zeta and the signaling domain of ICOS. 
     A costimulatory molecule can be a cell surface molecule other than an antigen receptor or its ligands that is required for an efficient response of lymphocytes to an antigen. Examples of such molecules include CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds with CD83, and the like. For example, CD27 costimulation has been demonstrated to enhance expansion, effector function, and survival of human CART cells in vitro and augments human T cell persistence and antitumor activity in vivo (Song et al. Blood. 2012; 119(3):696-706). Further examples of such costimulatory molecules include MHC class I molecule, TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CD11a/CD18), 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, and a ligand that specifically binds with CD83. 
     The intracellular signaling sequences within the cytoplasmic portion of the CAR of the invention may be linked to each other in a random or specified order. Optionally, a short oligo- or polypeptide linker, for example, between 2 and 10 amino acids (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) in length may form the linkage between intracellular signaling sequence. In one embodiment, a glycine-serine doublet can be used as a suitable linker. In one embodiment, a single amino acid, e.g., an alanine, a glycine, can be used as a suitable linker. 
     In one aspect, the intracellular signaling domain is designed to comprise two or more, e.g., 2, 3, 4, 5, or more, costimulatory signaling domains. In an embodiment, the two or more, e.g., 2, 3, 4, 5, or more, costimulatory signaling domains, are separated by a linker molecule, e.g., a linker molecule described herein. In one embodiment, the intracellular signaling domain comprises two costimulatory signaling domains. In some embodiments, the linker molecule is a glycine residue. In some embodiments, the linker is an alanine residue. 
     In one aspect, the intracellular signaling domain is designed to comprise the signaling domain of CD3-zeta and the signaling domain of CD28. In one aspect, the intracellular signaling domain is designed to comprise the signaling domain of CD3-zeta and the signaling domain of 4-1BB. In one aspect, the signaling domain of 4-1BB is a signaling domain of SEQ ID NO: 16. In one aspect, the signaling domain of CD3-zeta is a signaling domain of SEQ ID NO: 17. 
     In one aspect, the intracellular signaling domain is designed to comprise the signaling domain of CD3-zeta and the signaling domain of CD27. In one aspect, the signaling domain of CD27 comprises an amino acid sequence of 
                    (SEQ ID NO: 51)       QRRKYRSNKGESPVEPAEPCRYSCPREEEGSTIPIQEDYRKPEPACSP.            
In one aspect, the signalling domain of CD27 is encoded by a nucleic acid sequence of
 
     
       
         
           
               
            
               
                 (SEQ ID NO: 52) 
               
               
                 AGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCC 
               
               
                 CCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCAC 
               
               
                 GCGACTTCGCAGCCTATCGCTCC. 
               
            
           
         
       
     
     Natural Killer Cell Receptor (NKR) CARs 
     In an embodiment, a CAR molecule described herein comprises one or more components of a natural killer cell receptor (NKR), thereby forming an NKR-CAR. The NKR component can be a transmembrane domain, a hinge domain, or a cytoplasmic domain from any of the following natural killer cell receptors: killer cell immunoglobulin-like receptor (KIR), e.g., KIR2DL1, KIR2DL2/L3, KIR2DL4, KIR2DL5A, KIR2DL5B, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, DIR2DS5, KIR3DL1/S1, KIR3DL2, KIR3DL3, KIR2DP1, and KIR3DP1; natural cytotoxicity receptor (NCR), e.g., NKp30, NKp44, NKp46; signaling lymphocyte activation molecule (SLAM) family of immune cell receptors, e.g., CD48, CD229, 2B4, CD84, NTB-A, CRACC, BLAME, and CD2F-10; Fc receptor (FcR), e.g., CD16, and CD64; and Ly49 receptors, e.g., LY49A, LY49C. The NKR-CAR molecules described herein may interact with an adaptor molecule or intracellular signaling domain, e.g., DAP12. Exemplary configurations and sequences of CAR molecules comprising NKR components are described in International Publication No. WO2014/145252, the contents of which are hereby incorporated by reference. 
     Strategies for Regulating Chimeric Antigen Receptors 
     In some embodiments, a regulatable CAR (RCAR) where the CAR activity can be controlled is desirable to optimize the safety and efficacy of a CAR therapy. There are many ways CAR activities can be regulated. For example, inducing apoptosis using, e.g., a caspase fused to a dimerization domain (see, e.g., Di et al., N Engl. J. Med. 2011 Nov. 3; 365(18):1673-1683), can be used as a safety switch in the CAR therapy of the instant invention. In one embodiment, the cells (e.g., T cells or NK cells) expressing a CAR of the present invention further comprise an inducible apoptosis switch, wherein a human caspase (e.g., caspase 9) or a modified version is fused to a modification of the human FKB protein that allows conditional dimerization. In the presence of a small molecule, such as a rapalog (e.g., AP 1903, AP20187), the inducible caspase (e.g., caspase 9) is activated and leads to the rapid apoptosis and death of the cells (e.g., T cells or NK cells) expressing a CAR of the present invention. Examples of a caspase-based inducible apoptosis switch (or one or more aspects of such a switch) have been described in, e.g., US2004040047; US20110286980; US20140255360; WO1997031899; WO2014151960; WO2014164348; WO2014197638; WO2014197638; all of which are incorporated by reference herein. 
     In another example, CAR-expressing cells can also express an inducible Caspase-9 (iCaspase-9) molecule that, upon administration of a dimerizer drug (e.g., rimiducid (also called AP1903 (Bellicum Pharmaceuticals) or AP20187 (Ariad)) leads to activation of the Caspase-9 and apoptosis of the cells. The iCaspase-9 molecule contains a chemical inducer of dimerization (CID) binding domain that mediates dimerization in the presence of a CID. This results in inducible and selective depletion of CAR-expressing cells. In some cases, the iCaspase-9 molecule is encoded by a nucleic acid molecule separate from the CAR-encoding vector(s). In some cases, the iCaspase-9 molecule is encoded by the same nucleic acid molecule as the CAR-encoding vector. The iCaspase-9 can provide a safety switch to avoid any toxicity of CAR-expressing cells. See, e.g., Song et al. Cancer Gene Ther. 2008; 15(10):667-75; Clinical Trial Id. No. NCT02107963; and Di Stasi et al. N. Engl. J. Med. 2011; 365:1673-83. 
     Alternative strategies for regulating the CAR therapy of the instant invention include utilizing small molecules or antibodies that deactivate or turn off CAR activity, e.g., by deleting CAR-expressing cells, e.g., by inducing antibody dependent cell-mediated cytotoxicity (ADCC). For example, CAR-expressing cells described herein may also express an antigen that is recognized by molecules capable of inducing cell death, e.g., ADCC or complement-induced cell death. For example, CAR expressing cells described herein may also express a receptor capable of being targeted by an antibody or antibody fragment. Examples of such receptors include EpCAM, VEGFR, integrins (e.g., integrins αvβ3, α4, αI3/4β3, α4β7, α5β1, αvβ3, αv), members of the TNF receptor superfamily (e.g., TRAIL-R1, TRAIL-R2), PDGF Receptor, interferon receptor, folate receptor, GPNMB, ICAM-1, HLA-DR, CEA, CA-125, MUC1, TAG-72, IL-6 receptor, 5T4, GD2, GD3, CD2, CD3, CD4, CD5, CD1 1, CD1 1 a/LFA-1, CD15, CD18/ITGB2, CD19, CD20, CD22, CD23/lgE Receptor, CD25, CD28, CD30, CD33, CD38, CD40, CD41, CD44, CD51, CD52, CD62L, CD74, CD80, CD125, CD147/basigin, CD152/CTLA-4, CD154/CD40L, CD195/CCR5, CD319/SLAMF7, and EGFR, and truncated versions thereof (e.g., versions preserving one or more extracellular epitopes but lacking one or more regions within the cytoplasmic domain). 
     For example, a CAR-expressing cell described herein may also express a truncated epidermal growth factor receptor (EGFR) which lacks signaling capacity but retains the epitope that is recognized by molecules capable of inducing ADCC, e.g., cetuximab (ERBITUX®), such that administration of cetuximab induces ADCC and subsequent depletion of the CAR-expressing cells (see, e.g., WO2011/056894, and Jonnalagadda et al., Gene Ther. 2013; 20(8)853-860). Another strategy includes expressing a highly compact marker/suicide gene that combines target epitopes from both CD32 and CD20 antigens in the CAR-expressing cells described herein, which binds rituximab, resulting in selective depletion of the CAR-expressing cells, e.g., by ADCC (see, e.g., Philip et al., Blood. 2014; 124(8)1277-1287). Other methods for depleting CAR-expressing cells described herein include administration of CAMPATH, a monoclonal anti-CD52 antibody that selectively binds and targets mature lymphocytes, e.g., CAR-expressing cells, for destruction, e.g., by inducing ADCC. In other embodiments, the CAR-expressing cell can be selectively targeted using a CAR ligand, e.g., an anti-idiotypic antibody. In some embodiments, the anti-idiotypic antibody can cause effector cell activity, e.g., ADCC or ADC activities, thereby reducing the number of CAR-expressing cells. In other embodiments, the CAR ligand, e.g., the anti-idiotypic antibody, can be coupled to an agent that induces cell killing, e.g., a toxin, thereby reducing the number of CAR-expressing cells. Alternatively, the CAR molecules themselves can be configured such that the activity can be regulated, e.g., turned on and off, as described below. 
     In other embodiments, a CAR-expressing cell described herein may also express a target protein recognized by the T cell depleting agent. In one embodiment, the target protein is CD20 and the T cell depleting agent is an anti-CD20 antibody, e.g., rituximab. In such embodiment, the T cell depleting agent is administered once it is desirable to reduce or eliminate the CAR-expressing cell, e.g., to mitigate the CAR induced toxicity. In other embodiments, the T cell depleting agent is an anti-CD52 antibody, e.g., alemtuzumab. 
     In an aspect, a RCAR comprises a set of polypeptides, typically two in the simplest embodiments, in which the components of a standard CAR described herein, e.g., an antigen binding domain and an intracellular signaling domain, are partitioned on separate polypeptides or members. In some embodiments, the set of polypeptides include a dimerization switch that, upon the presence of a dimerization molecule, can couple the polypeptides to one another, e.g., can couple an antigen binding domain to an intracellular signaling domain. In one embodiment, a CAR of the present invention utilizes a dimerization switch as those described in, e.g., WO2014127261, which is incorporated by reference herein. Additional description and exemplary configurations of such regulatable CARs are provided herein and in International Publication No. WO 2015/090229, hereby incorporated by reference in its entirety. 
     In some embodiments, an RCAR involves a switch domain, e.g., a FKBP switch domain, as set out SEQ ID NO: 122, or comprise a fragment of FKBP having the ability to bind with FRB, e.g., as set out in SEQ ID NO: 123. In some embodiments, the RCAR involves a switch domain comprising a FRB sequence, e.g., as set out in SEQ ID NO: 124, or a mutant FRB sequence, e.g., as set out in any of SEQ ID Nos. 125-130. 
     
       
         
           
               
            
               
                 (SEQ ID NO: 122) 
               
               
                 D V P D Y A S L G G P S S P K K K R K V S R G  V Q   
               
               
                   
               
               
                   V E T I S P G D G R T F P K R G   Q T C V V H Y T G   
               
               
                   
               
               
                 
                   M L E D G K K F D S S R D R N K P F K F M L G K Q 
                 
               
               
                   
               
               
                   E V I R G   W E E G V A Q M S V G Q R A K L T I S P   
               
               
                   
               
               
                   D Y A Y G A T G H P G I I P P H A T L V  F  D V E L   
               
               
                   
               
               
                   L K L E T S  Y 
               
               
                   
               
               
                 (SEQ ID NO: 123) 
               
               
                 V Q V E T I S P G D G R T F P K R G Q T C V V H Y  
               
               
                   
               
               
                 T G M L E D G K K F D S S R D R N K P F K F M L G  
               
               
                   
               
               
                 K Q E V I R G W E E G V A Q M S V G Q R A K L T I  
               
               
                   
               
               
                 S P D Y A Y G A T G H P G I I P P H A T L V F D V  
               
               
                   
               
               
                 E L L K L E T S 
               
               
                   
               
               
                 (SEQ ID NO: 124) 
               
               
                 ILWHEMWHEG LEEASRLYFG ERNVKGMFEV LEPLHAMMER 
               
               
                 GPQTLKETSF NQAYGRDLME AQEWCRKYMK SGNVKDLTQA 
               
               
                 WDLYYHVFRR ISK 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Exemplary mutant FRB having increased affinity for a dimerization molecule. 
               
            
           
           
               
               
               
            
               
                   
                   
                 SEQ 
               
               
                 FRB mutant 
                 Amino Acid Sequence 
                 ID NO: 
               
               
                   
               
               
                 E2032I mutant 
                 ILWHEMWHEGLIEASRLYFGERNVKGMFEVLEPLHAMMERGPQTLKETSFNQAYGR 
                 125 
               
               
                   
                 DLMEAQEWCRKYMKSGNVKDLTQAWDLYYHVFRRISKTS 
                   
               
               
                   
               
               
                 E2032L mutant 
                 ILWHEMWHEGLLEASRLYFGERNVKGMFEVLEPLHAMMERGPQTLKETSFNQAYGR 
                 126 
               
               
                   
                 DLMEAQEWCRKYMKSGNVKDLTQAWDLYYHVFRRISKTS 
                   
               
               
                   
               
               
                 T2098L mutant 
                 ILWHEMWHEGLEEASRLYFGERNVKGMFEVLEPLHAMMERGPQTLKETSFNQAYGR 
                 127 
               
               
                   
                 DLMEAQEWCRKYMKSGNVKDLLQAWDLYYHVFRRISKTS 
                   
               
               
                   
               
               
                 E2032, T2098 
                 ILWHEMWHEGL   X   EASRLYFGERNVKGMFEVLEPLHAMMERGPQTLKETSFNQAYGR 
                 128 
               
               
                 mutant 
                 DLMEAQEWCRKYMKSGNVKDL   X   QAWDLYYHVFRRISKTS 
                   
               
               
                   
               
               
                 E2032I, T2098L 
                 ILWHEMWHEGLIEASRLYFGERNVKGMFEVLEPLHAMMERGPQTLKETSFNQAYGR 
                 129 
               
               
                 mutant 
                 DLMEAQEWCRKYMKSGNVKDLLQAWDLYYHVERRISKTS 
                   
               
               
                   
               
               
                 E2032L, T2098L 
                 ILWHEMWHEGLLEASRLYFGERNVKGMFEVLEPLHAMMERGPQTLKETSFNQAYGR 
                 130 
               
               
                 mutant 
                 DLMEAQEWCRKYMKSGNVKDLLQAWDLYYHVERRISKTS 
               
               
                   
               
            
           
         
       
     
     Split CAR 
     In some embodiments, the CAR-expressing cell uses a split CAR. The split CAR approach is described in more detail in publications WO2014/055442 and WO2014/055657. Briefly, a split CAR system comprises a cell expressing a first CAR having a first antigen binding domain and a costimulatory domain (e.g., 41BB), and the cell also expresses a second CAR having a second antigen binding domain and an intracellular signaling domain (e.g., CD3 zeta). When the cell encounters the first antigen, the costimulatory domain is activated, and the cell proliferates. When the cell encounters the second antigen, the intracellular signaling domain is activated and cell-killing activity begins. Thus, the CAR-expressing cell is only fully activated in the presence of both antigens. 
     RNA Transfection 
     Disclosed herein are methods for producing an in vitro transcribed RNA CAR. The present invention also includes (among other things) a CAR encoding RNA construct that can be directly transfected into a cell. A method for generating mRNA for use in transfection can involve in vitro transcription (IVT) of a template with specially designed primers, followed by polyA addition, to produce a construct containing 3′ and 5′ untranslated sequence (“UTR”), a 5′ cap and/or Internal Ribosome Entry Site (IRES), the nucleic acid to be expressed, and a polyA tail, typically 50-2000 bases in length (SEQ ID NO:118). 
     In one aspect the CAR is encoded by a messenger RNA (mRNA). In one aspect the mRNA encoding the CAR is introduced into an immune effector cell, e.g., a T cell or a NK cell, for production of a CAR-expressing cell, e.g., a CART cell or a CAR NK cell. In one embodiment, the in vitro transcribed RNA CAR can be introduced to a cell as a form of transient transfection. 
     Additional method of RNA transfection are described on pages 192-196 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     Non-Viral Delivery Methods 
     In some aspects, non-viral methods can be used to deliver a nucleic acid encoding a CAR described herein into a cell or tissue or a subject. In some embodiments, the non-viral method includes the use of a transposon (also called a transposable element). In some embodiments, a transposon is a piece of DNA that can insert itself at a location in a genome, for example, a piece of DNA that is capable of self-replicating and inserting its copy into a genome, or a piece of DNA that can be spliced out of a longer nucleic acid and inserted into another place in a genome. 
     Additional and exemplary transposons and non-viral delivery methods are described on pages 196-198 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     Nucleic Acid Constructs Encoding a CAR 
     The present invention also provides nucleic acid molecules encoding one or more CAR 20 constructs described herein, e.g., CD19 CAR, CD20 CAR, or CD22 CAR. In one aspect, the nucleic acid molecule is provided as a messenger RNA transcript. In one aspect, the nucleic acid molecule is provided as a DNA construct. 
     Accordingly, in one aspect, the invention pertains to an isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein the CAR comprises a binding domain (e.g., that binds CD19, CD20, or CD22) a transmembrane domain, and an intracellular signaling domain comprising a stimulatory domain, e.g., a costimulatory signaling domain and/or a primary signaling domain, e.g., zeta chain. 
     In one embodiment, the binding domain is an anti-CD19 binding domain described herein, e.g., an anti-CD19 binding domain which comprises a sequence selected from a group 30 consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:59, or a sequence with 95-99% identity thereof. 
     In one embodiment, the nucleic acid comprises CD22-encoding a nucleic acid set out in 5 Table 6A on pages 364-403 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety, or a sequence with 95-99% identity thereof 
     In one embodiment, the nucleic acid comprises CD20-encoding a nucleic acid set out in Table 11A on pages 422-446 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety, or a sequence with 95-99% identity thereof. 
     In one embodiment, the transmembrane domain is transmembrane domain of a protein selected from the group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154. In one embodiment, the transmembrane domain comprises a sequence of SEQ ID NO: 15, or a sequence with 95-99% identity thereof. In one embodiment, the anti-CD19 binding domain is connected to the transmembrane domain by a hinge region, e.g., a hinge described herein. In one embodiment, the hinge region comprises SEQ ID NO:14 or SEQ ID NO:45 or SEQ ID NO:47 or SEQ ID NO:49, or a sequence with 95-99% identity thereof. In one embodiment, the isolated nucleic acid molecule further comprises a sequence encoding a costimulatory domain. In one embodiment, the costimulatory domain is a functional signaling domain of a protein selected from the group consisting of OX40, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), and 4-1BB (CD137). In one embodiment, the costimulatory domain is a functional signaling domain of a protein selected from the group consisting of MHC class I molecule, TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CD11a/CD18), 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, and a ligand that specifically binds with CD83. In one embodiment, the costimulatory domain comprises a sequence of SEQ ID NO:16, or a sequence with 95-99% identity thereof. In one embodiment, the intracellular signaling domain comprises a functional signaling domain of 4-1BB and a functional signaling domain of CD3 zeta. In one embodiment, the intracellular signaling domain comprises the sequence of SEQ ID NO: 16 or SEQ ID NO:51, or a sequence with 95-99% identity thereof, and the sequence of SEQ ID NO: 17 or SEQ ID NO:43, or a sequence with 95-99% identity thereof, wherein the sequences comprising the intracellular signaling domain are expressed in the same frame and as a single polypeptide chain. 
     In another aspect, the invention pertains to an isolated nucleic acid molecule encoding a CAR construct comprising a leader sequence of SEQ ID NO: 13, a scFv domain having a sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:59, (or a sequence with 95-99% identity thereof), a hinge region of SEQ ID NO:14 or SEQ ID NO:45 or SEQ ID NO:47 or SEQ ID NO:49 (or a sequence with 95-99% identity thereof), a transmembrane domain having a sequence of SEQ ID NO: 15 (or a sequence with 95-99% identity thereof), a 4-1BB costimulatory domain having a sequence of SEQ ID NO:16 or a CD27 costimulatory domain having a sequence of SEQ ID NO:51 (or a sequence with 95-99% identity thereof), and a CD3 zeta stimulatory domain having a sequence of SEQ ID NO:17 or SEQ ID NO:43 (or a sequence with 95-99% identity thereof). 
     In another aspect, the invention pertains to an isolated polypeptide molecule encoded by the nucleic acid molecule. In one embodiment, the isolated polypeptide molecule comprises a sequence selected from the group consisting of SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:59 or a sequence with 95-99% identity thereof. 
     In another aspect, the invention pertains to a nucleic acid molecule encoding a chimeric antigen receptor (CAR) molecule that comprises an anti-CD19 binding domain, a transmembrane domain, and an intracellular signaling domain comprising a stimulatory domain, and wherein said anti-CD19 binding domain comprises a sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12 and SEQ 5 ID NO:59, or a sequence with 95-99% identity thereof. 
     In one embodiment, the encoded CAR molecule (e.g., CD19 CAR, CD20 CAR, or CD22 CAR) further comprises a sequence encoding a costimulatory domain. In one embodiment, the costimulatory domain is a functional signaling domain of a protein selected from the group consisting of OX40, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18) and 4-1BB (CD137). In one embodiment, the costimulatory domain comprises a sequence of SEQ ID NO:16. In one embodiment, the transmembrane domain is a transmembrane domain of a protein selected from the group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154. In one embodiment, the transmembrane domain comprises a sequence of SEQ ID NO:15. In one embodiment, the intracellular signaling domain comprises a functional signaling domain of 4-1BB and a functional signaling domain of zeta. In one embodiment, the intracellular signaling domain comprises the sequence of SEQ ID NO: 16 and the sequence of SEQ ID NO: 17, wherein the sequences comprising the intracellular signaling domain are expressed in the same frame and as a single polypeptide chain. In one embodiment, the anti-CD19 binding domain is connected to the transmembrane domain by a hinge region. In one embodiment, the hinge region comprises SEQ ID NO:14. In one embodiment, the hinge region comprises SEQ ID NO:45 or SEQ ID NO:47 or SEQ ID NO:49. 
     In another aspect, the invention pertains to an encoded CAR molecule comprising a leader sequence of SEQ ID NO: 13, a scFv domain having a sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:59, or a sequence with 95-99% identity thereof, a hinge region of SEQ ID NO:14 or SEQ ID NO:45 or SEQ ID NO:47 or SEQ ID NO:49, a transmembrane domain having a sequence of SEQ ID NO: 15, a 4-1BB costimulatory domain having a sequence of SEQ ID NO:16 or a CD27 costimulatory domain having a sequence of SEQ ID NO:51, and a CD3 zeta stimulatory domain having a sequence of SEQ ID NO:17 or SEQ ID NO:43. In one embodiment, the encoded CAR molecule comprises a sequence selected from a group consisting of SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, and SEQ ID NO:59, or a sequence with 95-99% identity thereof. 
     The nucleic acid sequences coding for the desired molecules can be obtained using recombinant methods known in the art, such as, for example by screening libraries from cells expressing the gene, by deriving the gene from a vector known to include the same, or by isolating directly from cells and tissues containing the same, using standard techniques. Alternatively, the gene of interest can be produced synthetically, rather than cloned. 
     The present invention also provides vectors in which a DNA of the present invention is inserted. Vectors derived from retroviruses such as the lentivirus are suitable tools to achieve long-term gene transfer since they allow long-term, stable integration of a transgene and its propagation in daughter cells. Lentiviral vectors have the added advantage over vectors derived from onco-retroviruses such as murine leukemia viruses in that they can transduce non-proliferating cells, such as hepatocytes. They also have the added advantage of low immunogenicity. A retroviral vector may also be, e.g., a gammaretroviral vector. A gammaretroviral vector may include, e.g., a promoter, a packaging signal (W), a primer binding site (PBS), one or more (e.g., two) long terminal repeats (LTR), and a transgene of interest, e.g., a gene encoding a CAR. A gammaretroviral vector may lack viral structural gens such as gag, pol, and env. Exemplary gammaretroviral vectors include Murine Leukemia Virus (MLV), Spleen-Focus Forming Virus (SFFV), and Myeloproliferative Sarcoma Virus (MPSV), and vectors derived therefrom. Other gammaretroviral vectors are described, e.g., in Tobias Maetzig et al., “Gammaretroviral Vectors: Biology, Technology and Application” Viruses. 2011 June; 3(6): 677-713. 
     In another embodiment, the vector comprising the nucleic acid encoding the desired CAR of the invention is an adenoviral vector (A5/35). In another embodiment, the expression of nucleic acids encoding CARs can be accomplished using of transposons such as sleeping beauty, crispr, CAS9, and zinc finger nucleases. See below June et al. 2009  Nature Reviews Immunology  9.10: 704-716, is incorporated herein by reference. 
     A vector may also include, e.g., a signal sequence to facilitate secretion, a polyadenylation signal and transcription terminator (e.g., from Bovine Growth Hormone (BGH) gene), an element allowing episomal replication and replication in prokaryotes (e.g. SV40 origin and ColE1 or others known in the art) and/or elements to allow selection (e.g., ampicillin resistance gene and/or zeocin marker). 
     In brief summary, the expression of natural or synthetic nucleic acids encoding CARs is typically achieved by operably linking a nucleic acid encoding the CAR polypeptide or portions thereof to a promoter, and incorporating the construct into an expression vector. The vectors can be suitable for replication and integration eukaryotes. Typical cloning vectors contain transcription and translation terminators, initiation sequences, and promoters useful for regulation of the expression of the desired nucleic acid sequence. 
     In some aspects, the expression constructs of the present invention may also be used for nucleic acid immunization and gene therapy, using standard gene delivery protocols. Methods for gene delivery are known in the art. See, e.g., U.S. Pat. Nos. 5,399,346, 5,580,859, 5,589,466, incorporated by reference herein in their entireties. In another embodiment, the invention provides a gene therapy vector. 
     The nucleic acid can be cloned into a number of types of vectors. For example, the nucleic acid can be cloned into a vector including, but not limited to a plasmid, a phagemid, a phage derivative, an animal virus, and a cosmid. Vectors of particular interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors. 
     Further, the expression vector may be provided to a cell in the form of a viral vector. Viral vector technology is well known in the art and is described, for example, in Sambrook et al., 2012, MOLECULAR CLONING: A LABORATORY MANUAL, volumes 1-4, Cold Spring Harbor Press, NY), and in other virology and molecular biology manuals. Viruses, which are useful as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses. In general, a suitable vector contains an origin of replication functional in at least one organism, a promoter sequence, convenient restriction endonuclease sites, and one or more selectable markers, (e.g., WO 01/96584; WO 01/29058; and U.S. Pat. No. 6,326,193). 
     A number of viral based systems have been developed for gene transfer into mammalian cells. For example, retroviruses provide a convenient platform for gene delivery systems. A selected gene can be inserted into a vector and packaged in retroviral particles using techniques known in the art. The recombinant virus can then be isolated and delivered to cells of the subject either in vivo or ex vivo. A number of retroviral systems are known in the art. In some embodiments, adenovirus vectors are used. A number of adenovirus vectors are known in the art. In one embodiment, lentivirus vectors are used. 
     Additional promoter elements, e.g., enhancers, regulate the frequency of transcriptional initiation. Typically, these are located in the region 30-110 bp upstream of the start site, although a number of promoters have been shown to contain functional elements downstream of the start site as well. The spacing between promoter elements frequently is flexible, so that promoter function is preserved when elements are inverted or moved relative to one another. In the thymidine kinase (tk) promoter, the spacing between promoter elements can be increased to 50 bp apart before activity begins to decline. Depending on the promoter, it appears that individual elements can function either cooperatively or independently to activate transcription. Exemplary promoters include the CMV IE gene, EF-la, ubiquitin C, or phosphoglycerokinase (PGK) promoters. In an embodiment, the promoter is a PGK promoter, e.g., a truncated PGK promoter as described herein. 
     An example of a promoter that is capable of expressing a CAR transgene in a mammalian T cell is the EF1a promoter. The native EF1a promoter drives expression of the alpha subunit of the elongation factor-1 complex, which is responsible for the enzymatic delivery of aminoacyl tRNAs to the ribosome. The EF1a promoter has been extensively used in mammalian expression plasmids and has been shown to be effective in driving CAR expression from transgenes cloned into a lentiviral vector. See, e.g., Milone et al., Mol. Ther. 17(8): 1453-1464 (2009). In one aspect, the EF1a promoter comprises the sequence provided as SEQ ID NO:100. 
     Another example of a promoter is the immediate early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a strong constitutive promoter sequence capable of driving high levels of expression of any polynucleotide sequence operatively linked thereto. However, other constitutive promoter sequences may also be used, including, but not limited to the simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter, MoMuLV promoter, an avian leukemia virus promoter, an Epstein-Barr virus immediate early promoter, a Rous sarcoma virus promoter, as well as human gene promoters such as, but not limited to, the actin promoter, the myosin promoter, the elongation factor-la promoter, the hemoglobin promoter, and the creatine kinase promoter. Further, the invention should not be limited to the use of constitutive promoters. Inducible promoters are also contemplated as part of the invention. The use of an inducible promoter provides a molecular switch capable of turning on expression of the polynucleotide sequence which it is operatively linked when such expression is desired, or turning off the expression when expression is not desired. Examples of inducible promoters include, but are not limited to a metallothionine promoter, a glucocorticoid promoter, a progesterone promoter, and a tetracycline promoter. 
     Another example of a promoter is the phosphoglycerate kinase (PGK) promoter. In embodiments, a truncated PGK promoter (e.g., a PGK promoter with one or more, e.g., 1, 2, 5, 10, 100, 200, 300, or 400, nucleotide deletions when compared to the wild-type PGK promoter sequence) may be desired. The nucleotide sequences of exemplary PGK promoters are provided below. 
     WT PGK Promoter: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 1323) 
               
               
                 ACCCCTCTCTCCAGCCACTAAGCCAGTTGCTCCCTCGGCTGACGGCTGCA 
               
               
                   
               
               
                 CGCGAGGCCTCCGAACGTCTTACGCCTTGTGGCGCGCCCGTCCTTGTCCC 
               
               
                   
               
               
                 GGGTGTGATGGCGGGGTGTGGGGCGGAGGGCGTGGCGGGGAAGGGCCGGC 
               
               
                   
               
               
                 GACGAGAGCCGCGCGGGACGACTCGTCGGCGATAACCGGTGTCGGGTAGC 
               
               
                   
               
               
                 GCCAGCCGCGCGACGGTAACGAGGGACCGCGACAGGCAGACGCTCCCATG 
               
               
                   
               
               
                 ATCACTCTGCACGCCGAAGGCAAATAGTGCAGGCCGTGCGGCGCTTGGCG 
               
               
                   
               
               
                 TTCCTTGGAAGGGCTGAATCCCCGCCTCGTCCTTCGCAGCGGCCCCCCGG 
               
               
                   
               
               
                 GTGTTCCCATCGCCGCTTCTAGGCCCACTGCGACGCTTGCCTGCACTTCT 
               
               
                   
               
               
                 TACACGCTCTGGGTCCCAGCCGCGGCGACGCAAAGGGCCTTGGTGCGGGT 
               
               
                   
               
               
                 CTCGTCGGCGCAGGGACGCGTTTGGGTCCCGACGGAACCTTTTCCGCGTT 
               
               
                   
               
               
                 GGGGTTGGGGCACCATAAGCT  
               
            
           
         
       
     
     Exemplary Truncated PGK Promoters: 
     
       
         
           
               
            
               
                 PGK100: 
               
               
                 (SEQ ID NO: 1324) 
               
               
                 ACCCCTCTCTCCAGCCACTAAGCCAGTTGCTCCCTCGGCTGACGGCTGCA 
               
               
                   
               
               
                 CGCGAGGCCTCCGAACGTCTTACGCCTTGTGGCGCGCCCGTCCTTGTCCC 
               
               
                   
               
               
                 GGGTGTGATGGCGGGGTG 
               
               
                   
               
               
                 PGK200: 
               
               
                 (SEQ ID NO: 1325) 
               
               
                 ACCCCTCTCTCCAGCCACTAAGCCAGTTGCTCCCTCGGCTGACGGCTGCA 
               
               
                   
               
               
                 CGCGAGGCCTCCGAACGTCTTACGCCTTGTGGCGCGCCCGTCCTTGTCCC 
               
               
                   
               
               
                 GGGTGTGATGGCGGGGTGTGGGGCGGAGGGCGTGGCGGGGAAGGGCCGGC 
               
               
                   
               
               
                 GACGAGAGCCGCGCGGGACGACTCGTCGGCGATAACCGGTGTCGGGTAGC 
               
               
                   
               
               
                 GCCAGCCGCGCGACGGTAACG 
               
               
                   
               
               
                 PGK300: 
               
               
                 (SEQ ID NO: 1326) 
               
               
                 ACCCCTCTCTCCAGCCACTAAGCCAGTTGCTCCCTCGGCTGACGGCTGCA 
               
               
                   
               
               
                 CGCGAGGCCTCCGAACGTCTTACGCCTTGTGGCGCGCCCGTCCTTGTCCC 
               
               
                   
               
               
                 GGGTGTGATGGCGGGGTGTGGGGCGGAGGGCGTGGCGGGGAAGGGCCGGC 
               
               
                   
               
               
                 GACGAGAGCCGCGCGGGACGACTCGTCGGCGATAACCGGTGTCGGGTAGC 
               
               
                   
               
               
                 GCCAGCCGCGCGACGGTAACGAGGGACCGCGACAGGCAGACGCTCCCATG 
               
               
                   
               
               
                 ATCACTCTGCACGCCGAAGGCAAATAGTGCAGGCCGTGCGGCGCTTGGCG 
               
               
                   
               
               
                 TTCCTTGGAAGGGCTGAATCCCCG 
               
               
                   
               
               
                 PGK400: 
               
               
                 (SEQ ID NO: 1327) 
               
               
                 ACCCCTCTCTCCAGCCACTAAGCCAGTTGCTCCCTCGGCTGACGGCTGCA 
               
               
                   
               
               
                 CGCGAGGCCTCCGAACGTCTTACGCCTTGTGGCGCGCCCGTCCTTGTCCC 
               
               
                   
               
               
                 GGGTGTGATGGCGGGGTGTGGGGCGGAGGGCGTGGCGGGGAAGGGCCGGC 
               
               
                   
               
               
                 GACGAGAGCCGCGCGGGACGACTCGTCGGCGATAACCGGTGTCGGGTAGC 
               
               
                   
               
               
                 GCCAGCCGCGCGACGGTAACGAGGGACCGCGACAGGCAGACGCTCCCATG 
               
               
                   
               
               
                 ATCACTCTGCACGCCGAAGGCAAATAGTGCAGGCCGTGCGGCGCTTGGCG 
               
               
                   
               
               
                 TTCCTTGGAAGGGCTGAATCCCCGCCTCGTCCTTCGCAGCGGCCCCCCGG 
               
               
                   
               
               
                 GTGTTCCCATCGCCGCTTCTAGGCCCACTGCGACGCTTGCCTGCACTTCT 
               
               
                   
               
               
                 TACACGCTCTGGGTCCCAGCCG 
               
            
           
         
       
     
     A vector may also include, e.g., a signal sequence to facilitate secretion, a polyadenylation signal and transcription terminator (e.g., from Bovine Growth Hormone (BGH) gene), an element allowing episomal replication and replication in prokaryotes (e.g. SV40 origin and ColE1 or others known in the art) and/or elements to allow selection (e.g., ampicillin resistance gene and/or zeocin marker). 
     In order to assess the expression of a CAR polypeptide or portions thereof, the expression vector to be introduced into a cell can also contain either a selectable marker gene or a reporter gene or both to facilitate identification and selection of expressing cells from the population of cells sought to be transfected or infected through viral vectors. In other aspects, the selectable marker may be carried on a separate piece of DNA and used in a co-transfection procedure. Both selectable markers and reporter genes may be flanked with appropriate regulatory sequences to enable expression in the host cells. Useful selectable markers include, for example, antibiotic-resistance genes, such as neo and the like. 
     Reporter genes are used for identifying potentially transfected cells and for evaluating the functionality of regulatory sequences. In general, a reporter gene is a gene that is not present in or expressed by the recipient organism or tissue and that encodes a polypeptide whose expression is manifested by some easily detectable property, e.g., enzymatic activity. Expression of the reporter gene is assayed at a suitable time after the DNA has been introduced into the recipient cells. Suitable reporter genes may include genes encoding luciferase, beta-galactosidase, chloramphenicol acetyl transferase, secreted alkaline phosphatase, or the green fluorescent protein gene (e.g., Ui-Tei et al., 2000 FEBS Letters 479: 79-82). Suitable expression systems are well known and may be prepared using known techniques or obtained commercially. In general, the construct with the minimal 5′ flanking region showing the highest level of expression of reporter gene is identified as the promoter. Such promoter regions may be linked to a reporter gene and used to evaluate agents for the ability to modulate promoter-driven transcription. 
     In embodiments, the vector may comprise two or more nucleic acid sequences encoding a CAR, e.g., a first CAR that binds to CD19 and a second CAR, e.g., an inhibitory CAR or a CAR that specifically binds to a second antigen, e.g., CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. In such embodiments, the two or more nucleic acid sequences encoding the CAR are encoded by a single nucleic molecule in the same frame and as a single polypeptide chain. In this aspect, the two or more CARs, can, e.g., be separated by one or more peptide cleavage sites. (e.g., an auto-cleavage site or a substrate for an intracellular protease). Examples of peptide cleavage sites include the following, wherein the GSG residues are optional: 
     
       
         
           
               
               
            
               
                   
                 T2A: 
               
               
                   
                 (SEQ ID NO: 1328) 
               
               
                   
                 (GSG)EGRGSLLTCGDVEENPGP 
               
               
                   
                   
               
               
                   
                 P2A: 
               
               
                   
                 (SEQ ID NO: 1329) 
               
               
                   
                 (GSG)ATNFSLLKQAGDVEENPGP 
               
               
                   
                   
               
               
                   
                 E2A: 
               
               
                   
                 (SEQ ID NO: 1330) 
               
               
                   
                 (GSG)QCTNYALLKLAGDVESNPGP 
               
               
                   
                   
               
               
                   
                 F2A: 
               
               
                   
                 (SEQ ID NO: 1331) 
               
               
                   
                 (GSG)VKQTLNFDLLKLAGDVESNPGP 
               
            
           
         
       
     
     Methods of introducing and expressing genes into a cell are known in the art. In the context of an expression vector, the vector can be readily introduced into a host cell, e.g., mammalian, bacterial, yeast, or insect cell by any method in the art. For example, the expression vector can be transferred into a host cell by physical, chemical, or biological means. 
     Physical methods for introducing a polynucleotide into a host cell include calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electroporation, and the like. Methods for producing cells comprising vectors and/or exogenous nucleic acids are well-known in the art. See, for example, Sambrook et al., 2012, MOLECULAR CLONING: A LABORATORY MANUAL, volumes 1-4, Cold Spring Harbor Press, NY). A suitable method for the introduction of a polynucleotide into a host cell is calcium phosphate transfection 
     Biological methods for introducing a polynucleotide of interest into a host cell include the use of DNA and RNA vectors. Viral vectors, and especially retroviral vectors, have become the most widely used method for inserting genes into mammalian, e.g., human cells. Other viral vectors can be derived from lentivirus, poxviruses, herpes simplex virus I, adenoviruses and adeno-associated viruses, and the like. See, for example, U.S. Pat. Nos. 5,350,674 and 5,585,362. 
     Chemical means for introducing a polynucleotide into a host cell include colloidal dispersion systems, such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system for use as a delivery vehicle in vitro and in vivo is a liposome (e.g., an artificial membrane vesicle). Other methods of state-of-the-art targeted delivery of nucleic acids are available, such as delivery of polynucleotides with targeted nanoparticles or other suitable sub-micron sized delivery system. 
     In the case where a non-viral delivery system is utilized, an exemplary delivery vehicle is a liposome. The use of lipid formulations is contemplated for the introduction of the nucleic acids into a host cell (in vitro, ex vivo or in vivo). In another aspect, the nucleic acid may be associated with a lipid. The nucleic acid associated with a lipid may be encapsulated in the aqueous interior of a liposome, interspersed within the lipid bilayer of a liposome, attached to a liposome via a linking molecule that is associated with both the liposome and the oligonucleotide, entrapped in a liposome, complexed with a liposome, dispersed in a solution containing a lipid, mixed with a lipid, combined with a lipid, contained as a suspension in a lipid, contained or complexed with a micelle, or otherwise associated with a lipid. Lipid, lipid/DNA or lipid/expression vector associated compositions are not limited to any particular structure in solution. For example, they may be present in a bilayer structure, as micelles, or with a “collapsed” structure. They may also simply be interspersed in a solution, possibly forming aggregates that are not uniform in size or shape. Lipids are fatty substances which may be naturally occurring or synthetic lipids. For example, lipids include the fatty droplets that naturally occur in the cytoplasm as well as the class of compounds which contain long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, amino alcohols, and aldehydes. 
     Lipids suitable for use can be obtained from commercial sources. For example, dimyristyl phosphatidylcholine (“DMPC”) can be obtained from Sigma, St. Louis, Mo.; dicetyl phosphate (“DCP”) can be obtained from K &amp; K Laboratories (Plainview, N.Y.); cholesterol (“Choi”) can be obtained from Calbiochem-Behring; dimyristyl phosphatidylglycerol (“DMPG”) and other lipids may be obtained from Avanti Polar Lipids, Inc. (Birmingham, Ala.). Stock solutions of lipids in chloroform or chloroform/methanol can be stored at about −20° C. Chloroform is used as the only solvent since it is more readily evaporated than methanol. “Liposome” is a generic term encompassing a variety of single and multilamellar lipid vehicles formed by the generation of enclosed lipid bilayers or aggregates. Liposomes can be characterized as having vesicular structures with a phospholipid bilayer membrane and an inner aqueous medium. Multilamellar liposomes have multiple lipid layers separated by aqueous medium. They form spontaneously when phospholipids are suspended in an excess of aqueous solution. The lipid components undergo self-rearrangement before the formation of closed structures and entrap water and dissolved solutes between the lipid bilayers (Ghosh et al., 1991 Glycobiology 5: 505-10). However, compositions that have different structures in solution than the normal vesicular structure are also encompassed. For example, the lipids may assume a micellar structure or merely exist as nonuniform aggregates of lipid molecules. Also contemplated are lipofectamine-nucleic acid complexes. 
     Regardless of the method used to introduce exogenous nucleic acids into a host cell or otherwise expose a cell to the inhibitor of the present invention, in order to confirm the presence of the recombinant DNA sequence in the host cell, a variety of assays may be performed. Such assays include, for example, “molecular biological” assays well known to those of skill in the art, such as Southern and Northern blotting, RT-PCR and PCR; “biochemical” assays, such as detecting the presence or absence of a particular peptide, e.g., by immunological means (ELISAs and Western blots) or by assays described herein to identify agents falling within the scope of the invention. 
     The present invention further provides a vector comprising a CAR encoding nucleic acid molecule. In one aspect, a CAR vector can be directly transduced into a cell, e.g., a T cell. In one aspect, the vector is a cloning or expression vector, e.g., a vector including, but not limited to, one or more plasmids (e.g., expression plasmids, cloning vectors, minicircles, minivectors, double minute chromosomes), retroviral and lentiviral vector constructs. In one aspect, the vector is capable of expressing the CAR construct in mammalian T cells. In one aspect, the mammalian T cell is a human T cell. 
     Immune Effector Cells Expressing a CAR 
     In another aspect, the present invention provides a population of CAR-expressing cells. In some embodiments, the population of CAR-expressing cells comprises a cell that expresses one or more CARs described herein. In some embodiments, the population of CAR-expressing cells comprises a mixture of cells expressing different CARs. 
     For example, in one embodiment, the population of CART cells can include a first cell expressing a CAR having an antigen binding domain to a tumor antigen described herein, e.g., CD19, and a second cell expressing a CAR having a different antigen binding domain, e.g., an antigen binding domain to a different tumor antigen described herein, e.g., an antigen binding domain to a tumor antigen described herein that differs from the tumor antigen bound by the antigen binding domain of the CAR expressed by the first cell, e.g., CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. 
     As another example, the population of CAR-expressing cells can include a first cell expressing a CAR that includes an antigen binding domain to a tumor antigen described herein, and a second cell expressing a CAR that includes an antigen binding domain to a target other than a tumor antigen as described herein. In one embodiment, the population of CAR-expressing cells includes, e.g., a first cell expressing a CAR that includes a primary intracellular signaling domain, and a second cell expressing a CAR that includes a secondary signaling domain. Either one or both of the CAR expressing cells can have a truncated PGK promoter, e.g., as described herein, operably linked to the nucleic acid encoding the CAR. 
     In another aspect, the present invention provides a population of cells wherein at least one cell in the population expresses a CAR having an antigen binding domain to a tumor antigen described herein, and a second cell expressing another agent, e.g., an agent which enhances the activity of a CAR-expressing cell. The CAR expressing cells of the population can have a truncated PGK promoter, e.g., as described herein, operably linked to the nucleic acid encoding the CAR. In one embodiment, the agent can be an agent which inhibits an inhibitory molecule. Inhibitory molecules, e.g., PD-1, can, in some embodiments, decrease the ability of a CAR-expressing cell to mount an immune effector response. Examples of inhibitory molecules include PD-1, PD-L1, PD-L2, CTLA4, TIM3, CEACAM (CEACAM-1, CEACAM-3, and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GAL9, adenosine, and TGF (e.g., TGF beta). In one embodiment, the agent which inhibits an inhibitory molecule comprises a first polypeptide, e.g., an inhibitory molecule, associated with a second polypeptide that provides a positive signal to the cell, e.g., an intracellular signaling domain described herein. In one embodiment, the agent comprises a first polypeptide, e.g., of an inhibitory molecule such as PD1, PD-L1, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3, and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGF beta, or a fragment of any of these, and a second polypeptide which is an intracellular signaling domain described herein (e.g., comprising a costimulatory domain (e.g., 41BB, CD27, OX40 or CD28, e.g., as described herein) and/or a primary signaling domain (e.g., a CD3 zeta signaling domain described herein). In one embodiment, the agent comprises a first polypeptide of PD-1 or a fragment thereof, and a second polypeptide of an intracellular signaling domain described herein (e.g., a CD28 signaling domain described herein and/or a CD3 zeta signaling domain described herein). 
     Co-expression of CAR with Other Molecules or Agents 
     Co-expression of a Second CAR 
     In one aspect, the CAR-expressing cell described herein can further comprise a second CAR, e.g., a second CAR that includes a different antigen binding domain, e.g., to the same target (CD19) or a different target (e.g., CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a). In one embodiment, the second CAR includes an antigen binding domain to a target expressed on acute myeloid leukemia cells, such as, e.g., CD20, CD22, ROR1, CD10, CD33, CLL-1, CD34, CD123, FLT3, CD79b, CD179b, and CD79a. In one embodiment, the CAR-expressing cell comprises a first CAR that targets a first antigen and includes an intracellular signaling domain having a costimulatory signaling domain but not a primary signaling domain, and a second CAR that targets a second, different, antigen and includes an intracellular signaling domain having a primary signaling domain but not a costimulatory signaling domain. While not wishing to be bound by theory, placement of a costimulatory signaling domain, e.g., 4-1BB, CD28, CD27 or OX-40, onto the first CAR, and the primary signaling domain, e.g., CD3 zeta, on the second CAR can limit the CAR activity to cells where both targets are expressed. In one embodiment, the CAR expressing cell comprises a first CD19 CAR that includes a CD19 binding domain, a transmembrane domain and a costimulatory domain and a second CAR that targets an antigen other than CD19 (e.g., an antigen expressed on AML cells, e.g., CD22, CD20, ROR1, CD10, CD33, CLL-1, CD34, CD123, FLT3, CD79b, CD179b, or CD79a) and includes an antigen binding domain, a transmembrane domain and a primary signaling domain. In another embodiment, the CAR expressing cell comprises a first CD19 CAR that includes a CD19 binding domain, a transmembrane domain and a primary signaling domain and a second CAR that targets an antigen other than CD19 (e.g., an antigen expressed on AML cells, e.g., CD22, CD20, ROR1, CD10, CD33, CD123, CLL-1, CD34, FLT3, CD79b, CD179b, or CD79a) and includes an antigen binding domain to the antigen, a transmembrane domain and a costimulatory signaling domain. 
     In one aspect, the CAR-expressing cell described herein can further comprise a second CAR, e.g., a second CAR that includes a different antigen binding domain, e.g., to the same target (e.g., CD19) or a different target (e.g., a target other than CD19, e.g., CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a). In one embodiment, the CAR-expressing cell comprises a first CAR that targets a first antigen and includes an intracellular signaling domain having a costimulatory signaling domain but not a primary signaling domain, and a second CAR that targets a second, different, antigen and includes an intracellular signaling domain having a primary signaling domain but not a costimulatory signaling domain. Placement of a costimulatory signaling domain, e.g., 4-1BB, CD28, CD27, OX-40 or ICOS, onto the first CAR, and the primary signaling domain, e.g., CD3 zeta, on the second CAR can limit the CAR activity to cells where both targets are expressed. In one embodiment, the CAR expressing cell comprises a first CAR that includes an antigen binding domain, a transmembrane domain and a costimulatory domain and a second CAR that targets another antigen and includes an antigen binding domain, a transmembrane domain and a primary signaling domain. In another embodiment, the CAR expressing cell comprises a first CAR that includes an antigen binding domain, a transmembrane domain and a primary signaling domain and a second CAR that targets another antigen and includes an antigen binding domain to the antigen, a transmembrane domain and a costimulatory signaling domain. 
     In one embodiment, the CAR-expressing cell comprises an XCAR described herein (e.g., CD19 CAR, CD20 CAR, or CD22 CAR) and an inhibitory CAR. In one embodiment, the CAR-expressing cell comprises a CD19 CAR described herein and an inhibitory CAR. In one embodiment, the inhibitory CAR comprises an antigen binding domain that binds an antigen found on normal cells but not cancer cells, e.g., normal cells that also express CD19. In one embodiment, the inhibitory CAR comprises the antigen binding domain, a transmembrane domain and an intracellular domain of an inhibitory molecule. For example, the intracellular domain of the inhibitory CAR can be an intracellular domain PD-1, PD-L1, PD-L2, CTLA4, TIM3, CEACAM (CEACAM-1, CEACAM-3, and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GAL9, adenosine, and TGF (e.g., TGF beta). 
     In one embodiment, when the CAR-expressing cell comprises two or more different CARs, the antigen binding domains of the different CARs can be such that the antigen binding domains do not interact with one another. For example, a cell expressing a first and second CAR can have an antigen binding domain of the first CAR, e.g., as a fragment, e.g., an scFv, that does not form an association with the antigen binding domain of the second CAR, e.g., the antigen binding domain of the second CAR is a VHH. 
     Co-Expression of an Agent that Enhances CAR Activity 
     In another aspect, the CAR-expressing cell described herein can further express another agent, e.g., an agent that enhances the activity or fitness of a CAR-expressing cell. 
     For example, in one embodiment, the agent can be an agent which inhibits a molecule that modulates or regulates, e.g., inhibits, T cell function. In some embodiments, the molecule that modulates or regulates T cell function is an inhibitory molecule. Inhibitory molecules, e.g., PD1, can, in some embodiments, decrease the ability of a CAR-expressing cell to mount an immune effector response. Examples of inhibitory molecules include PD1, PD-L1, PD-L2, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GAL9, adenosine, and TGF (e.g., TGF beta). 
     In one embodiment, an inhibitory nucleic acid, e.g., an inhibitory nucleic acid, e.g., a dsRNA, e.g., an siRNA or shRNA, a clustered regularly interspaced short palindromic repeats (CRISPR), a transcription-activator like effector nuclease (TALEN), or a zinc finger endonuclease (ZFN), e.g., as described herein, can be used to inhibit expression of a molecule that modulates or regulates, e.g., inhibits, T-cell function in the CAR-expressing cell. In an embodiment the agent is an shRNA, e.g., an shRNA described herein. In an embodiment, the agent that modulates or regulates, e.g., inhibits, T-cell function is inhibited within a CAR-expressing cell. For example, a dsRNA molecule that inhibits expression of a molecule that modulates or regulates, e.g., inhibits, T-cell function is linked to the nucleic acid that encodes a component, e.g., all of the components, of the CAR. 
     In one embodiment, the agent which inhibits an inhibitory molecule comprises a first polypeptide, e.g., an inhibitory molecule, associated with a second polypeptide that provides a positive signal to the cell, e.g., an intracellular signaling domain described herein. In one embodiment, the agent comprises a first polypeptide, e.g., of an inhibitory molecule such as PD1, PD-L1, PD-L2, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GAL9, adenosine, or TGF (e.g., TGF beta), or a fragment of any of these (e.g., at least a portion of an extracellular domain of any of these), and a second polypeptide which is an intracellular signaling domain described herein (e.g., comprising a costimulatory domain (e.g., 41BB, CD27 or CD28, e.g., as described herein) and/or a primary signaling domain (e.g., a CD3 zeta signaling domain described herein). In one embodiment, the agent comprises a first polypeptide of PD1 or a fragment thereof (e.g., at least a portion of an extracellular domain of PD1), and a second polypeptide of an intracellular signaling domain described herein (e.g., a CD28 signaling domain described herein and/or a CD3 zeta signaling domain described herein). PD1 is an inhibitory member of the CD28 family of receptors that also includes CD28, CTLA-4, ICOS, and BTLA. PD-1 is expressed on activated B cells, T cells and myeloid cells (Agata et al. 1996 Int. Immunol 8:765-75). Two ligands for PD1, PD-L1 and PD-L2 have been shown to downregulate T cell activation upon binding to PD1 (Freeman et a. 2000 J Exp Med 192:1027-34; Latchman et al. 2001 Nat Immunol 2:261-8; Carter et al. 2002 Eur J Immunol 32:634-43). PD-L1 is abundant in human cancers (Dong et al. 2003 J Mol Med 81:281-7; Blank et al. 2005 Cancer Immunol. Immunother 54:307-314; Konishi et al. 2004 Clin Cancer Res 10:5094). Immune suppression can be reversed by inhibiting the local interaction of PD1 with PD-L1. 
     In one embodiment, the agent comprises the extracellular domain (ECD) of an inhibitory molecule, e.g., Programmed Death 1 (PD1), can be fused to a transmembrane domain and intracellular signaling domains such as 41BB and CD3 zeta (also referred to herein as a PD1 CAR). In one embodiment, the PD1 CAR, when used in combinations with a CD19 CAR described herein, improves the persistence of the T cell. In one embodiment, the CAR is a PD1 CAR comprising the extracellular domain of PD1 indicated as underlined in SEQ ID NO: 121. In one embodiment, the PD1 CAR comprises the amino acid sequence of SEQ ID NO:121. 
     
       
         
           
               
            
               
                 (SEQ ID NO: 121) 
               
               
                 Malpvtalllplalllhaarp pgwfldspdrpwnpptfspallvvtegd   
               
               
                   
               
               
                 
                   natftcsfsntsesfvlnwyrmspsnqtdklaafpedrsqpgqdcrfrv 
                 
               
               
                   
               
               
                 
                   tqlpngrdfhmsvvrarrndsgtylcgaislapkaqikeslraelrvte 
                 
               
               
                   
               
               
                   rraevptahpspsprpagqfqtlv tttpaprpptpaptiasqplslrpe 
               
               
                   
               
               
                 acrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrk 
               
               
                   
               
               
                 kllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapa 
               
               
                   
               
               
                 ykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglyne 
               
               
                   
               
               
                 lqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalp 
               
               
                   
               
               
                 pr. 
               
            
           
         
       
     
     In one embodiment, the PD1 CAR comprises the amino acid sequence provided below (SEQ ID NO:119). 
     
       
         
           
               
            
               
                 (SEQ ID NO: 119) 
               
               
                 pgwfldspdrpwnpptfspallvvtegdnatftcsfsntsesfvlnwyr 
               
               
                   
               
               
                 mspsnqtdklaafpedrsqpgqdcrfrvtqlpngrdfhmsvvrarrnds 
               
               
                   
               
               
                 gtylcgaislapkaqikeslraelrvterraevptahpspsprpagqfq 
               
               
                   
               
               
                 tlvtttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdi 
               
               
                   
               
               
                 yiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeed 
               
               
                   
               
               
                 gcscrfpeeeeggcelrvkfsrsadapaykqgqnqlynelnlgrreeyd 
               
               
                   
               
               
                 vldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrr 
               
               
                   
               
               
                 gkghdglyqglstatkdtydalhmqalppr. 
               
            
           
         
       
     
     Tin one embodiment, the agent comprises a nucleic acid sequence encoding the PD1 CAR, e.g., the PD1 CAR described herein. In one embodiment, the nucleic acid sequence for the PD1 CAR is shown below, with the PD1 ECD underlined below in SEQ ID NO: 120 
     
       
         
           
               
            
               
                 (SEQ ID NO: 120) 
               
               
                 atggccctccctgtcactgccctgcttctccccctcgcactcctgctcca 
               
               
                   
               
               
                 cgccgctagacca cccggatggtttctggactctccggatcgcccgtgga   
               
               
                   
               
               
                 
                   atcccccaaccttctcaccggcactcttggttgtgactgagggcgataat 
                 
               
               
                   
               
               
                 
                   gcgaccttcacgtgctcgttctccaacacctccgaatcattcgtgctgaa 
                 
               
               
                   
               
               
                 
                   ctggtaccgcatgagcccgtcaaaccagaccgacaagctcgccgcgtttc 
                 
               
               
                   
               
               
                 
                   cggaagatcggtcgcaaccgggacaggattgtcggttccgcgtgactcaa 
                 
               
               
                   
               
               
                 ctgccgaatggcagagacttccacatgagcgtggtccgcgctaggcgaaa 
               
               
                   
               
               
                 
                   cgactccgggacctacctgtgcggagccatctcgctggcgcctaaggccc 
                 
               
               
                   
               
               
                 
                   aaatcaaagagagcttgagggccgaactgagagtgaccgagcgcagagct 
                 
               
               
                   
               
               
                 
                   gaggtgccaactgcacatccatccccatcgcctcggcctgcggggcagtt 
                 
               
               
                   
               
               
                   tcagaccctggtc acgaccactccggcgccgcgcccaccgactccggccc 
               
               
                   
               
               
                 caactatcgcgagccagcccctgtcgctgaggccggaagcatgccgccct 
               
               
                   
               
               
                 gccgccggaggtgctgtgcatacccggggattggacttcgcatgcgacat 
               
               
                   
               
               
                 ctacatttgggctcctctcgccggaacttgtggcgtgctccttctgtccc 
               
               
                   
               
               
                 tggtcatcaccctgtactgcaagcggggtcggaaaaagcttctgtacatt 
               
               
                   
               
               
                 ttcaagcagcccttcatgaggcccgtgcaaaccacccaggaggaggacgg 
               
               
                   
               
               
                 ttgctcctgccggttccccgaagaggaagaaggaggttgcgagctgcgcg 
               
               
                   
               
               
                 tgaagttctcccggagcgccgacgcccccgcctataagcagggccagaac 
               
               
                   
               
               
                 cagctgtacaacgaactgaacctgggacggcgggaagagtacgatgtgct 
               
               
                   
               
               
                 ggacaagcggcgcggccgggaccccgaaatgggcgggaagcctagaagaa 
               
               
                   
               
               
                 agaaccctcaggaaggcctgtataacgagctgcagaaggacaagatggcc 
               
               
                   
               
               
                 gaggcctactccgaaattgggatgaagggagagcggcggaggggaaaggg 
               
               
                   
               
               
                 gcacgacggcctgtaccaaggactgtccaccgccaccaaggacacatacg 
               
               
                   
               
               
                 atgccctgcacatgcaggcccttccccctcgc. 
               
            
           
         
       
     
     In another example, in one embodiment, the agent which enhances the activity of a CAR-expressing cell can be a costimulatory molecule or costimulatory molecule ligand. Examples of costimulatory molecules include MHC class I molecule, BTLA and a Toll ligand receptor, as well as OX40, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), and 4-1BB (CD137). Further examples of such costimulatory molecules include CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD160, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, and a ligand that specifically binds with CD83., e.g., as described herein. Examples of costimulatory molecule ligands include CD80, CD86, CD40L, ICOSL, CD70, OX40L, 4-1BBL, GITRL, and LIGHT. In embodiments, the costimulatory molecule ligand is a ligand for a costimulatory molecule different from the costimulatory molecule domain of the CAR. In embodiments, the costimulatory molecule ligand is a ligand for a costimulatory molecule that is the same as the costimulatory molecule domain of the CAR. In an embodiment, the costimulatory molecule ligand is 4-1BBL. In an embodiment, the costimulatory ligand is CD80 or CD86. In an embodiment, the costimulatory molecule ligand is CD70. In embodiments, a CAR-expressing immune effector cell described herein can be further engineered to express one or more additional costimulatory molecules or costimulatory molecule ligands. 
     Co-Expression of CAR with a Chemokine Receptor 
     In embodiments, the CAR-expressing cell described herein further comprises a chemokine receptor molecule. Transgenic expression of chemokine receptors CCR2b or CXCR2 in T cells enhances trafficking to CCL2- or CXCL1-secreting solid tumors including melanoma and neuroblastoma (Craddock et al.,  J Immunother.  2010 October; 33(8):780-8 and Kershaw et al., Hum Gene Ther. 2002 Nov. 1; 13(16):1971-80). Thus, without wishing to be bound by theory, it is believed that chemokine receptors expressed in CAR-expressing cells that recognize chemokines secreted by tumors, e.g., solid tumors, can improve homing of the CAR-expressing cell to the tumor, facilitate the infiltration of the CAR-expressing cell to the tumor, and enhances antitumor efficacy of the CAR-expressing cell. The chemokine receptor molecule can comprise a naturally occurring or recombinant chemokine receptor or a chemokine-binding fragment thereof. A chemokine receptor molecule suitable for expression in a CAR-expressing cell described herein include a CXC chemokine receptor (e.g., CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, or CXCR7), a CC chemokine receptor (e.g., CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, or CCR11), a CX3C chemokine receptor (e.g., CX3CR1), a XC chemokine receptor (e.g., XCR1), or a chemokine-binding fragment thereof. In one embodiment, the chemokine receptor molecule to be expressed with a CAR described herein is selected based on the chemokine(s) secreted by the tumor. In one embodiment, the CAR-expressing cell described herein further comprises, e.g., expresses, a CCR2b receptor or a CXCR2 receptor. In an embodiment, the CAR described herein and the chemokine receptor molecule are on the same vector or are on two different vectors. In embodiments where the CAR described herein and the chemokine receptor molecule are on the same vector, the CAR and the chemokine receptor molecule are each under control of two different promoters or are under the control of the same promoter. 
     Conditional Expression of Immune Response-Enhancing Agents 
     Also provided herein are compositions and methods for conditionally expressing an agent that enhances the immune response or activity of a CAR-expressing cell described herein. 
     In one aspect, the present disclosure features an immune effector cell that is engineered to constitutively express a CAR, also referred to herein as a nonconditional CAR. In one embodiment, a nonconditional CAR as described herein comprises an antigen binding domain that binds to a cancer associated antigen, e.g., CD19, CD10, CD20, CD22, CD34, CD123, FLT-3, or ROR1. In embodiments, the nonconditional CAR-expressing immune effector cell further comprises a conditionally-expressed agent that enhances the therapeutic efficacy, e.g., the immune response, of the CAR-expressing immune effector cell. In such embodiments, the expression of the conditionally expressed agent occurs upon activation of the nonconditional CAR-expressing immune effector cell, e.g., upon binding of the nonconditional CAR molecule to its target, e.g., a cancer associated antigen, e.g., CD19, CD10, CD20, CD22, CD34, CD123, FLT-3, or ROR1. 
     Immune response-enhancing agents as described herein can be characterized by one or more of the following: 1) targets or binds to a different cancer associated antigen than that targeted by the nonconditional CAR; 2) inhibits the expression or activity of an immune checkpoint or inhibitory molecule; and/or 3) activates the expression and/or secretion of a component that enhances immune response or activation of an immune effector cell. The immune response-enhancing agent can be a polypeptide or a nucleic acid, e.g., a nucleic acid that encodes a polypeptide that enhances immune response. Examples of conditionally expressed agents that enhance the immune response include, but are not limited to, an additional CAR (referred to as a conditional CAR); a TCR-based molecule (e.g., a TCR-CAR); an inhibitor of an immune checkpoint or an inhibitory molecule; and/or a cytokine. In embodiments, the conditional CAR binds to a different cancer associated antigen than that targeted by the nonconditional CAR. In embodiments, the inhibitor of an immune checkpoint or inhibitory molecule described herein is an antibody or antigen binding fragment thereof, an inhibitory nucleic acid (e.g., an siRNA or shRNA), or a small molecule that inhibits or decreases the activity of an immune checkpoint or inhibitory molecule selected from PD1, PD-L1, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GAL9, adenosine, or TGF beta. In embodiments, the cytokine comprises IL-2, IL-7, IL-15, or IL-21, or functional fragments or derivatives thereof. 
     In embodiments, the immune effector cell comprises a nonconditional CAR and one or more conditional CARs, where the conditional CAR binds to a different cancer associated antigen than that targeted by the nonconditional CAR. By way of example, in one embodiment, an immune effector cell comprises a nonconditional CAR that binds to CD19 and one or more conditional CARs that bind to CD10, CD20, CD22, CD34, CD123, FLT-3, or ROR1, or a combination thereof. In another embodiment, an immune effector cell comprises a nonconditional CAR that binds to CD10, CD20, CD22, CD34, CD123, FLT-3, or ROR1 and a conditional CAR that binds to CD19. 
     Conditional expression of the agent that enhances the immune response upon activation of the CAR-expressing immune effector cell is achieved by operatively linking an activation-conditional control region to the agent that enhances the immune response (e.g., to a nucleic acid sequence encoding such an agent). In one embodiment, the activation conditional control region comprises a promoter sequence that initiates expression, e.g., transcription, of the operatively linked immune response enhancing agent upon activation of the immune effector cell. In one embodiment, the activation conditional control region comprises one or more regulatory sequences (e.g., a transcription factor binding sequence or site) that facilitate the initiation of expression upon activation of the immune effector cell. In embodiments, the activation-conditional control region comprises a promoter sequence and/or one or more transcription factor binding sequences from a promoter or regulatory sequence of a gene that is upregulated upon one or more of the following: immune effector cell (e.g., T cell) activation, T-cell differentiation, T-cell polarization, or helper T cell development. Examples of such genes include, but are not limited to, NFAT (nuclear factor of activated T cells), ATF2 (activating transcription factor 2), NF-κB (nuclear factor-κB), IL-2, IL-2 receptor (IL-2R), IL-3, GM-CSF, IL-4, IL-10, and IFN-7. 
     In one embodiment, the activation-conditional control region comprises one or more, e.g., 1, 2, 3, 4, 5, 6, or more, NFAT binding sequences or sites. In embodiments, the NFAT-binding sequence in the promoter comprises (5′-GGAAA-3′) (SEQ ID NO: 1312), optionally situated in a longer consensus sequence of 5′ (A/T)GGAAA(A/N)(A/T/C)N 3′ (SEQ ID NO: 1313). In embodiments, the NFAT-binding sequence is a xb-like sequence such as GGGACT (SEQ ID NO: 1314). (See, Gibson et al., The Journal of Immunology, 2007, 179: 3831-3840.) 
     In one embodiment, the activation-conditional control region further comprises an IL-2 promoter (or a minimal IL-2 promoter), an IL-2R promoter, an ATF2 promoter, or a NF-κB promoter, or any functional fragment or derivative thereof. In one embodiment, the activation-conditional control region comprises one or more NFAT-binding sequences, e.g., 3 or 6 NFAT-binding sequences, and an IL-2 promoter, e.g., an IL-2 minimal promoter. In one embodiment, the activation-conditional control region comprises the sequence of 
     
       
         
           
               
            
               
                 (SEQ ID NO: 1315) 
               
               
                 AGCTTGGATCCAAGAGGAAAATTTGTTTCATACAGAAGGCGTTAAGAGGA 
               
               
                 AAATTTGTTTCATACAGAAGGCGTTAAGAGGAAAATTTGTTTCATACAGA 
               
               
                 AGGCGTTCAAGCTTGTCGAC. 
               
            
           
         
       
     
     Sources of Cells 
     Prior to expansion and genetic modification or other modification, a source of cells, e.g., T cells or natural killer (NK) cells, can be obtained from a subject. Examples of subjects include humans, monkeys, chimpanzees, dogs, cats, mice, rats, and transgenic species thereof. T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. 
     In embodiments, immune effector cells (e.g., a population of immune effector cells), e.g., T cells, are derived from (e.g., differentiated from) a stem cell, e.g., an embryonic stem cell or a pluripotent stem cell, e.g., an induced pluripotent stem cell (iPSC). In embodiments, the cells are autologous or allogeneic. In embodiments wherein the cells are allogeneic, the cells, e.g., derived from stem cells (e.g., iPSCs), are modified to reduce their alloreactivity. For example, the cells can be modified to reduce alloreactivity, e.g., by modifying (e.g., disrupting) their T cell receptor. In embodiments, a site specific nuclease can be used to disrupt the T cell receptor, e.g., after T-cell differentiation. In other examples, cells, e.g., T cells derived from iPSCs, can be generated from virus-specific T cells, which are less likely to cause graft-versus-host disease because of their recognition of a pathogen-derived antigen. In yet other examples, alloreactivity can be reduced, e.g., minimized, by generating iPSCs from common HLA haplotypes such that they are histocompatible with matched, unrelated recipient subjects. In yet other examples, alloreactivity can be reduced, e.g., minimized, by repressing HLA expression through genetic modification. For example, T cells derived from iPSCs can be processed as described in, e.g., Themeli et al.  Nat. Biotechnol.  31.10(2013):928-35, incorporated herein by reference. In some examples, immune effector cells, e.g., T cells, derived from stem cells, can be processed/generated using methods described in WO2014/165707, incorporated herein by reference. 
     In certain aspects of the present disclosure, immune effector cells, e.g., T cells, can be obtained from a unit of blood collected from a subject using any number of techniques known to the skilled artisan, such as Ficoll™ separation. In one aspect, cells from the circulating blood of an individual are obtained by apheresis. The apheresis product typically contains lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and platelets. In one aspect, the cells collected by apheresis may be washed to remove the plasma fraction and, optionally, to place the cells in an appropriate buffer or media for subsequent processing steps. In one embodiment, the cells are washed with phosphate buffered saline (PBS). In an alternative embodiment, the wash solution lacks calcium and may lack magnesium or may lack many if not all divalent cations. 
     Initial activation steps in the absence of calcium can lead to magnified activation. As those of ordinary skill in the art would readily appreciate a washing step may be accomplished by methods known to those in the art, such as by using a semi-automated “flow-through” centrifuge (for example, the Cobe 2991 cell processor, the Baxter CytoMate, or the Haemonetics Cell Saver 5) according to the manufacturer&#39;s instructions. After washing, the cells may be resuspended in a variety of biocompatible buffers, such as, for example, Ca-free, Mg-free PBS, PlasmaLyte A, or other saline solution with or without buffer. Alternatively, the undesirable components of the apheresis sample may be removed and the cells directly resuspended in culture media. 
     It is recognized that the methods of the application can utilize culture media conditions comprising 5% or less, for example 2%, human AB serum, and employ known culture media conditions and compositions, for example those described in Smith et al., “Ex vivo expansion of human T cells for adoptive immunotherapy using the novel Xeno-free CTS Immune Cell Serum Replacement” Clinical &amp; Translational Immunology (2015) 4, e31; doi:10.1038/cti.2014.31. In one aspect, T cells are isolated from peripheral blood lymphocytes by lysing the red blood cells and depleting the monocytes, for example, by centrifugation through a PERCOLL™ gradient or by counterflow centrifugal elutriation. 
     The methods described herein can include, e.g., selection of a specific subpopulation of immune effector cells, e.g., T cells, that are a T regulatory cell-depleted population, CD25+ depleted cells, using, e.g., a negative selection technique, e.g., described herein. In some embodiments, the population of T regulatory depleted cells contains less than 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% of CD25+ cells. 
     In one embodiment, T regulatory cells, e.g., CD25+ T cells, are removed from the population using an anti-CD25 antibody, or fragment thereof, or a CD25-binding ligand, IL-2. In one embodiment, the anti-CD25 antibody, or fragment thereof, or CD25-binding ligand is conjugated to a substrate, e.g., a bead, or is otherwise coated on a substrate, e.g., a bead. In one embodiment, the anti-CD25 antibody, or fragment thereof, is conjugated to a substrate as described herein. 
     In one embodiment, the T regulatory cells, e.g., CD25+ T cells, are removed from the population using CD25 depletion reagent from Miltenyi™. In one embodiment, the ratio of cells to CD25 depletion reagent is 1e7 cells to 20 uL, or 1e7 cells to 15 uL, or 1e7 cells to 10 uL, or 1e7 cells to 5 uL, or 1e7 cells to 2.5 uL, or 1e7 cells to 1.25 uL. In one embodiment, e.g., for T regulatory cells, e.g., CD25+ depletion, greater than 500 million cells/ml is used. In a further aspect, a concentration of cells of 600, 700, 800, or 900 million cells/ml is used. 
     In one embodiment, the population of immune effector cells to be depleted includes about 6×10 9  CD25+ T cells. In other aspects, the population of immune effector cells to be depleted include about 1×10 9  to 1×10 10  CD25+ T cell, and any integer value in between. In one embodiment, the resulting population T regulatory depleted cells has 2×10 9  T regulatory cells, e.g., CD25+ cells, or less (e.g., 1×10 9 , 5×10 8 , 1×10 8 , 5×10 7 , 1×10 7 , or less CD25+ cells). 
     In one embodiment, the T regulatory cells, e.g., CD25+ cells, are removed from the population using the CliniMAC system with a depletion tubing set, such as, e.g., tubing 162-01. In one embodiment, the CliniMAC system is run on a depletion setting such as, e.g., DEPLETION2.1. 
     Without wishing to be bound by a particular theory, decreasing the level of negative regulators of immune cells (e.g., decreasing the number of unwanted immune cells, e.g., T REG  cells), in a subject prior to apheresis or during manufacturing of a CAR-expressing cell product significantly reduces the risk of subject relapse. For example, methods of depleting T REG  cells are known in the art. Methods of decreasing T REG  cells include, but are not limited to, cyclophosphamide, anti-GITR antibody (an anti-GITR antibody described herein), CD25-depletion, mTOR inhibitor, and combinations thereof. 
     In some embodiments, the manufacturing methods comprise reducing the number of (e.g., depleting) T REG  cells prior to manufacturing of the CAR-expressing cell. For example, manufacturing methods comprise contacting the sample, e.g., the apheresis sample, with an anti-GITR antibody and/or an anti-CD25 antibody (or fragment thereof, or a CD25-binding ligand), e.g., to deplete T REG  cells prior to manufacturing of the CAR-expressing cell (e.g., T cell, NK cell) product. 
     Without wishing to be bound by a particular theory, decreasing the level of negative regulators of immune cells (e.g., decreasing the number of unwanted immune cells, e.g., T REG  cells), in a subject prior to apheresis or during manufacturing of a CAR-expressing cell product can reduce the risk of a T REG  relapse. In an embodiment, a subject is pre-treated with one or more therapies that reduce TREG cells prior to collection of cells for CAR-expressing cell product manufacturing, thereby reducing the risk of subject relapse to CAR-expressing cell treatment. In an embodiment, methods of decreasing T REG  cells include, but are not limited to, administration to the subject of one or more of cyclophosphamide, anti-GITR antibody, CD25-depletion, or a combination thereof. In an embodiment, methods of decreasing T REG  cells include, but are not limited to, administration to the subject of one or more of cyclophosphamide, anti-GITR antibody, CD25-depletion, mTOR inhibitor, or a combination thereof. Administration of one or more of cyclophosphamide, anti-GITR antibody, CD25-depletion, or a combination thereof, can occur before, during or after an infusion of the CAR-expressing cell product. Administration of one or more of cyclophosphamide, anti-GITR antibody, CD25-depletion, mTOR inhibitor, or a combination thereof, can occur before, during or after an infusion of the CAR-expressing cell product. 
     In some embodiments, the manufacturing methods comprise reducing the number of (e.g., depleting) T REG  cells prior to manufacturing of the CAR-expressing cell. For example, manufacturing methods comprise contacting the sample, e.g., the apheresis sample, with an anti-GITR antibody and/or an anti-CD25 antibody (or fragment thereof, or a CD25-binding ligand), e.g., to deplete T REG  cells prior to manufacturing of the CAR-expressing cell (e.g., T cell, NK cell) product. 
     In an embodiment, a subject is pre-treated with one or more therapies that reduce T RE G cells prior to collection of cells for CAR-expressing cell product manufacturing, thereby reducing the risk of subject relapse to CAR-expressing cell treatment. In an embodiment, methods of decreasing T REG  cells include, but are not limited to, administration to the subject of one or more of cyclophosphamide, anti-GITR antibody, CD25-depletion, or a combination thereof. Administration of one or more of cyclophosphamide, anti-GITR antibody, CD25-depletion, or a combination thereof, can occur before, during or after an infusion of the CAR-expressing cell product. 
     In an embodiment, a subject is pre-treated with cyclophosphamide prior to collection of cells for CAR-expressing cell product manufacturing, thereby reducing the risk of subject relapse to CAR-expressing cell treatment. In an embodiment, a subject is pre-treated with an anti-GITR antibody prior to collection of cells for CAR-expressing cell product manufacturing, thereby reducing the risk of subject relapse to CAR-expressing cell treatment. 
     In one embodiment, the population of cells to be removed are neither the regulatory T cells or tumor cells, but cells that otherwise negatively affect the expansion and/or function of CART cells, e.g. cells expressing CD14, CD11b, CD33, CD15, or other markers expressed by potentially immune suppressive cells. In one embodiment, such cells are envisioned to be removed concurrently with regulatory T cells and/or tumor cells, or following said depletion, or in another order. 
     The methods described herein can include more than one selection step, e.g., more than one depletion step. Enrichment of a T cell population by negative selection can be accomplished, e.g., with a combination of antibodies directed to surface markers unique to the negatively selected cells. One method is cell sorting and/or selection via negative magnetic immunoadherence or flow cytometry that uses a cocktail of monoclonal antibodies directed to cell surface markers present on the cells negatively selected. For example, to enrich for CD4+ cells by negative selection, a monoclonal antibody cocktail can include antibodies to CD14, CD20, CD11b, CD16, HLA-DR, and CD8. 
     The methods described herein can further include removing cells from the population which express a tumor antigen, e.g., a tumor antigen that does not comprise CD25, e.g., CD19, CD30, CD38, CD123, CD20, CD14 or CD11b, to thereby provide a population of T regulatory depleted, e.g., CD25+ depleted, and tumor antigen depleted cells that are suitable for expression of a CAR, e.g., a CAR described herein. In one embodiment, tumor antigen expressing cells are removed simultaneously with the T regulatory, e.g., CD25+ cells. For example, an anti-CD25 antibody, or fragment thereof, and an anti-tumor antigen antibody, or fragment thereof, can be attached to the same substrate, e.g., bead, which can be used to remove the cells or an anti-CD25 antibody, or fragment thereof, or the anti-tumor antigen antibody, or fragment thereof, can be attached to separate beads, a mixture of which can be used to remove the cells. In other embodiments, the removal of T regulatory cells, e.g., CD25+ cells, and the removal of the tumor antigen expressing cells is sequential, and can occur, e.g., in either order. 
     Also provided are methods that include removing cells from the population which express a check point inhibitor, e.g., a check point inhibitor described herein, e.g., one or more of PD1+ cells, LAG3+ cells, and TIM3+ cells, to thereby provide a population of T regulatory depleted, e.g., CD25+ depleted cells, and check point inhibitor depleted cells, e.g., PD1+, LAG3+ and/or TIM3+ depleted cells. Exemplary check point inhibitors include PD1, PD-L1, PD-L2, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GAL9, adenosine, and TGF (e.g., TGF beta), e.g., as described herein. In one embodiment, check point inhibitor expressing cells are removed simultaneously with the T regulatory, e.g., CD25+ cells. For example, an anti-CD25 antibody, or fragment thereof, and an anti-check point inhibitor antibody, or fragment thereof, can be attached to the same bead which can be used to remove the cells, or an anti-CD25 antibody, or fragment thereof, and the anti-check point inhibitor antibody, or fragment thereof, can be attached to separate beads, a mixture of which can be used to remove the cells. In other embodiments, the removal of T regulatory cells, e.g., CD25+ cells, and the removal of the check point inhibitor expressing cells is sequential, and can occur, e.g., in either order. 
     Methods described herein can include a positive selection step For example, T cells can be isolated by incubation with anti-CD3/anti-CD28 (e.g., 3×28)-conjugated beads, such as DYNABEADS® M-450 CD3/CD28 T, for a time period sufficient for positive selection of the desired T cells. In one aspect, the time period is about 30 minutes. In a further aspect, the time period ranges from 30 minutes to 36 hours or longer and all integer values there between. In a further aspect, the time period is at least 1, 2, 3, 4, 5, or 6 hours. In yet another aspect, the time period is 10 to 24 hours. In one aspect, the incubation time period is 24 hours. Longer incubation times may be used to isolate T cells in any situation where there are few T cells as compared to other cell types, such in isolating tumor infiltrating lymphocytes (TIL) from tumor tissue or from immunocompromised individuals. Further, use of longer incubation times can increase the efficiency of capture of CD8+ T cells. Thus, by simply shortening or lengthening the time T cells are allowed to bind to the CD3/CD28 beads and/or by increasing or decreasing the ratio of beads to T cells (as described further herein), subpopulations of T cells can be preferentially selected for or against at culture initiation or at other time points during the process. Additionally, by increasing or decreasing the ratio of anti-CD3 and/or anti-CD28 antibodies on the beads or other surface, subpopulations of T cells can be preferentially selected for or against at culture initiation or at other desired time points. 
     In one embodiment, a T cell population can be selected that expresses one or more of IFN-γ, TNFα, IL-17A, IL-2, IL-3, IL-4, GM-CSF, IL-10, IL-13, granzyme B, and perforin, or other appropriate molecules, e.g., other cytokines. Methods for screening for cell expression can be determined, e.g., by the methods described in PCT Publication No.: WO 2013/126712. 
     For isolation of a desired population of cells by positive or negative selection, the concentration of cells and surface (e.g., particles such as beads) can be varied. In certain aspects, it may be desirable to significantly decrease the volume in which beads and cells are mixed together (e.g., increase the concentration of cells), to ensure maximum contact of cells and beads. For example, in one aspect, a concentration of about 10 billion cells/ml, 9 billion/ml, 8 billion/ml, 7 billion/ml, 6 billion/ml, or 5 billion/ml is used. In one aspect, a concentration of 1 billion cells/ml is used. In one aspect, a concentration of cells from 75, 80, 85, 90, 95, or 100 million cells/ml is used. In further aspects, concentrations of 125 or 150 million cells/ml can be used. 
     Using high concentrations can result in increased cell yield, cell activation, and cell expansion. Further, use of high cell concentrations allows more efficient capture of cells that may weakly express target antigens of interest, such as CD28-negative T cells, or from samples where there are many tumor cells present (e.g., leukemic blood, tumor tissue, etc.). Such populations of cells may have therapeutic value and would be desirable to obtain. For example, using high concentration of cells allows more efficient selection of CD8+ T cells that normally have weaker CD28 expression. 
     In a related aspect, it may be desirable to use lower concentrations of cells. By significantly diluting the mixture of T cells and surface (e.g., particles such as beads), interactions between the particles and cells is minimized. This selects for cells that express high amounts of desired antigens to be bound to the particles. For example, CD4+ T cells express higher levels of CD28 and are more efficiently captured than CD8+ T cells in dilute concentrations. In one aspect, the concentration of cells used is 5×10 6 /ml. In other aspects, the concentration used can be from about 1×10 5 /ml to 1×10 6 /ml, and any integer value in between. 
     In other aspects, the cells may be incubated on a rotator for varying lengths of time at varying speeds at either 2-10° C. or at room temperature. 
     T cells for stimulation can also be frozen after a washing step. Wishing not to be bound by theory, the freeze and subsequent thaw step provides a more uniform product by removing granulocytes and to some extent monocytes in the cell population. After the washing step that removes plasma and platelets, the cells may be suspended in a freezing solution. While many freezing solutions and parameters are known in the art and will be useful in this context, one method involves using PBS containing 20% DMSO and 8% human serum albumin, or culture media containing 10% Dextran 40 and 5% Dextrose, 20% Human Serum Albumin and 7.5% DMSO, or 31.25% Plasmalyte-A, 31.25% Dextrose 5%, 0.45% NaCl, 10% Dextran 40 and 5% Dextrose, 20% Human Serum Albumin, and 7.5% DMSO or other suitable cell freezing media containing for example, Hespan and PlasmaLyte A, the cells then are frozen to −80° C. at a rate of 1° per minute and stored in the vapor phase of a liquid nitrogen storage tank. Other methods of controlled freezing may be used as well as uncontrolled freezing immediately at −20° C. or in liquid nitrogen. 
     In certain aspects, cryopreserved cells are thawed and washed as described herein and allowed to rest for one hour at room temperature prior to activation using the methods of the present invention. 
     Also contemplated in the context of the invention is the collection of blood samples or apheresis product from a subject at a time period prior to when the expanded cells as described herein might be needed. As such, the source of the cells to be expanded can be collected at any time point necessary, and desired cells, such as T cells, isolated and frozen for later use in immune effector cell therapy for any number of diseases or conditions that would benefit from immune effector cell therapy, such as those described herein. In one aspect a blood sample or an apheresis is taken from a generally healthy subject. In certain aspects, a blood sample or an apheresis is taken from a generally healthy subject who is at risk of developing a disease, but who has not yet developed a disease, and the cells of interest are isolated and frozen for later use. In certain aspects, the T cells may be expanded, frozen, and used at a later time. In certain aspects, samples are collected from a patient shortly after diagnosis of a particular disease as described herein but prior to any treatments. In a further aspect, the cells are isolated from a blood sample or an apheresis from a subject prior to any number of relevant treatment modalities, including but not limited to treatment with agents such as natalizumab, efalizumab, antiviral agents, chemotherapy, radiation, immunosuppressive agents, such as cyclosporin, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunoablative agents such as CAMPATH, anti-CD3 antibodies, cytoxan, fludarabine, cyclosporin, FK506, rapamycin, mycophenolic acid, steroids, FR901228, and irradiation. 
     In a further aspect of the present invention, T cells are obtained from a patient directly following treatment that leaves the subject with functional T cells. In this regard, it has been observed that following certain cancer treatments, in particular treatments with drugs that damage the immune system, shortly after treatment during the period when patients would normally be recovering from the treatment, the quality of T cells obtained may be optimal or improved for their ability to expand ex vivo. Likewise, following ex vivo manipulation using the methods described herein, these cells may be in a preferred state for enhanced engraftment and in vivo expansion. Thus, it is contemplated within the context of the present invention to collect blood cells, including T cells, dendritic cells, or other cells of the hematopoietic lineage, during this recovery phase. Further, in certain aspects, mobilization (for example, mobilization with GM-CSF) and conditioning regimens can be used to create a condition in a subject wherein repopulation, recirculation, regeneration, and/or expansion of particular cell types is favored, especially during a defined window of time following therapy. Illustrative cell types include T cells, B cells, dendritic cells, and other cells of the immune system. 
     In one embodiment, the immune effector cells expressing a CAR molecule, e.g., a CAR molecule described herein, are obtained from a subject that has received a low, immune enhancing dose of an mTOR inhibitor. In an embodiment, the population of immune effector cells, e.g., T cells, to be engineered to express a CAR, are harvested after a sufficient time, or after sufficient dosing of the low, immune enhancing, dose of an mTOR inhibitor, such that the level of PD1 negative immune effector cells, e.g., T cells, or the ratio of PD1 negative immune effector cells, e.g., T cells/PD1 positive immune effector cells, e.g., T cells, in the subject or harvested from the subject has been, at least transiently, increased. 
     In other embodiments, population of immune effector cells, e.g., T cells, which have, or will be engineered to express a CAR, can be treated ex vivo by contact with an amount of an mTOR inhibitor that increases the number of PD1 negative immune effector cells, e.g., T cells or increases the ratio of PD1 negative immune effector cells, e.g., T cells/PD1 positive immune effector cells, e.g., T cells. 
     In one embodiment, a T cell population is diacylglycerol kinase (DGK)-deficient. DGK-deficient cells include cells that do not express DGK RNA or protein, or have reduced or inhibited DGK activity. DGK-deficient cells can be generated by genetic approaches, e.g., administering RNA-interfering agents, e.g., siRNA, shRNA, miRNA, to reduce or prevent DGK expression. Alternatively, DGK-deficient cells can be generated by treatment with DGK inhibitors described herein. 
     In one embodiment, a T cell population is Ikaros-deficient. Ikaros-deficient cells include cells that do not express Ikaros RNA or protein, or have reduced or inhibited Ikaros activity, Ikaros-deficient cells can be generated by genetic approaches, e.g., administering RNA-interfering agents, e.g., siRNA, shRNA, miRNA, to reduce or prevent Ikaros expression. Alternatively, Ikaros-deficient cells can be generated by treatment with Ikaros inhibitors, e.g., lenalidomide. 
     In embodiments, a T cell population is DGK-deficient and Ikaros-deficient, e.g., does not express DGK and Ikaros, or has reduced or inhibited DGK and Ikaros activity. Such DGK and Ikaros-deficient cells can be generated by any of the methods described herein. 
     In an embodiment, the NK cells are obtained from the subject. In another embodiment, the NK cells are an NK cell line, e.g., NK-92 cell line (Conkwest). 
     Allogeneic CAR 
     In embodiments described herein, the immune effector cell can be an allogeneic immune effector cell, e.g., T cell or NK cell. For example, the cell can be an allogeneic T cell, e.g., an allogeneic T cell lacking expression of a functional T cell receptor (TCR) and/or human leukocyte antigen (HLA), e.g., HLA class I and/or HLA class II. 
     A T cell lacking a functional TCR can be, e.g., engineered such that it does not express any functional TCR on its surface, engineered such that it does not express one or more subunits that comprise a functional TCR (e.g., engineered such that it does not express (or exhibits reduced expression) of TCR alpha, TCR beta, TCR gamma, TCR delta, TCR epsilon, and/or TCR zeta) or engineered such that it produces very little functional TCR on its surface (e.g., engineered such that it does not express (or exhibits reduced expression) of TCR alpha, TCR beta, TCR gamma, TCR delta, TCR epsilon, and/or TCR zeta). Alternatively, the T cell can express a substantially impaired TCR, e.g., by expression of mutated or truncated forms of one or more of the subunits of the TCR. The term “substantially impaired TCR” means that this TCR will not elicit an adverse immune reaction in a host. 
     A T cell described herein can be, e.g., engineered such that it does not express a functional HLA on its surface. For example, a T cell described herein, can be engineered such that cell surface expression HLA, e.g., HLA class 1 and/or HLA class II, is downregulated. In some embodiments, downregulation of HLA may be accomplished by reducing or eliminating expression of beta-2 microglobulin (B2M). 
     In some embodiments, the T cell can lack a functional TCR and a functional HLA, e.g., HLA class I and/or HLA class II. 
     Modified T cells that lack expression of a functional TCR and/or HLA can be obtained by any suitable means, including a knock out or knock down of one or more subunit of TCR or HLA. For example, the T cell can include a knock down of TCR and/or HLA using siRNA, shRNA, clustered regularly interspaced short palindromic repeats (CRISPR) transcription-activator like effector nuclease (TALEN), or zinc finger endonuclease (ZFN). 
     In some embodiments, the allogeneic cell can be a cell which does not express or expresses at low levels an inhibitory molecule, e.g. a cell engineered by any method described herein. For example, the cell can be a cell that does not express or expresses at low levels an inhibitory molecule, e.g., that can decrease the ability of a CAR-expressing cell to mount an immune effector response. Examples of inhibitory molecules include PD1, PD-L1, PD-L2, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GAL9, adenosine, and TGF (e.g., TGF beta). Inhibition of an inhibitory molecule, e.g., by inhibition at the DNA, RNA or protein level, can optimize a CAR-expressing cell performance. In embodiments, an inhibitory nucleic acid, e.g., an inhibitory nucleic acid, e.g., a dsRNA, e.g., an siRNA or shRNA, a clustered regularly interspaced short palindromic repeats (CRISPR), a transcription-activator like effector nuclease (TALEN), or a zinc finger endonuclease (ZFN), e.g., as described herein, can be used. 
     siRNA and shRNA to inhibit TCR or HLA 
     In some embodiments, TCR expression and/or HLA expression can be inhibited using siRNA or shRNA that targets a nucleic acid encoding a TCR and/or HLA, and/or an inhibitory molecule described herein (e.g., PD1, PD-L1, PD-L2, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GAL9, adenosine, and TGF beta), in a T cell. 
     Expression systems for siRNA and shRNAs, and exemplary shRNAs, are described, e.g., in paragraphs 649 and 650 of International Application WO2015/142675, filed Mar. 13, 2015, which is incorporated by reference in its entirety 
     CRISPR to Inhibit TCR or HLA 
     “CRISPR” or “CRISPR to TCR and/or HLA” or “CRISPR to inhibit TCR and/or HLA” as used herein refers to a set of clustered regularly interspaced short palindromic repeats, or a system comprising such a set of repeats. “Cas”, as used herein, refers to a CRISPR-associated protein. A “CRISPR/Cas” system refers to a system derived from CRISPR and Cas which can be used to silence or mutate a TCR and/or HLA gene, and/or an inhibitory molecule described herein (e.g., PD1, PD-L1, PD-L2, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GAL9, adenosine, and TGF beta). 
     The CRISPR/Cas system, and uses thereof, are described, e.g., in paragraphs 651-658 of International Application WO2015/142675, filed Mar. 13, 2015, which is incorporated by reference in its entirety. 
     TALEN to Inhibit TCR and/or HLA 
     “TALEN” or “TALEN to HLA and/or TCR” or “TALEN to inhibit HLA and/or TCR” refers to a transcription activator-like effector nuclease, an artificial nuclease which can be used to edit the HLA and/or TCR gene, and/or an inhibitory molecule described herein (e.g., PD1, PD-L1, PD-L2, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GAL9, adenosine, and TGF beta). 
     TALENs, TALEs, and uses thereof, are described, e.g., in paragraphs 659-665 of International Application WO2015/142675, filed Mar. 13, 2015, which is incorporated by reference in its entirety. 
     Zinc Finger Nuclease to Inhibit HLA and/or TCR 
     “ZFN” or “Zinc Finger Nuclease” or “ZFN to HLA and/or TCR” or “ZFN to inhibit HLA and/or TCR” refer to a zinc finger nuclease, an artificial nuclease which can be used to edit the HLA and/or TCR gene, and/or an inhibitory molecule described herein (e.g., PD1, PD-L1, PD-L2, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GAL9, adenosine, and TGF beta). 
     ZFNs, and uses thereof, are described, e.g., in paragraphs 666-671 of International Application WO2015/142675, filed Mar. 13, 2015, which is incorporated by reference in its entirety. 
     Telomerase Expression 
     While not wishing to be bound by any particular theory, in some embodiments, a therapeutic T cell has short term persistence in a patient, due to shortened telomeres in the T cell; accordingly, transfection with a telomerase gene can lengthen the telomeres of the T cell and improve persistence of the T cell in the patient. See Carl June, “Adoptive T cell therapy for cancer in the clinic”, Journal of Clinical Investigation, 117:1466-1476 (2007). Thus, in an embodiment, an immune effector cell, e.g., a T cell, ectopically expresses a telomerase subunit, e.g., the catalytic subunit of telomerase, e.g., TERT, e.g., hTERT. In some aspects, this disclosure provides a method of producing a CAR-expressing cell, comprising contacting a cell with a nucleic acid encoding a telomerase subunit, e.g., the catalytic subunit of telomerase, e.g., TERT, e.g., hTERT. The cell may be contacted with the nucleic acid before, simultaneous with, or after being contacted with a construct encoding a CAR. 
     In one aspect, the disclosure features a method of making a population of immune effector cells (e.g., T cells or NK cells). In an embodiment, the method comprises: providing a population of immune effector cells (e.g., T cells or NK cells), contacting the population of immune effector cells with a nucleic acid encoding a CAR; and contacting the population of immune effector cells with a nucleic acid encoding a telomerase subunit, e.g., hTERT, under conditions that allow for CAR and telomerase expression. 
     In an embodiment, the nucleic acid encoding the telomerase subunit is DNA. In an embodiment, the nucleic acid encoding the telomerase subunit comprises a promoter capable of driving expression of the telomerase subunit. 
     In an embodiment, hTERT has the amino acid sequence of GenBank Protein ID AAC51724.1 (Meyerson et al., “hEST2, the Putative Human Telomerase Catalytic Subunit Gene, Is Up-Regulated in Tumor Cells and during Immortalization” Cell Volume 90, Issue 4, 22 Aug. 1997, Pages 785-795) as disclosed on pages 233-234 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     In an embodiment, the hTERT has a sequence at least 80%, 85%, 90%, 95%, 96{circumflex over ( )},97%, 98%, or 99% identical to the sequence of SEQ ID NO: 1332. In an embodiment, the hTERT has a sequence of SEQ ID NO: 1332. In an embodiment, the hTERT comprises a deletion (e.g., of no more than 5, 10, 15, 20, or 30 amino acids) at the N-terminus, the C-terminus, or both. In an embodiment, the hTERT comprises a transgenic amino acid sequence (e.g., of no more than 5, 10, 15, 20, or 30 amino acids) at the N-terminus, the C-terminus, or both. 
     In an embodiment, the hTERT is encoded by the nucleic acid sequence of GenBank Accession No. AF018167 (Meyerson et al., “hEST2, the Putative Human Telomerase Catalytic Subunit Gene, Is Up-Regulated in Tumor Cells and during Immortalization” Cell Volume 90, Issue 4, 22 Aug. 1997, Pages 785-795) as disclosed on pages 234-235 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     In an embodiment, the hTERT is encoded by a nucleic acid having a sequence at least 80%, 85%, 90%, 95%, 96, 97%, 98%, or 99% identical to the sequence of SEQ ID NO: 1333. In an embodiment, the hTERT is encoded by a nucleic acid of SEQ ID NO: 1333. 
     Activation and Expansion of Immune Effector Cells (e.g., T Cells) 
     Immune effector cells such as T cells may be activated and expanded generally using methods as described, for example, in U.S. Pat. Nos. 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041; and U.S. Patent Application Publication No. 20060121005. 
     The procedure for ex vivo expansion of hematopoietic stem and progenitor cells is described in U.S. Pat. No. 5,199,942, incorporated herein by reference, can be applied to the cells of the present invention. Other suitable methods are known in the art, therefore the present invention is not limited to any particular method of ex vivo expansion of the cells. Briefly, ex vivo culture and expansion of T cells can comprise: (1) collecting CD34+ hematopoietic stem and progenitor cells from a mammal from peripheral blood harvest or bone marrow explants; and (2) expanding such cells ex vivo. In addition to the cellular growth factors described in U.S. Pat. No. 5,199,942, other factors such as flt3-L, IL-1, IL-3 and c-kit ligand, can be used for culturing and expansion of the cells. 
     Generally, a population of immune effector cells may be expanded by contact with a surface having attached thereto an agent that stimulates a CD3/TCR complex associated signal and a ligand that stimulates a costimulatory molecule on the surface of the T cells. In particular, T cell populations may be stimulated as described herein, such as by contact with an anti-CD3 antibody, or antigen-binding fragment thereof, or an anti-CD2 antibody immobilized on a surface, or by contact with a protein kinase C activator (e.g., bryostatin) in conjunction with a calcium ionophore. For co-stimulation of an accessory molecule on the surface of the T cells, a ligand that binds the accessory molecule is used. For example, a population of T cells can be contacted with an anti-CD3 antibody and an anti-CD28 antibody, under conditions appropriate for stimulating proliferation of the T cells. To stimulate proliferation of either CD4+ T cells or CD8+ T cells, an anti-CD3 antibody and an anti-CD28 antibody may be used. Examples of an anti-CD28 antibody include 9.3, B-T3, XR-CD28 (Diaclone, Besangon, France) can be used as can other methods commonly known in the art (Berg et al., Transplant Proc. 30(8):3975-3977, 1998; Haanen et al., J. Exp. Med. 190(9):13191328, 1999; Garland et al., J. Immunol Meth. 227(1-2):53-63, 1999). 
     In some embodiments, immune effector cells (such as PBMCs or T cells) are expanded and stimulated by contacting the cells to one or both of an anti-CD3 antibody and IL-2. In embodiments, the cells are expanded without anti-CD3 or anti-CD28 beads. 
     In certain aspects, the primary stimulatory signal and the costimulatory signal for the T cell may be provided by different protocols. For example, the agents providing each signal may be in solution or coupled to a surface. When coupled to a surface, the agents may be coupled to the same surface (i.e., in “cis” formation) or to separate surfaces (i.e., in “trans” formation). Alternatively, one agent may be coupled to a surface and the other agent in solution. In one aspect, the agent providing the costimulatory signal is bound to a cell surface and the agent providing the primary activation signal is in solution or coupled to a surface. In certain aspects, both agents can be in solution. In one aspect, the agents may be in soluble form, and then cross-linked to a surface, such as a cell expressing Fc receptors or an antibody or other binding agent which will bind to the agents. In this regard, see for example, U.S. Patent Application Publication Nos. 20040101519 and 20060034810 for artificial antigen presenting cells (aAPCs) that are contemplated for use in activating and expanding T cells in the present invention. 
     In one aspect, the two agents are immobilized on beads, either on the same bead, i.e., “cis,” or to separate beads, i.e., “trans.” By way of example, the agent providing the primary activation signal is an anti-CD3 antibody or an antigen-binding fragment thereof and the agent providing the costimulatory signal is an anti-CD28 antibody or antigen-binding fragment thereof; and both agents are co-immobilized to the same bead in equivalent molecular amounts. In one aspect, a 1:1 ratio of each antibody bound to the beads for CD4+ T cell expansion and T cell growth is used. In certain aspects, a ratio of anti CD3:CD28 antibodies bound to the beads is used such that an increase in T cell expansion is observed as compared to the expansion observed using a ratio of 1:1. In one particular aspect an increase of from about 1 to about 3 fold is observed as compared to the expansion observed using a ratio of 1:1. In one aspect, the ratio of CD3:CD28 antibody bound to the beads ranges from 100:1 to 1:100 and all integer values there between. In one aspect, more anti-CD28 antibody is bound to the particles than anti-CD3 antibody, i.e., the ratio of CD3:CD28 is less than one. In certain aspects, the ratio of anti CD28 antibody to anti CD3 antibody bound to the beads is greater than 2:1. In one particular aspect, a 1:100 CD3:CD28 ratio of antibody bound to beads is used. In one aspect, a 1:75 CD3:CD28 ratio of antibody bound to beads is used. In a further aspect, a 1:50 CD3:CD28 ratio of antibody bound to beads is used. In one aspect, a 1:30 CD3:CD28 ratio of antibody bound to beads is used. In one aspect, a 1:10 CD3:CD28 ratio of antibody bound to beads is used. In one aspect, a 1:3 CD3:CD28 ratio of antibody bound to the beads is used. In yet one aspect, a 3:1 CD3:CD28 ratio of antibody bound to the beads is used. 
     Ratios of particles to cells from 1:500 to 500:1 and any integer values in between may be used to stimulate T cells or other target cells. As those of ordinary skill in the art can readily appreciate, the ratio of particles to cells may depend on particle size relative to the target cell. For example, small sized beads could only bind a few cells, while larger beads could bind many. In certain aspects the ratio of cells to particles ranges from 1:100 to 100:1 and any integer values in-between and in further aspects the ratio comprises 1:9 to 9:1 and any integer values in between, can also be used to stimulate T cells. The ratio of anti-CD3- and anti-CD28-coupled particles to T cells that result in T cell stimulation can vary as noted above, however certain suitable values include 1:100, 1:50, 1:40, 1:30, 1:20, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, and 15:1 with one suitable ratio being at least 1:1 particles per T cell. In one aspect, a ratio of particles to cells of 1:1 or less is used. In one particular aspect, a suitable particle: cell ratio is 1:5. In further aspects, the ratio of particles to cells can be varied depending on the day of stimulation. For example, in one aspect, the ratio of particles to cells is from 1:1 to 10:1 on the first day and additional particles are added to the cells every day or every other day thereafter for up to 10 days, at final ratios of from 1:1 to 1:10 (based on cell counts on the day of addition). In one particular aspect, the ratio of particles to cells is 1:1 on the first day of stimulation and adjusted to 1:5 on the third and fifth days of stimulation. In one aspect, particles are added on a daily or every other day basis to a final ratio of 1:1 on the first day, and 1:5 on the third and fifth days of stimulation. In one aspect, the ratio of particles to cells is 2:1 on the first day of stimulation and adjusted to 1:10 on the third and fifth days of stimulation. In one aspect, particles are added on a daily or every other day basis to a final ratio of 1:1 on the first day, and 1:10 on the third and fifth days of stimulation. One of skill in the art will appreciate that a variety of other ratios may be suitable for use in the present invention. In particular, ratios will vary depending on particle size and on cell size and type. In one aspect, the most typical ratios for use are in the neighborhood of 1:1, 2:1 and 3:1 on the first day. 
     In further aspects of the present invention, the cells, such as T cells, are combined with agent-coated beads, the beads and the cells are subsequently separated, and then the cells are cultured. In an alternative aspect, prior to culture, the agent-coated beads and cells are not separated but are cultured together. In a further aspect, the beads and cells are first concentrated by application of a force, such as a magnetic force, resulting in increased ligation of cell surface markers, thereby inducing cell stimulation. 
     By way of example, cell surface proteins may be ligated by allowing paramagnetic beads to which anti-CD3 and anti-CD28 are attached (3×28 beads) to contact the T cells. In one aspect the cells (for example, 10 4  to 10 9  T cells) and beads (for example, DYNABEADS® M-450 CD3/CD28 T paramagnetic beads at a ratio of 1:1) are combined in a buffer, for example PBS (without divalent cations such as, calcium and magnesium). Again, those of ordinary skill in the art can readily appreciate any cell concentration may be used. For example, the target cell may be very rare in the sample and comprise only 0.01% of the sample or the entire sample (i.e., 100%) may comprise the target cell of interest. Accordingly, any cell number is within the context of the present invention. In certain aspects, it may be desirable to significantly decrease the volume in which particles and cells are mixed together (i.e., increase the concentration of cells), to ensure maximum contact of cells and particles. For example, in one aspect, a concentration of about 10 billion cells/ml, 9 billion/ml, 8 billion/ml, 7 billion/ml, 6 billion/ml, or billion/ml or 2 billion cells/ml is used. In one aspect, greater than 100 million cells/ml is used. In a further aspect, a concentration of cells of 10, 15, 20, 25, 30, 35, 40, 45, or 50 million cells/ml is used. In yet one aspect, a concentration of cells from 75, 80, 85, 90, 95, or 100 million cells/ml is used. In further aspects, concentrations of 125 or 150 million cells/ml can be used. Using high concentrations can result in increased cell yield, cell activation, and cell expansion. Further, use of high cell concentrations allows more efficient capture of cells that may weakly express target antigens of interest, such as CD28-negative T cells. Such populations of cells may have therapeutic value and would be desirable to obtain in certain aspects. For example, using high concentration of cells allows more efficient selection of CD8+ T cells that normally have weaker CD28 expression. 
     In one embodiment, cells transduced with a nucleic acid encoding a CAR, e.g., a CAR described herein, are expanded, e.g., by a method described herein. In one embodiment, the cells are expanded in culture for a period of several hours (e.g., about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 18, 21 hours) to about 14 days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days). In one embodiment, the cells are expanded for a period of 4 to 9 days. In one embodiment, the cells are expanded for a period of 8 days or less, e.g., 7, 6 or 5 days. In one embodiment, the cells, e.g., a CAR cell described herein, are expanded in culture for 5 days, and the resulting cells are more potent than the same cells expanded in culture for 9 days under the same culture conditions. Potency can be defined, e.g., by various T cell functions, e.g. proliferation, target cell killing, cytokine production, activation, migration, or combinations thereof. In one embodiment, the cells, e.g., a CD19 CAR cell described herein, expanded for 5 days show at least a one, two, three or four fold increase in cells doublings upon antigen stimulation as compared to the same cells expanded in culture for 9 days under the same culture conditions. In one embodiment, the cells, e.g., the cells expressing a CAR described herein, are expanded in culture for 5 days, and the resulting cells exhibit higher proinflammatory cytokine production, e.g., IFN-γ and/or GM-CSF levels, as compared to the same cells expanded in culture for 9 days under the same culture conditions. In one embodiment, the cells, e.g., a CAR cell described herein, expanded for 5 days show at least a one, two, three, four, five, ten fold or more increase in pg/ml of proinflammatory cytokine production, e.g., IFN-γ and/or GM-CSF levels, as compared to the same cells expanded in culture for 9 days under the same culture conditions. 
     In one aspect of the present invention, the mixture may be cultured for several hours (about 3 hours) to about 14 days or any hourly integer value in between. In one aspect, the mixture may be cultured for 21 days. In one aspect of the invention the beads and the T cells are cultured together for about eight days. In one aspect, the beads and T cells are cultured together for 2-3 days. 
     Several cycles of stimulation may also be desired such that culture time of T cells can be 60 days or more. Conditions appropriate for T cell culture include an appropriate media (e.g., Minimal Essential Media or RPMI Media 1640 or, X-vivo 15, (Lonza)) that may contain factors necessary for proliferation and viability, including serum (e.g., fetal bovine or human serum), interleukin-2 (IL-2), insulin, IFN-γ, IL-4, IL-7, GM-CSF, IL-10, IL-12, IL-15, TGFβ, and TNF-α or any other additives for the growth of cells known to the skilled artisan. Other additives for the growth of cells include, but are not limited to, surfactant, plasmanate, and reducing agents such as N-acetyl-cysteine and 2-mercaptoethanol. Media can include RPMI 1640, AIM-V, DMEM, MEM, α-MEM, F-12, X-Vivo 15, and X-Vivo 20, Optimizer, with added amino acids, sodium pyruvate, and vitamins, either serum-free or supplemented with an appropriate amount of serum (or plasma) or a defined set of hormones, and/or an amount of cytokine(s) sufficient for the growth and expansion of T cells. Antibiotics, e.g., penicillin and streptomycin, are included only in experimental cultures, not in cultures of cells that are to be infused into a subject. The target cells are maintained under conditions necessary to support growth, for example, an appropriate temperature (e.g., 37° C.) and atmosphere (e.g., air plus 5% CO 2 ). 
     In one embodiment, the cells are expanded in an appropriate media (e.g., media described herein) that includes one or more interleukin that result in at least a 200-fold (e.g., 200-fold, 250-fold, 300-fold, 350-fold) increase in cells over a 14 day expansion period, e.g., as measured by a method described herein such as flow cytometry. In one embodiment, the cells are expanded in the presence IL-15 and/or IL-7 (e.g., IL-15 and IL-7). 
     In some embodiments a CAR-expressing cell described herein (e.g., a T cell such as a CD4+ T cell or a CD8+ T cell) is contacted with a composition comprising a interleukin-15 (IL-15) polypeptide, a interleukin-15 receptor alpha (IL-15Ra) polypeptide, or a combination of both a IL-15 polypeptide and a IL-15Ra polypeptide e.g., hetIL-15, during the manufacturing of the CAR-expressing cell, e.g., ex vivo. In embodiments, a CAR-expressing cell described herein is contacted with a composition comprising a IL-15 polypeptide during the manufacturing of the CAR-expressing cell, e.g., ex vivo. In embodiments, a CAR-expressing cell described herein is contacted with a composition comprising a combination of both a IL-15 polypeptide and a IL-15 Ra polypeptide during the manufacturing of the CAR-expressing cell, e.g., ex vivo. In embodiments, a CAR-expressing cell described herein is contacted with a composition comprising hetIL-15 during the manufacturing of the CAR-expressing cell, e.g., ex vivo. 
     In one embodiment the CAR-expressing cell (e.g., a T cell or NK cell) described herein is contacted with a composition comprising hetIL-15 during ex vivo expansion. In an embodiment, the CAR-expressing cell described herein is contacted with a composition comprising an IL-15 polypeptide during ex vivo expansion. In an embodiment, the CAR-expressing cell described herein is contacted with a composition comprising both an IL-15 polypeptide and an IL-15Ra polypeptide during ex vivo expansion. In one embodiment the contacting results in the survival and proliferation of a lymphocyte subpopulation, e.g., CD8+ T cells. 
     In an embodiment, the method of making disclosed herein further comprises contacting the population of immune effector cells (e.g., T cells or NK cells) with a nucleic acid encoding a telomerase subunit, e.g., hTERT. The nucleic acid encoding the telomerase subunit can be DNA. 
     T cells that have been exposed to varied stimulation times may exhibit different characteristics. For example, typical blood or apheresed peripheral blood mononuclear cell products have a helper T cell population (TH, CD4+) that is greater than the cytotoxic or suppressor T cell population (TC, CD8+). Ex vivo expansion of T cells by stimulating CD3 and CD28 receptors produces a population of T cells that prior to about days 8-9 consists predominately of TH cells, while after about days 8-9, the population of T cells comprises an increasingly greater population of TC cells. Accordingly, depending on the purpose of treatment, infusing a subject with a T cell population comprising predominately of TH cells may be advantageous. Similarly, if an antigen-specific subset of TC cells has been isolated it may be beneficial to expand this subset to a greater degree. 
     Further, in addition to CD4 and CD8 markers, other phenotypic markers vary significantly, but in large part, reproducibly during the course of the cell expansion process. Thus, such reproducibility enables the ability to tailor an activated T cell product for specific purposes. 
     Once a CAR, e.g., CD19 CAR is constructed, various assays can be used to evaluate the activity of the molecule, such as but not limited to, the ability to expand T cells following antigen stimulation, sustain T cell expansion in the absence of re-stimulation, and anti-cancer activities in appropriate in vitro and animal models. Assays to evaluate the effects of a CAR, e.g., CD19 CAR are described in further detail below Western blot analysis of CAR expression in primary T cells can be used to detect the presence of monomers and dimers, e.g., as described in paragraph 695 of International Application WO2015/142675, filed Mar. 13, 2015, which is herein incorporated by reference in its entirety. 
     In vitro expansion of CAR +  T cells following antigen stimulation can be measured by flow cytometry. For example, a mixture of CD4+ and CD8+ T cells are stimulated with αCD3/αCD28 beads followed by transduction with lentiviral vectors expressing GFP under the control of the promoters to be analyzed. Exemplary promoters include the CMV IE gene, EF-la, ubiquitin C, or phosphoglycerokinase (PGK) promoters. GFP fluorescence is evaluated on day 6 of culture in the CD4+ and/or CD8+ T cell subsets by flow cytometry. See, e.g., Milone et al., Molecular Therapy 17(8): 1453-1464 (2009). Alternatively, a mixture of CD4+ and CD8+ T cells are stimulated with αCD3/αCD28 coated magnetic beads on day 0, and transduced with CAR on day 1 using a bicistronic lentiviral vector expressing CAR along with eGFP using a 2A ribosomal skipping sequence. Cultures are re-stimulated with either CD19 +  K562 cells (K562-CD19), wild-type K562 cells (K562 wild type) or K562 cells expressing hCD32 and 4-1BBL in the presence of anti-CD3 and anti-CD28 antibody (K562-BBL-3/28) following washing. Exogenous IL-2 is added to the cultures every other day at 100 IU/ml. GFP +  T cells are enumerated by flow cytometry using bead-based counting. See, e.g., Milone et al., Molecular Therapy 17(8): 1453-1464 (2009). 
     Sustained CAR +  T cell expansion in the absence of re-stimulation can also be measured. See, e.g., Milone et al., Molecular Therapy 17(8): 1453-1464 (2009). Briefly, mean T cell volume (fl) is measured on day 8 of culture using a Coulter Multisizer particle counter, a Nexcelom Cellometer Vision, or Millipore Scepter following stimulation with αCD3/αCD28 coated magnetic beads on day 0, and transduction with the indicated CAR on day 1. 
     Animal models can also be used to measure a CAR-expressing cell activity, e.g., as described in paragraph 698 of International Application WO2015/142675, filed Mar. 13, 2015, which is herein incorporated by reference in its entirety. 
     Dose dependent CAR treatment response can be evaluated, e.g., as described in paragraph 699 of International Application WO2015/142675, filed Mar. 13, 2015, which is herein incorporated by reference in its entirety. Assessment of cell proliferation and cytokine production has been previously described, e.g., as described in paragraph 700 of International Application WO2015/142675, filed Mar. 13, 2015, which is herein incorporated by reference in its entirety. Cytotoxicity can be assessed by a standard  51 Cr-release assay, e.g., as described in paragraph 701 of International Application WO2015/142675, filed Mar. 13, 2015, which is herein incorporated by reference in its entirety. Imaging technologies can be used to evaluate specific trafficking and proliferation of CARs in tumor-bearing animal models, e.g., as described in paragraph 702 of International Application WO2015/142675, filed Mar. 13, 2015, which is herein incorporated by reference in its entirety. 
     Other assays, including those described in the Example section herein as well as those that are known in the art can also be used to evaluate the CARs described herein. 
     Alternatively, or in combination to the methods disclosed herein, methods and compositions for one or more of detection and/or quantification of CAR-expressing cells (e.g., in vitro or in vivo (e.g., clinical monitoring)), immune cell expansion and/or activation, and/or CAR-specific selection, that involve the use of a CAR ligand, are disclosed. In one exemplary embodiment, the CAR ligand is an antibody that binds to the CAR molecule, e.g., binds to the extracellular antigen binding domain of CAR (e.g., an antibody that binds to the antigen binding domain, e.g., an anti-idiotypic antibody; or an antibody that binds to a constant region of the extracellular binding domain). In other embodiments, the CAR ligand is a CAR antigen molecule (e.g., a CAR antigen molecule as described herein). 
     In one aspect, a method for detecting and/or quantifying CAR-expressing cells is disclosed. For example, the CAR ligand can be used to detect and/or quantify CAR-expressing cells in vitro or in vivo (e.g., clinical monitoring of CAR-expressing cells in a patient, or dosing a patient). The method includes: 
     providing the CAR ligand (optionally, a labelled CAR ligand, e.g., a CAR ligand that includes a tag, a bead, a radioactive or fluorescent label); 
     acquiring the CAR-expressing cell (e.g., acquiring a sample containing CAR-expressing cells, such as a manufacturing sample or a clinical sample); 
     contacting the CAR-expressing cell with the CAR ligand under conditions where binding occurs, thereby detecting the level (e.g., amount) of the CAR-expressing cells present. Binding of the CAR-expressing cell with the CAR ligand can be detected using standard techniques such as FACS, ELISA and the like. 
     In another aspect, a method of expanding and/or activating cells (e.g., immune effector cells) is disclosed. The method includes: 
     providing a CAR-expressing cell (e.g., a first CAR-expressing cell or a transiently expressing CAR cell); 
     contacting said CAR-expressing cell with a CAR ligand, e.g., a CAR ligand as described herein), under conditions where immune cell expansion and/or proliferation occurs, thereby producing the activated and/or expanded cell population. 
     In certain embodiments, the CAR ligand is present on (e.g., is immobilized or attached to a substrate, e.g., a non-naturally occurring substrate). In some embodiments, the substrate is a non-cellular substrate. The non-cellular substrate can be a solid support chosen from, e.g., a plate (e.g., a microtiter plate), a membrane (e.g., a nitrocellulose membrane), a matrix, a chip or a bead. In embodiments, the CAR ligand is present in the substrate (e.g., on the substrate surface). The CAR ligand can be immobilized, attached, or associated covalently or non-covalently (e.g., cross-linked) to the substrate. In one embodiment, the CAR ligand is attached (e.g., covalently attached) to a bead. In the aforesaid embodiments, the immune cell population can be expanded in vitro or ex vivo. The method can further include culturing the population of immune cells in the presence of the ligand of the CAR molecule, e.g., using any of the methods described herein. 
     In other embodiments, the method of expanding and/or activating the cells further comprises addition of a second stimulatory molecule, e.g., CD28. For example, the CAR ligand and the second stimulatory molecule can be immobilized to a substrate, e.g., one or more beads, thereby providing increased cell expansion and/or activation. 
     In other embodiments, a method for selecting or enriching for a CAR expressing cell is provided. The method includes contacting the CAR expressing cell with a CAR ligand as described herein; and selecting the cell on the basis of binding of the CAR ligand. 
     In yet other embodiments, a method for depleting (e.g., reducing and/or killing) a CAR expressing cell is provided. The method includes contacting the CAR expressing cell with a CAR ligand as described herein; and targeting the cell on the basis of binding of the CAR ligand thereby reducing the number, and/or killing, the CAR-expressing cell. In one embodiment, the CAR ligand is coupled to a toxic agent (e.g., a toxin or a cell ablative drug). In another embodiment, the anti-idiotypic antibody can cause effector cell activity, e.g., ADCC or ADC activities. 
     Exemplary anti-CAR antibodies that can be used in the methods disclosed herein are described, e.g., in WO 2014/190273 and by Jena et al., “Chimeric Antigen Receptor (CAR)-Specific Monoclonal Antibody to Detect CD19-Specific T cells in Clinical Trials”, PLOS March 2013 8:3 e57838, the contents of which are incorporated by reference. In some aspects and embodiments, the compositions and methods herein are optimized for a specific subset of T cells, e.g., as described in US Serial No. PCT/US2015/043219 filed Jul. 31, 2015, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the optimized subsets of T cells display an enhanced persistence compared to a control T cell, e.g., a T cell of a different type (e.g., CD8+ or CD4+) expressing the same construct. 
     In some embodiments, a CD4+ T cell comprises a CAR described herein, which CAR comprises an intracellular signaling domain suitable for (e.g., optimized for, e.g., leading to enhanced persistence in) a CD4+ T cell, e.g., an ICOS domain. In some embodiments, a CD8+ T cell comprises a CAR described herein, which CAR comprises an intracellular signaling domain suitable for (e.g., optimized for, e.g., leading to enhanced persistence of) a CD8+ T cell, e.g., a 4-1BB domain, a CD28 domain, or another costimulatory domain other than an ICOS domain. In some embodiments, the CAR described herein comprises an antigen binding domain described herein, e.g., a CAR comprising an antigen binding domain. 
     In an aspect, described herein is a method of treating a subject, e.g., a subject having cancer. The method includes administering to said subject, an effective amount of: 
     1) a CD4+ T cell comprising a CAR (the CARCD4+) comprising: 
     an antigen binding domain, e.g., an antigen binding domain described herein; 
     a transmembrane domain; and 
     an intracellular signaling domain, e.g., a first costimulatory domain, e.g., an ICOS domain; and 
     2) a CD8+ T cell comprising a CAR (the CARCD8+) comprising: 
     an antigen binding domain, e.g., an antigen binding domain described herein; 
     a transmembrane domain; and 
     an intracellular signaling domain, e.g., a second costimulatory domain, e.g., a 4-1BB domain, a CD28 domain, or another costimulatory domain other than an ICOS domain; 
     wherein the CARCD4+ and the CARCD8+ differ from one another. 
     Optionally, the method further includes administering: 
     3) a second CD8+ T cell comprising a CAR (the second CARCD8+) comprising: 
     an antigen binding domain, e.g., an antigen binding domain described herein; 
     a transmembrane domain; and 
     an intracellular signaling domain, wherein the second CARCD8+ comprises an intracellular signaling domain, e.g., a costimulatory signaling domain, not present on the CARCD8+, and, optionally, does not comprise an ICOS signaling domain. 
     Methods of Manufacture/Production 
     In some embodiments, the methods disclosed herein further include administering a T cell depleting agent after treatment with the cell (e.g., an immune effector cell as described herein, e.g., an immune effector cell expressing CAR driven by a truncated PGK1 promoter), thereby reducing (e.g., depleting) the CAR-expressing cells (e.g., the CD19CAR-expressing cells). Such T cell depleting agents can be used to effectively deplete CAR-expressing cells (e.g., CD19CAR-expressing cells) to mitigate toxicity. In some embodiments, the CAR-expressing cells were manufactured according to a method herein, e.g., assayed (e.g., before or after transfection or transduction) according to a method herein. 
     In some embodiments, the T cell depleting agent is administered one, two, three, four, or five weeks after administration of the cell, e.g., the population of immune effector cells, described herein. 
     In one embodiment, the T cell depleting agent is an agent that depletes CAR-expressing cells, e.g., by inducing antibody dependent cell-mediated cytotoxicity (ADCC) and/or complement-induced cell death. For example, CAR-expressing cells described herein may also express an antigen (e.g., a target antigen) that is recognized by molecules capable of inducing cell death, e.g., ADCC or complement-induced cell death. For example, CAR expressing cells described herein may also express a target protein (e.g., a receptor) capable of being targeted by an antibody or antibody fragment. Examples of such target proteins include, but are not limited to, EpCAM, VEGFR, integrins (e.g., integrins αvβ3, α4, αI3/4β3, α4β7, α5β1, αvβ3, αv), members of the TNF receptor superfamily (e.g., TRAIL-R1, TRAIL-R2), PDGF Receptor, interferon receptor, folate receptor, GPNMB, ICAM-1, HLA-DR, CEA, CA-125, MUC1, TAG-72, IL-6 receptor, 5T4, GD2, GD3, CD2, CD3, CD4, CD5, CD11, CD11a/LFA-1, CD15, CD18/ITGB2, CD19, CD20, CD22, CD23/lgE Receptor, CD25, CD28, CD30, CD33, CD38, CD40, CD41, CD44, CD51, CD52, CD62L, CD74, CD80, CD125, CD147/basigin, CD152/CTLA-4, CD154/CD40L, CD195/CCR5, CD319/SLAMF7, and EGFR, and truncated versions thereof (e.g., versions preserving one or more extracellular epitopes but lacking one or more regions within the cytoplasmic domain). 
     In some embodiments, the CAR expressing cell co-expresses the CAR and the target protein, e.g., naturally expresses the target protein or is engineered to express the target protein. For example, the cell, e.g., the population of immune effector cells, can include a nucleic acid (e.g., vector) comprising the CAR nucleic acid (e.g., a CAR nucleic acid as described herein) and a nucleic acid encoding the target protein. 
     In one embodiment, the T cell depleting agent is a CD52 inhibitor, e.g., an anti-CD52 antibody molecule, e.g., alemtuzumab. 
     In other embodiments, the cell, e.g., the population of immune effector cells, expresses a CAR molecule as described herein (e.g., CD19CAR) and the target protein recognized by the T cell depleting agent. In one embodiment, the target protein is CD20. In embodiments where the target protein is CD20, the T cell depleting agent is an anti-CD20 antibody, e.g., rituximab. 
     In further embodiments of any of the aforesaid methods, the methods further include transplanting a cell, e.g., a hematopoietic stem cell, or a bone marrow, into the mammal. 
     In another aspect, the invention features a method of conditioning a mammal prior to cell transplantation. The method includes administering to the mammal an effective amount of the cell comprising a CAR nucleic acid or polypeptide, e.g., a CD19 CAR nucleic acid or polypeptide. In some embodiments, the cell transplantation is a stem cell transplantation, e.g., a hematopoietic stem cell transplantation, or a bone marrow transplantation. In other embodiments, conditioning a subject prior to cell transplantation includes reducing the number of target-expressing cells in a subject, e.g., CD19-expressing normal cells or CD19-expressing cancer cells. 
     Biopolymer Delivery Methods 
     In some embodiments, one or more CAR-expressing cells as disclosed herein can be administered or delivered to the subject via a biopolymer scaffold, e.g., a biopolymer implant. Biopolymer scaffolds can support or enhance the delivery, expansion, and/or dispersion of the CAR-expressing cells described herein. A biopolymer scaffold comprises a biocompatible (e.g., does not substantially induce an inflammatory or immune response) and/or a biodegradable polymer that can be naturally occurring or synthetic. Exemplary biopolymers are described, e.g., in paragraphs 1004-1006 of International Application WO2015/142675, filed Mar. 13, 2015, which is herein incorporated by reference in its entirety. 
     Therapeutic Applications 
     CD19 Associated Diseases and/or Disorders 
     In one aspect, the invention provides methods for treating a disease associated with CD19 expression. In one aspect, the invention provides methods for treating a disease wherein part of the cancer is negative for CD19 and part of the cancer is positive for CD19. For example, the methods and compositions of the invention are useful for treating subjects that have undergone treatment for a disease associated with expression of CD19, wherein the subject that has undergone treatment related to CD19 expression, e.g., treatment with a CD19 CAR, exhibits a disease associated with expression of CD19. 
     In another aspect, the invention provides methods for treating a disease associated with expression of a B-cell antigen, e.g., one or more of CD10, CD20, CD22, CD34, CD123, FLT-3, or ROR1. In one aspect, the invention provides methods for treating a disease wherein part of the tumor is negative for the B-cell antigen and part of the tumor is positive for B-cell antigen. For example, the compositions and methods of the invention are useful for treating subjects that have undergone treatment for a disease associated with expression of the B-cell antigen, wherein the subject that has undergone treatment related to expression of a B-cell antigen, e.g., treatment with a CAR targeting a B-cell antigen, exhibits a disease associated with expression of the B-cell antigen. In a third aspect, the invention provides methods for treating a disease associated with expression of the B-cell antigen, e.g., associated with the expression of CD19 and one or more other B-cell antigens. 
     In one aspect, the invention pertains to a vector comprising CD19 CAR operably linked to promoter for expression in mammalian cells, e.g., T cells or NK cells. In one aspect, the invention provides a recombinant cell, e.g., a T cell or NK cell, expressing the CD19 CAR for use in treating CD19-expressing cancers, wherein the recombinant T cell expressing the CD19 CAR is termed a CD19 CART. In one aspect, the CD19 CART described herein, is capable of contacting a cancer cell with at least one CD19 CAR expressed on its surface such that the CART targets the cancer cell and growth of the cancer is inhibited. 
     In one aspect, the invention pertains to a method of inhibiting growth of a CD19-expressing cancer cell, comprising contacting the cancer cell with a CD19 CAR expressing cell, e.g., a CD19 CART cell, described, and one or more other CAR expressing cells, e.g., as described herein, such that the CART is activated in response to the antigen and targets the cancer cell, wherein the growth of the cancer is inhibited. The CD19 CAR-expressing cell, e.g., T cell, is administered in combination with a B-cell inhibitor, e.g., a B-cell inhibitor described herein. 
     In an aspect, the disclosure provides one or more B-cell inhibitors, wherein the B-cell inhibitor comprises an inhibitor of one or more of CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a, for use in the treatment of a subject having a disease associated with expression of CD19, and wherein said subject has received, is receiving or is about to receive a cell that expresses a CAR molecule that binds CD19, e.g., a CD19 CAR. 
     In some embodiments, the CD19 inhibitor (e.g., one or more cells that express a CAR molecule that binds CD19, e.g., a CAR molecule that binds CD19 described herein) and the B cell inhibitor (e.g., one or more inhibitors of CD10, CD19, CD20, CD22, CD34, CD123, FLT-3, or ROR1, e.g., as described herein) are administered simultaneously. In some embodiments, the CD19 inhibitor and the B cell inhibitor are infused into a subject simultaneously, e.g., are admixed in the same infusion volume. In other embodiments, the simultaneous administration comprises separate administration of the CD19 inhibitor and the B cell inhibitor, e.g., administration of each is initiated within a predetermined time interval (e.g., within 15, 30, or 45 minutes of each other). 
     In some embodiments, the start of CD19 inhibitor delivery and the start of B cell inhibitor delivery are within 1, 2, 3, 4, 6, 12, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 60, 80, or 100 days of each other. In some embodiments, the end of CD19 inhibitor delivery and the end of B cell inhibitor delivery are within 1, 2, 3, 4, 6, 12, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 60, 80, or 100 days of each other. In some embodiments, the overlap in terms of administration between the CD19 inhibitor delivery (e.g., infusion) and the end of B cell inhibitor delivery (e.g., infusion) is at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, or 45 minutes. 
     In some embodiments, the B cell inhibitor is administered while the one or more cells that express a CAR molecule that binds CD19 are present (e.g., undergoing expansion) in the subject. In some embodiments, the CD19 inhibitor is administered while the one or more cells that express a CAR molecule that binds one or more of CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a are present (e.g., undergoing expansion) in the subject. 
     The invention includes (among other things) a type of cellular therapy where T cells are genetically modified to express a chimeric antigen receptor (CAR) and the CAR T cell is infused to a recipient in need thereof. The infused cell is able to kill tumor cells in the recipient. Unlike antibody therapies, CAR-modified T cells are able to replicate in vivo resulting in long-term persistence that can lead to sustained tumor control. In various aspects, the T cells administered to the patient, or their progeny, persist in the patient for at least four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, thirteen months, fourteen month, fifteen months, sixteen months, seventeen months, eighteen months, nineteen months, twenty months, twenty-one months, twenty-two months, twenty-three months, two years, three years, four years, or five years after administration of the T cell to the patient. 
     The invention also includes a type of cellular therapy where immune effector cells, e.g., NK cells or T cells are modified, e.g., by in vitro transcribed RNA, to transiently express a chimeric antigen receptor (CAR) and the CAR-expressing (e.g., CAR T) cell is infused to a recipient in need thereof. The infused cell is able to kill cancer cells in the recipient. Thus, in various aspects, the CAR-expressing cells, e.g., T cells, administered to the patient, is present for less than one month, e.g., three weeks, two weeks, one week, after administration of the CAR-expressing cell, e.g., T cell, to the patient. 
     Without wishing to be bound by any particular theory, the anti-cancer immunity response elicited by the CAR-modified T cells may be an active or a passive immune response, or alternatively may be due to a direct vs indirect immune response. In one aspect, the CAR (e.g., CD19-CAR) transduced T cells exhibit specific proinflammatory cytokine secretion and potent cytolytic activity in response to human cancer cells expressing the target antigen (e.g., CD19), resist soluble target antigen inhibition, mediate bystander killing and mediate regression of an established human cancer. For example, antigen-less cancer cells within a heterogeneous field of target antigen-expressing cancer may be susceptible to indirect destruction by target antigen-redirected T cells that has previously reacted against adjacent antigen-positive cancer cells. 
     In one aspect, the CAR-modified cells of the invention, e.g., fully human CAR T cells, may be a type of vaccine for ex vivo immunization and/or in vivo therapy in a mammal. In one aspect, the mammal is a human. 
     With respect to ex vivo immunization, at least one of the following occurs in vitro prior to administering the cell into a mammal: i) expansion of the cells, ii) introducing a nucleic acid encoding a CAR to the cells or iii) cryopreservation of the cells. 
     Ex vivo procedures are well known in the art and are discussed more fully below. Briefly, cells are isolated from a mammal (e.g., a human) and genetically modified (i.e., transduced or transfected in vitro) with a vector expressing a CAR disclosed herein. The CAR-modified cell can be administered to a mammalian recipient to provide a therapeutic benefit. The mammalian recipient may be a human and the CAR-modified cell can be autologous with respect to the recipient. Alternatively, the cells can be allogeneic, syngeneic or xenogeneic with respect to the recipient. 
     The procedure for ex vivo expansion of hematopoietic stem and progenitor cells is described in U.S. Pat. No. 5,199,942, incorporated herein by reference, can be applied to the cells of the present invention. Other suitable methods are known in the art, therefore the present invention is not limited to any particular method of ex vivo expansion of the cells. Briefly, ex vivo culture and expansion of T cells can comprise: (1) collecting CD34+ hematopoietic stem and progenitor cells from a mammal from peripheral blood harvest or bone marrow explants; and (2) expanding such cells ex vivo. In addition to the cellular growth factors described in U.S. Pat. No. 5,199,942, other factors such as flt3-L, IL-1, IL-3 and c-kit ligand, can be used for culturing and expansion of the cells. 
     In addition to using a cell-based vaccine in terms of ex vivo immunization, also included in the methods described herein are compositions and methods for in vivo immunization to elicit an immune response directed against an antigen in a patient. 
     Generally, the cells activated and expanded as described herein may be utilized in the treatment and prevention of diseases that arise in individuals who are immunocompromised. In particular, the CAR-expressing cells described herein are used in the treatment of diseases, disorders and conditions associated with expression of one or more B-cell antigen. In certain aspects, the cells are used in the treatment of patients at risk for developing diseases, disorders and conditions associated with expression of one or more B-cell antigen. Thus, the present invention provides (among other things) methods for the treatment or prevention of diseases, disorders and conditions associated with expression of a B-cell antigen comprising administering to a subject in need thereof, a therapeutically effective amount of the CD19 CAR-expressing cells described herein, in combination with one or more of B-cell inhibitor described herein. 
     In one embodiment, the therapy described herein (e.g., a CD19 CAR therapy, or a combination of the B-cell inhibitor and the cells expressing a CD19 CAR molecule, e.g., a CD19 CAR molecule described herein) are administered as a first line treatment for the disease, e.g., the cancer, e.g., the cancer described herein. In another embodiment, the therapy described herein (e.g., a CD19 CAR therapy, or a combination of the B-cell inhibitor and the cells expressing a CD19 CAR molecule, e.g., a CD19 CAR molecule described herein) are administered as a second, third, fourth line treatment for the disease, e.g., the cancer, e.g., the cancer described herein. 
     In an embodiment, the method further comprises administering a CD19 inhibitor, e.g., a CD19 CAR-expressing cell. In an embodiment, the CD19 inhibitor comprises a CD19 CAR and the B-cell inhibitor comprises a CD123 CAR. In an embodiment, the CD19 CAR or CD123 CAR comprises a split intracellular signaling domain such that full activation of the cell, e.g., the population of immune effector cells, occurs when both the CD19 CAR and CD123 CAR bind to a target cell, e.g., a target CD19+CD123+ cell (e.g., a B-ALL blast cell), compared to activation when the CD19 CAR and CD123 CAR bind to a target cell that expresses one of CD19 or CD123 (e.g., a hematopoietic stem cell). In an embodiment, the CD123CAR comprises a 4-1BB signaling domain and the CD19 CAR comprises a CD3 zeta signaling domain. In an embodiment, the CD123CAR comprises a costimulatory domain, e.g., a 4-1BB signaling domain, and the CD19 CAR comprises a primary signaling domain, e.g., a CD3 zeta signaling domain. In an embodiment, the CD123CAR comprises a primary signaling domain, e.g., a CD3 zeta signaling domain, and the CD19 CAR comprises a costimulatory domain, e.g., a 4-1BB signaling domain. In an embodiment, the B cell inhibitor comprises a CAR (e.g., a CAR directed against CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a) which comprises a costimulatory domain, and the CD19 CAR comprises a primary signaling domain. In an embodiment, the B cell inhibitor comprises a CAR (e.g., a CAR directed against CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a) which comprises a primary signalling domain, and the CD19 CAR comprises a costimulatory domain. In an embodiment, the B-cell inhibitor comprises one or more cells that express a CAR molecule that binds CD123, and wherein a CD19 CAR-expressing cell is administered simultaneously with the B-cell inhibitor. In an embodiment, the CD123CAR comprises a 4-1BB signaling domain and the CD19 CAR comprises a CD3 zeta signaling domain. 
     The present invention also provides methods for inhibiting the proliferation or reducing a CD19-expressing cell population, the methods comprising contacting a population of cells comprising a CD19-expressing cell with an anti-CD19 CAR-expressing cell described herein that binds to the CD19-expressing cell, and contacting the population of CD19-expressing cells with one or more of a B-cell inhibitor described herein. In a specific aspect, the present invention provides methods for inhibiting the proliferation or reducing the population of cancer cells expressing CD19, the methods comprising contacting the CD19-expressing cancer cell population with an anti-CD19 CAR-expressing cell described herein that binds to the CD19-expressing cell, and contacting the CD19-expressing cell with one or more B-cell described herein. In one aspect, the present invention provides methods for inhibiting the proliferation or reducing the population of cancer cells expressing CD19, the methods comprising contacting the CD19-expressing cancer cell population with an anti-CD19 CAR-expressing cell described herein that binds to the CD19-expressing cell and contacting the CD19-expressing cell with one or more B-cell described herein. In certain aspects, the combination of the anti-CD19 CAR-expressing cell described herein and one or more B-cell described herein reduces the quantity, number, amount or percentage of cells and/or cancer cells by at least 25%, at least 30%, at least 40%, at least 50%, at least 65%, at least 75%, at least 85%, at least 95%, or at least 99% in a subject with or animal model for a hematological cancer or another cancer associated with CD19-expressing cells relative to a negative control. In one aspect, the subject is a human. 
     The present invention also provides methods for inhibiting the proliferation or reducing a cell population comprising CD19-expressing cells and cells expressing a second B-cell antigen. In one aspect, CD19 and second B-cell antigen are expressed by the same cells within the population. In another aspect, CD19 and second B-cell antigen are expressed by distinct subsets of cells within the population. In another aspect, CD19 and second B-cell antigen are expressed by overlapping subsets of cells within the population, such that some cells express CD19 and second B-cell antigen, some cells express CD19, and some cells express the second B-cell antigen. 
     The present invention also provides methods for inhibiting the proliferation or reducing a cell population expressing CD19 and a second B-cell antigen, the methods comprising (i) contacting a population of cells comprising a CD19-expressing cell with an anti-CD19 CAR-expressing cell described herein that binds to the CD19-expressing cell, and (ii) contacting the second B-cell antigen-expressing cell with a second CAR-expressing cell described herein that binds to the second B-cell antigen-expressing cell. In a specific aspect, the present invention provides methods for inhibiting the proliferation or reducing the population of cancer cells expressing CD19 and a second B-cell antigen, the methods comprising (i) contacting the CD19-expressing cancer cell population with an anti-CD19 CAR-expressing cell described herein that binds to the CD19-expressing cell, and (ii) contacting the second B-cell antigen-expressing cell population with a second CAR-expressing cell described herein that binds to the cell expressing the second B-cell antigen. In one aspect, the present invention provides methods for inhibiting the proliferation or reducing the population of cancer cells expressing CD19 and/or a second B-cell antigen, the methods comprising (i) contacting the CD19-expressing cancer cell population with an anti-CD19 CAR-expressing cell described herein that binds to the CD19-expressing cell and (ii) contacting the second B-cell antigen-expressing cell population with a second CAR-expressing cell described herein that binds to the cell expressing the second B-cell antigen. In certain aspects, the combination of the anti-CD19 CAR-expressing cell described herein and the second CAR-expressing cell described herein, reduces the quantity, number, amount or percentage of cells and/or cancer cells by at least 25%, at least 30%, at least 40%, at least 50%, at least 65%, at least 75%, at least 85%, at least 95%, or at least 99% in a subject with or animal model for a hematological cancer or another cancer associated with CD19 and/or second B-cell antigen-expressing cells relative to a negative control. In one aspect, the subject is a human. 
     The present invention also provides methods for preventing, treating and/or managing a disease associated with CD19-expressing cells (e.g., a hematologic cancer or atypical cancer expressing CD19), the methods comprising administering to a subject in need an anti-CD19 CAR-expressing cell that binds to the CD19-expressing cell and administering one or B-cell inhibitor described herein. In one aspect, the subject is a human. Non-limiting examples of disorders associated with CD19-expressing cells include autoimmune disorders (such as lupus), inflammatory disorders (such as allergies and asthma) and cancers (such as hematological cancers or atypical cancers expressing CD19). 
     The present invention also provides methods for preventing, treating and/or managing a disease associated with CD19 and/or a second B-cell antigen-expressing cells (e.g., a hematologic cancer or atypical cancer expressing CD19 and/or second B-cell antigen), the methods comprising administering to a subject in need an anti-CD19 CAR-expressing cell that binds to the CD19-expressing cell and a B-cell inhibitor. 
     The present invention also provides methods for preventing, treating and/or managing a disease associated with CD19-expressing cells, the methods comprising administering to a subject in need an anti-CD19 CART cell of the invention that binds to the CD19-expressing cell. In one aspect, the subject is a human. 
     The present invention also provides methods for preventing relapse of cancer associated with CD19-expressing cells, the methods comprising administering to a subject in need thereof an anti-CD19 CART cell of the invention that binds to the CD19-expressing cell. In one aspect, the methods comprise administering to the subject in need thereof an effective amount of an anti-CD19 CART cell described herein that binds to the CD19-expressing cell in combination with an effective amount of another therapy. 
     In one aspect, the invention pertains to a method of treating cancer in a subject. The method comprises administering to the subject a CD19 CAR-expressing cell, e.g., T cell, described herein, in combination with a B-cell inhibitor, such that the cancer is treated in the subject. An example of a cancer that is treatable by the methods described herein is a cancer associated with expression of CD19. In one embodiment, the disease is a solid or liquid tumor. In one embodiment, the disease is a hematologic cancer, e.g., as described herein. 
     Non-cancer related indications associated with expression of CD19 include, but are not limited to, e.g., autoimmune disease, (e.g., lupus), inflammatory disorders (allergy and asthma) and transplantation. 
     In one aspect, the CAR of the invention can be used to eradicate CD19-expressing normal cells, thereby applicable for use as a cellular conditioning therapy prior to cell transplantation. In one aspect, the CD19-expressing normal cell is a CD19-expressing normal stem cell and the cell transplantation is a stem cell transplantation. 
     In some embodiments, a cancer that can be treated with the combination described herein is multiple myeloma. Multiple myeloma is a cancer of the blood, characterized by accumulation of a plasma cell clone in the bone marrow. Current therapies for multiple myeloma include, but are not limited to, treatment with lenalidomide, which is an analog of thalidomide. Lenalidomide has activities which include anti-tumor activity, angiogenesis inhibition, and immunomodulation. In some embodiments, a CD19 CAR, e.g., as described herein, may be used to target myeloma cells. In some embodiments, the combination described herein can be used with one or more additional therapies, e.g., lenalidomide treatment. 
     The CAR-expressing cells described herein may be administered either alone, or as a pharmaceutical composition in combination with diluents and/or with other components such as IL-2 or other cytokines or cell populations. 
     Hematologic Cancers 
     Hematological cancer conditions are the types of cancer such as leukemia, lymphoma and malignant lymphoproliferative conditions that affect blood, bone marrow and the lymphatic system. 
     In one embodiment, the hematologic cancer is leukemia. In one embodiment, the cancer is selected from the group consisting of one or more acute leukemias including but not limited to B-cell acute lymphoid leukemia (BALL), T-cell acute lymphoid leukemia (TALL), small lymphocytic leukemia (SLL), acute lymphoid leukemia (ALL); one or more chronic leukemias including but not limited to chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL); additional hematologic cancers or hematologic conditions including, but not limited to mantle cell lymphoma (MCL), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt&#39;s lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, Marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin lymphoma, Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and “preleukemia” which are a diverse collection of hematological conditions united by ineffective production (or dysplasia) of myeloid blood cells. Diseases associated with CD19, CD20, or CD22 expression include, but not limited to atypical and/or non-classical cancers, malignancies, precancerous conditions or proliferative diseases expressing CD19, CD20, or CD22; and any combination thereof. 
     Leukemia can be classified as acute leukemia and chronic leukemia. Acute leukemia can be further classified as acute myelogenous leukemia (AML) and acute lymphoid leukemia (ALL). Chronic leukemia includes chronic myelogenous leukemia (CML) and chronic lymphoid leukemia (CLL). Other related conditions include myelodysplastic syndromes (MDS, formerly known as “preleukemia”) which are a diverse collection of hematological conditions united by ineffective production (or dysplasia) of myeloid blood cells and risk of transformation to AML. 
     Lymphoma is a group of blood cell tumors that develop from lymphocytes. Exemplary lymphomas include non-Hodgkin lymphoma and Hodgkin lymphoma. 
     In an aspect, the invention pertains to a method of treating a mammal having Hodgkin lymphoma, comprising administering to the mammal an effective amount of the cells expressing a CD19 CAR molecule, e.g., a CD19 CAR molecule described herein and a B-cell inhibitor. 
     In one aspect, the compositions and CART cells or CAR expressing NK cells of the present invention are particularly useful for treating B cell malignancies, such as non-Hodgkin lymphomas, e.g., DLBCL, Follicular lymphoma, or CLL. 
     Non-Hodgkin lymphoma (NHL) is a group of cancers of lymphocytes, formed from either B or T cells. NHLs occur at any age and are often characterized by lymph nodes that are larger than normal, weight loss, and fever. Different types of NHLs are categorized as aggressive (fast-growing) and indolent (slow-growing) types. B-cell non-Hodgkin lymphomas include Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle cell lymphoma. Examples of T-cell non-Hodgkin lymphomas include mycosis fungoides, anaplastic large cell lymphoma, and precursor T-lymphoblastic lymphoma. Lymphomas that occur after bone marrow or stem cell transplantation are typically B-cell non-Hodgkin lymphomas. See, e.g., Maloney. NEJM. 366.21(2012):2008-16. 
     Diffuse large B-cell lymphoma (DLBCL) is a form of NHL that develops from B cells. DLBCL is an aggressive lymphoma that can arise in lymph nodes or outside of the lymphatic system, e.g., in the gastrointestinal tract, testes, thyroid, skin, breast, bone, or brain. Three variants of cellular morphology are commonly observed in DLBCL: centroblastic, immunoblastic, and anaplastic. Centroblastic morphology is most common and has the appearance of medium-to-large-sized lymphocytes with minimal cytoplasm. There are several subtypes of DLBCL. For example, primary central nervous system lymphoma is a type of DLBCL that only affects the brain is called and is treated differently than DLBCL that affects areas outside of the brain. Another type of DLBCL is primary mediastinal B-cell lymphoma, which often occurs in younger patients and grows rapidly in the chest. Symptoms of DLBCL include a painless rapid swelling in the neck, armpit, or groin, which is caused by enlarged lymph nodes. For some subjects, the swelling may be painful. Other symptoms of DLBCL include night sweats, unexplained fevers, and weight loss. Although most patients with DLBCL are adults, this disease sometimes occurs in children. Treatment for DLBCL includes chemotherapy (e.g., cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide), antibodies (e.g., Rituxan), radiation, or stem cell transplants. 
     Follicular lymphoma a type of non-Hodgkin lymphoma and is a lymphoma of follicle center B-cells (centrocytes and centroblasts), which has at least a partially follicular pattern. Follicular lymphoma cells express the B-cell markers CD10, CD19, CD20, and CD22. Follicular lymphoma cells are commonly negative for CD5. Morphologically, a follicular lymphoma tumor is made up of follicles containing a mixture of centrocytes (also called cleaved follicle center cells or small cells) and centroblasts (also called large noncleaved follicle center cells or large cells). The follicles are surrounded by non-malignant cells, mostly T-cells. The follicles contain predominantly centrocytes with a minority of centroblasts. The World Health Organization (WHO) morphologically grades the disease as follows: grade 1 (&lt;5 centroblasts per high-power field (hpf); grade 2 (6-15 centroblasts/hpf); grade 3 (&gt;15 centroblasts/hpf). Grade 3 is further subdivided into the following grades: grade 3A (centrocytes still present); grade 3B (the follicles consist almost entirely of centroblasts). Treatment of follicular lymphoma includes chemotherapy, e.g., alkyating agents, nucleoside analogs, anthracycline-containing regimens, e.g., a combination therapy called CHOP-cyclophosphamide, doxorubicin, vincristine, prednisone/prednisolone, antibodies (e.g., rituximab), radioimmunotherapy, and hematopoietic stem cell transplantation. 
     CLL is a B-cell malignancy characterized by neoplastic cell proliferation and accumulation in bone morrow, blood, lymph nodes, and the spleen. The median age at time of diagnosis of CLL is about 65 years. Current treatments include chemotherapy, radiation therapy, biological therapy, or bone marrow transplantation. Sometimes symptoms are treated surgically (e.g., splenectomy removal of enlarged spleen) or by radiation therapy (e.g., de-bulking swollen lymph nodes). Chemotherapeutic agents to treat CLL include, e.g., fludarabine, 2-chlorodeoxyadenosine (cladribine), chlorambucil, vincristine, pentostatin, cyclophosphamide, alemtuzumab (Campath-1H), doxorubicin, and prednisone. Biological therapy for CLL includes antibodies, e.g., alemtuzumab, rituximab, and ofatumumab; as well as tyrosine kinase inhibitor therapies. A number of criteria can be used to classify stage of CLL, e.g., the Rai or Binet system. The Rai system describes CLL has having five stages: stage 0 where only lymphocytosis is present; stage I where lymphadenopathy is present; stage II where splenomegaly, lymphadenopathy, or both are present; stage III where anemia, organomegaly, or both are present (progression is defined by weight loss, fatigue, fever, massive organomegaly, and a rapidly increasing lymphocyte count); and stage IV where anemia, thrombocytopenia, organomegaly, or a combination thereof are present. Under the Binet staging system, there are three categories: stage A where lymphocytosis is present and less than three lymph nodes are enlarged (this stage is inclusive of all Rai stage 0 patients, one-half of Rai stage I patients, and one-third of Rai stage II patients); stage B where three or more lymph nodes are involved; and stage C wherein anemia or thrombocytopenia, or both are present. These classification systems can be combined with measurements of mutation of the immunoglobulin genes to provide a more accurate characterization of the state of the disease. The presence of mutated immunoglobulin genes correlates to improved prognosis. 
     In another embodiment, the CAR expressing cells of the present invention are used to treat cancers or leukemias, e.g., with leukemia stem cells. For example, the leukemia stem cells are CD34 + /CD38 −  leukemia cells. 
     In some embodiments, a CAR-expressing cell (e.g., CD19 CAR-expressing cell) described herein is used to deplete a B cell (e.g., a population of B cells, e.g., regulatory B cells). Without wishing to be bound by theory, it is believed that depletion of B cells, e.g., regulatory B cells, can improve the tumor microenvironment such that anti-cancer therapies (e.g., therapies described herein) can be more effective (e.g., than without depletion of the B cells). Thus, provided herein is a method for reducing, e.g., depleting, regulatory cells (e.g., regulatory B cells). The method includes administering a CAR-expressing cell (e.g., CD19 CAR-expressing cell) described herein in an amount sufficient to reduce the regulatory cells. In some embodiments, the methods can be used to modulate a tumor microenvironment, e.g., to enhance the effectiveness of a therapy described herein. 
     In some embodiments, a dose of CAR-expressing cells (e.g., CAR-expressing cells described herein, e.g., CD19 CAR-expressing cells described herein) comprises about 10 4  to about 10 9  cells/kg, e.g., about 10 4  to about 10 5  cells/kg, about 10 5  to about 10 6  cells/kg, about 10 6  to about 10 7  cells/kg, about 10 7  to about 10 8  cells/kg, or about 10 8  to about 10 9  cells/kg. In embodiments, the dose of CAR-expressing cells comprises about 0.6×10 6  cells/kg to about 2×10 7  cells/kg. 
     In some embodiments, a dose of CAR-expressing cells described herein (e.g., CD19 CAR-expressing cells) comprises about 2×10 5 , 1×10 6 , 1.1×10 6 , 2×10 6 , 3×10 6 , 3.6×10 6 , 5×10 6 , 1×10 7 , 1.8×10 7 ,2×07, 5×10 7 , 1×10 8 , 2×10 8 , 3×10 8 , or 5×10 8  cells/kg. In some embodiments, a dose of CAR cells (e.g., CD19 CAR-expressing cells) comprises at least about 1×10 6 ,1.1×10 6 ,2×10 6 ,3.6×10 6 ,5×10 6 ,1×10 7 ,1.8×10 7 , 2×10 7 , 5×10 7 ,1×10 8 , 2×10 8 ,3×10 8 , or 5×10 8  cells/kg. In some embodiments, a dose of CAR cells (e.g., CD19 CAR-expressing cells) comprises up to about 1×10 6 , 1.1×10 6 , 2×10 6 , 3.6×10 6 , 5×10 6 , 1×10 7 , 1.8×10 7 , 2×10 7 , 5×10 7 , 1×10 8 , 2×10 8 , 3×10 8 , or 5×10 8  cells/kg. In some embodiments, a dose of CAR cells (e.g., CD19 CAR-expressing cells) comprises about 1.1×10 6 -1.8×10 7  cells/kg. In some embodiments, a dose of CAR cells (e.g., CD19 CAR-expressing cell) comprises about 1×10 7 , 2×10 7 , 5×10 7 , 1×10 8 , 2×10 8 , 3×10 8 , 5×10 8 , 1×10 9 , 2×10 9 , or 5×10 9  cells. In some embodiments, a dose of CAR cells (e.g., e.g., CD19 CAR-expressing cells) comprises at least about 1×10 7 , 2×10 7 , 5×10 7 , 1×10 8 , 2×10 8 , 3×10 8 , 5×10 8 , 1×10 9 , 2×109, or 5×10 9  cells. In some embodiments, a dose of CAR cells (e.g., e.g., CD19 CAR-expressing cells) comprises up to about 1×10 7 , 2×10 7 , 5×10 7 , 1×10 8 , 2×10 8 , 3×10 8 , 5×10 8 , 1×10 9 , 2×10 9 , or 5×10 9  cells. 
     In some embodiments, a dose of CAR cells (e.g., CD19 CAR-expressing cells) comprises up to about 1×10 7 , 1.5×10 7 , 2×10 7 , 2.5×10 7 , 3×10 7 , 3.5×10 7 , 4×10 7 , 5×10 7 , 1×10 8 , 1.5×10 8 , 2×10 8 , 2.5×10 8 , 3×10 8 , 3.5×10 8 , 4×10 8 , 5×10 8 , 1×10 9 , 2×10 9 , or 5×10 9  cells. In some embodiments, a dose of CAR cells (e.g., CD19 CAR-expressing cell) comprises up to about 1-3×10 7  to 1-3×10 8  cells. In some embodiments, the subject is administered about 1-3×10 7  of CD19 CAR-expressing cells. In other embodiments, the subject is administered about 1-3×10 8  of CD19 CAR-expressing cells. 
     In some embodiments, a dose of CAR-expressing cells (e.g., CAR-expressing cells described herein, e.g., CD19 CAR-expressing cells described herein) comprises about 1×10 6  cells/m 2  to about 1×10 9  cells/m 2 , e.g., about 1×10 7  cells/m 2  to about 5×10 8  cells/m 2 , e.g., about 1.5×10 7  cells/m 2 , about 2×10 7  cells/m 2 , about 4.5×10 7  cells/m 2 , about 10 8  cells/m 2 , about 1.2×10 8  cells/m 2 , or about 2×10 8  cells/m 2 . 
     Selected Doses and Dosage Regimens 
     Accordingly, in one aspect, the invention pertains to a method of treating a subject (e.g., a mammal) having a cancer, comprising administering immune effector cells comprising a CAR molecule. In one embodiment, the immune effector cells are administered as a single dose, e.g., a single dose as described herein. In other embodiments the immune effector cells are administered as a plurality of doses, e.g., a first dose, a second dose, and optionally a third dose, e.g., as described herein. 
     In a related aspect, the invention pertains to a method of treating a subject (e.g., an adult subject) having a cancer (e.g., acute lymphoid leukemia (ALL)), comprising administering to the subject a a dose, e.g., a single dose, or a plurality of doses (e.g., a first dose, a second dose, and optionally one or more additional doses), each dose comprising immune effector cells expressing a CAR molecule, e.g., a CD19 CAR molecule, (e.g., a CAR molecule according to residues 22-486 of SEQ ID NO: 58) or a BCMA CAR molecule. 
     In yet another aspect, the invention pertains to a use of a single dose, or a plurality of doses (e.g., a first dose, a second dose, and optionally a third dose), of immune effector cells comprising a CAR molecule (e.g., a CD19 CAR molecule, (e.g., a CAR molecule according to residues 22-486 of SEQ ID NO: 58) or a BCMA CAR molecule), for treating a subject (e.g., an adult) having a cancer (e.g., acute lymphoid leukemia (ALL)). 
     In certain aspects, the invention features a method of treating a subject (e.g., a pediatric subject) having a cancer (e.g., ALL), comprising administering to the subject immune effector cells expressing a CAR molecule. The method comprises administering one of the following: 
     (i) administering a dose of 2-5×10 6  viable CAR-expressing cells/kg, e.g., transduced viable T cells cells/kg, wherein the subject has a body mass of less than or equal to 50 kg; 
     (ii) administering a dose of 1.0-2.5 ×10 viable CAR-expressing cells, e.g., transduced viable T cells, wherein the subject has a body mass of at least 50 kg; 
     (iii) administering a dose of 0.2-5×10 6  viable CAR-expressing cells/kg, e.g., transduced viable T cells/kg, wherein the subject has a body mass of less than or equal to 50 kg; or 
     (iv) administering a dose of 0.1-2.5 ×10 viable CAR-expressing cells, e.g., transduced viable T cells, wherein the subject has a body mass of at least 50 kg. 
     In embodiments, a single dose is administered to the subject, e.g., the pediatric subject. In embodiments, the CAR-expressing cell is a CD19 CAR-expressing cell, e.g., a cell expressing a CD19 CAR of any Tables 2 or 3 herein, e.g., CTL019 or CTL119. 
     In embodiments, the doses are administered on sequential days, e.g., the first dose is administered on day 1, the second dose is administered on day 2, and the optional third dose (if administered) is administered on day 3. 
     In embodiments, a fourth, fifth, or sixth dose, or more doses, are administered. 
     In embodiments, the first dose comprises about 10% of the total dose, the second dose comprises about 30% of the total dose, and the third dose comprises about 60% of the total dose, wherein the aforementioned percentages have a sum of 100%. In embodiments, the first dose comprises about 9-11%, 8-12%, 7-13%, or 5-15% of the total dose. In embodiments, the second dose comprises about 29-31%, 28-32%, 27-33%, 26-34%, 25-35%, 24-36%, 23-37%, 22-38%, 21-39%, or 20-40% of the total dose. In embodiments, the third dose comprises about 55-65%, 50-70%, 45-75%, or 40-80% of the total dose. In embodiments, the total dose refers to the total number of viable CAR-expressing cells administered over the course of 1 week, 2 weeks, 3 weeks, or 4 weeks. In some embodiments wherein two doses are administered, the total dose refers to the sum of the number of viable CAR-expressing cells administered to the subject in the first and second doses. In some embodiments wherein three doses are administered, the total dose refers to the sum of the number of viable CAR-expressing cells administered to the subject in the first, second, and third doses. 
     In embodiments, the dose is measured according to the number of viable CAR-expressing cells therein. CAR expression can be measured, e.g., by flow cytometry using an antibody molecule that binds the CAR molecule and a detectable label. Viability can be measured, e.g., by Cellometer. 
     In embodiments, the viable CAR-expressing cells are administered in ascending doses. In embodiments, the second dose is larger than the first dose, e.g., larger by 10%, 20%, 30%, or 50%. In embodiments, the second dose is twice, three times, four times, or five times the size of the first dose. In embodiments, the third dose is larger than the second dose, e.g., larger by 10%, 20%, 30%, or 50%. In embodiments, the third dose is twice, three times, four times, or five times the size of the second dose. 
     In certain embodiments, the method includes one, two, three, four, five, six, seven or all of a)-h) of the following: 
     a) the number of CAR-expressing, viable cells administered in the first dose is no more than 1/3, of the number of CAR-expressing, viable cells administered in the second dose; 
     b) the number of CAR-expressing, viable cells administered in the first dose is no more than 1/X, wherein X is 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40 or 50, of the total number of CAR-expressing, viable cells administered; 
     c) the number of CAR-expressing, viable cells administered in the first dose is no more than 1×10 7 , 2×10 7 , 3×10 7 , 4×10 7 , 5×10 7 , 6×10 7 , 7×10 7 , 8×10 7 , 9×10 7 , 1×10, 2×10 8 , 3×10 8 , 4×10 8 , or 5×10 8  CAR-expressing, viable cells, and the second dose is greater than the first dose; 
     d) the number of CAR-expressing, viable cells administered in the second dose is no more than 1/2, of the number of CAR-expressing, viable cells administered in the third dose; 
     e) the number of CAR-expressing, viable cells administered in the second dose is no more than 1/Y, wherein Y is 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40 or 50, of the total number of CAR-expressing, viable cells administered; 
     f) the number of CAR-expressing, viable cells administered in the second dose is no more than 1×10 7 , 2×10 7 , 3×10 7 , 4×10 7 , 5×10 7 , 6×10 7 , 7×10 7 , 8×10 7 , 9×10 7 , 1×10 8 , 2×10 8 , 3×10 8 , 4×10 8 , or 5×10 8  CAR-expressing, viable cells, and the third dose is greater than the second dose; 
     h) the dosages and time periods of administration of the first, second, and optionally third doses are selected such that the subject experiences CRS at a level no greater than 4, 3, 2, or 1. 
     In embodiments, the total dose is about 5×10 8  CAR-expressing, viable cells. In embodiments, the total dose is about 5×10 7 -5×10 8  CAR-expressing, viable cells. In embodiments, the first dose is about 5×10 7  (e.g., ±10%, 20%, or 30%) CAR-expressing, viable cells, the second dose is about 1.5×10 8  (e.g., ±10%, 20%, or 30%) CAR-expressing, viable cells, and the third dose is about 3×10 8  (e.g., ±10%, 20%, or 30%) CAR-expressing, viable cells. 
     In embodiments, the method comprises administering, e.g., as a single dose or as a plurality of doses as described herein, a dose of 0.02-5×10 6  viable CAR-expressing cells/kg, e.g., transduced viable T cells/kg, e.g., a dose of 0.02-5×10 6 , 0.03-5×10 6 , 0.04-5×10 6 , 0.05-5×10 6 , 0.06-5×10 6 , 0.07-5×10 6 , 0.08-5×10 6 , 0.09-5×10 6 , 0.10-5×10 6 , 0.11-5×10 6 , 0.12-5×10 6 , 0.13-5×10 6 , 0.14-5×10 6 , 0.15-5×10 6 , 0.16-5×10 6 , 0.17-5×10 6 , 0.18-5×10 6 , 0.19-5×10 6 , or 0.20-5×10 6 , wherein the subject has a body mass of less than or equal to 50 kg. 
     In embodiments, the method comprises administering, e.g., as a single dose or as a plurality of doses as described herein, a dose of 0.2-5×10 6  viable CAR-expressing cells/kg, e.g., transduced viable T cells/kg, e.g., a dose of 0.2-5×10 6 , 0.3-5×10 6 , 0.4-5×10 6 , 0.5-5×10 6 , 0.6-5×10 6 , 0.7-5×10 6 , 0.8-5×10 6 , 0.9-5×10 6 , 1.0-5×10 6 , 1.1-5×10 6 , 1.2-5×10 6 , 1.3-5×10 6 , 1.4-5×10 6 , 1.5-5×10 6 , 1.6-5×10 6 , 1.7-5×10 6 , 1.8-5×10 6 , 1.9-5×10 6 , or 2-5×10 6 , wherein the subject has a body mass of less than or equal to 50 kg. 
     In embodiments, the method comprises administering, e.g., as a single dose or as a plurality of doses as described herein, a dose of 2-50×10 6  viable CAR-expressing cells/kg, e.g., transduced viable T cells/kg, e.g., a dose of 2-5×10 6 , 2-10×10 6 , 2-15×10 6 , 2-20×10 6 , 2-25×10 6 , 2-30×10 6 , 2-35×10 6 , 2-40×10 6 , 2-45×10 6 , or 2-50×10 6 , wherein the subject has a body mass of less than or equal to 50 kg. 
     In embodiments, the method further comprises administering, e.g., as a single dose or as a plurality of doses as described herein, a dose of 0.2-50×10 6  viable CAR-expressing cells/kg, e.g., transduced viable T cells/kg, e.g., a dose of 0.2-5×10 6 , 0.2-10×10 6 , 0.2-15×10 6 , 0.2-20×10 6 , 0.2-25×10 6 , 0.2-30×10 6 , 0.2-35×10 6 , 0.2-40×10 6 , 0.2-45×10 6 , or 0.2-50×10 6 , wherein the subject has a body mass of less than or equal to 50 kg. 
     In embodiments, the method comprises administering, e.g., as a single dose or as a plurality of doses as described herein, a dose of 0.02-50×10 6  viable CAR-expressing cells/kg, e.g., transduced viable T cells/kg, e.g, a dose of 0.02-50×10 6 , 0.03-45×10 6 , 0.05-40×10 6 , 0.1-35×10 6 , 0.2-30×10 6 , 0.3-25×10 6 , 0.4-20×10 6 , 0.5-15×10 6 , 1-10×10 6 , 2-5×10 6 , wherein the subject has a body mass of less than or equal to 50 kg. 
     In embodiments, the method comprises administering, e.g., as a single dose or as a plurality of doses as described herein, a dose of 0.01-2.5×10 8  viable CAR-expressing cells, e.g., transduced viable T cells, e.g., a dose of 0.01-2.5×10 8 , 0.02-2.5×10 8 , 0.03-2.5×10 8 , 0.04-2.5×10 8 , 0.05-2.5×10 8 , 0.06-2.5×10 8 , 0.07-2.5×10 8 , 0.08-2.5×10 8 , 0.09-2.5×10 8 , or 0.10-2.5×10 8 , wherein the subject has a body mass of at least 50 kg. 
     In embodiments, the method comprises administering, e.g., as a single dose or as a plurality of doses as described herein, a dose of 0.1-2.5×10 8  viable CAR-expressing cells, e.g., transduced viable T cells, e.g., a dose of 0.1-2.5×10 8 , 0.2-2.5×10 8 , 0.3-2.5×10 8 , 0.4-2.5×10 8 , 0.5-2.5×10 8 , 0.6-2.5×10 8 , 0.7-2.5×10 8 , 0.8-2.5×10 8 , 0.9-2.5×10 8 , or 1.0-2.5×10 8 , wherein the subject has a body mass of at least 50 kg. 
     In embodiments, the method comprises administering, e.g., as a single dose or as a plurality of doses as described herein, a dose of 1-25×10 8  viable CAR-expressing cells, e.g., transduced viable T cells/kg, e.g., a dose of 1-2.5×10 8 , 1-5×10 8 , 1-7.5×10 8 , 1-10×10 8 , 1-12.5×10 8 , 1-15×10 8 , 1-17.5×10 8 , 1-20×10 8 , 1-22.5×10 8 , or 1-25×10 8 , wherein the subject has a body mass of at least 50 kg. 
     In embodiments, the method comprises administering, e.g., as a single dose or as a plurality of doses as described herein, a dose of 0.1-2.5×10 8  viable CAR-expressing cells, e.g., transduced viable T cells/kg, e.g., a dose of 0.1-2.5×10 8 , 0.1-5×10 8 , 0.1-7.5×10 8 , 0.1-10×10 8 , 0.1-12.5×10 8 , 0.1-15×10 8 , 0.1-17.5×10 8 , 0.1-20×10 8 , 0.1-22.5×10 8 , or 0.1-25×10 8 , wherein the subject has a body mass of at least 50 kg. 
     In embodiments, the method comprises administering, e.g., as a single dose or as a plurality of doses as described herein, a dose of 0.01-25 ×10 viable CAR-expressing cells, e.g., transduced viable T cells/kg, e.g., a dose of 0.01-25×10 8 , 0.05-22.5×10 8 , 0.1-20×10 8 , 0.2-17.5×10 8 , 0.5-15×10 8 , 0.6-12.5×10 8 , 0.7-10×10 8 , 0.8-7.5×10 8 , 0.9-5×10 8 , or 1-2.5×10 8 , wherein the subject has a body mass of at least 50 kg. 
     In any of the methods or compositions for use described herein, in some embodiments, a dose of CAR-expressing cells (e.g., CD19 CAR-expressing cells) comprises about 10 4  to about 10 9  cells/kg, e.g., about 10 4  to about 10 5  cells/kg, about 10 5  to about 10 6  cells/kg, about 10 6  to about 10 7  cells/kg, about 10 7  to about 10 8  cells/kg, or about 10 8  to about 10 9  cells/kg; or at least about one of: 1×10 7 , 1.5×10 7 , 2×10 7 , 2.5×10 7 , 3×10 7 , 3.5×10 7 , 4×10 7 , 5×10 7 , 1×10 8 , 1.5×10 8 , 2×10 8 , 2.5×10 8 , 3×10 8 , 3.5×10 8 , 4×10 8 , 5×10 8 , 1×10 9 , 2×10 9 , or 5×10 9  cells. In some embodiments, a dose of CAR-expressing cells (e.g., CD19 CAR-expressing cells or BCMA CAR-expressing cells) comprises at least about 1-5×10 7  to 1-5×10 8  CAR-expressing cells In some embodiments, the subject is administered about 1-5×10 7  CAR-expressing cells (e.g., CD19 CAR-expressing cells or BCMA CAR-expressing cells)). In other embodiments, the subject is administered about 1-5×10 8  CAR-expressing cells (e.g., CD19 CAR-expressing cells or BCMA CAR-expressing cells)). 
     Any of the dose ranges disclosed herein is intended to include the upper and lower endpoint values specified. For example, a dose range of 1-5×10 7  CAR-expressing cells includes a dose of 1×10 7  CAR-expressing cells and 5×10 7  CAR-expressing cells (unless explicitly noted otherwise). 
     Combination Therapies 
     The combination of a CAR as described herein (e.g., a CD19 or BCMA CAR-expressing cell described herein e.g., and one or more B-cell inhibitors, e.g., as described herein) may be used in combination with other known agents and therapies. 
     A CAR-expressing cell described herein and/or the at least one additional therapeutic agent can be administered simultaneously, in the same or in separate compositions, or sequentially. For sequential administration, the CAR-expressing cell described herein can be administered first, and the additional agent can be administered second, or the order of administration can be reversed. 
     The CAR therapy and/or other therapeutic agents (such as a second CAR therapy), procedures or modalities can be administered during periods of active disorder, or during a period of remission or less active disease. The CAR therapy can be administered before the other treatment, concurrently with the treatment, post-treatment, or during remission of the disorder. 
     For instance, in some embodiments, CAR therapy is administered to a subject having a disease associated with CD19 or BCMA expression, e.g., a cancer. The subject can be assayed for indicators of responsiveness or relapse. In some embodiments, when the subject shows one or more signs of relapse, e.g., a frameshift and/or premature stop codon in CD19, an additional therapy is administered. In embodiments, the additional therapy is a B-cell inhibitor. The CD19 therapy may be continued (for instance, when there are still some CD19-expressing cancer cells detectable in the subject) or may be discontinued (for instance, when a risk-benefit analysis favors discontinuing the therapy). 
     When administered in combination, the CAR therapy and the additional agent (e.g., second or third agent), or all, can be administered in an amount or dose that is higher, lower or the same than the amount or dosage of each agent used individually, e.g., as a monotherapy. In certain embodiments, the administered amount or dosage of the CAR therapy, the additional agent (e.g., second or third agent), or all, is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50%) than the amount or dosage of each agent used individually, e.g., as a monotherapy. In other embodiments, the amount or dosage of the CAR therapy, the additional agent (e.g., second or third agent), or all, that results in a desired effect (e.g., treatment of cancer) is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50% lower) than the amount or dosage of each agent used individually, e.g., as a monotherapy, required to achieve the same therapeutic effect. 
     The one or more therapies described herein can be administered to the subject substantially at the same time or in any order. For instance, a CD19 inhibitor, e.g., a CD19 CAR-expressing cell described herein, the one or more B-cell inhibitor, and/or optionally the at least one additional therapeutic agent can be administered simultaneously, in the same or in separate compositions, or sequentially. Additional timings of administration, e.g., sequence of administration, are described in pages 4-15 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety 
     In embodiments, one or more of the therapeutics in the combination therapy is an antibody molecule. Cancer antigens can be targeted with monoclonal antibody therapy. Monoclonal antibody (mAb) therapy has been shown to exert powerful antitumor effects by multiple mechanisms, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and direct cell inhibition or apoptosis-inducing effects on tumor cells that over-express the target molecules. 
     In further aspects, the combination of the CAR-expressing cell described herein may be used in a treatment regimen in combination with surgery, chemotherapy, radiation, an mTOR pathway inhibitor, immunosuppressive agents, such as cyclosporin, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunoablative agents such as CAMPATH, anti-CD3 antibodies or other antibody therapies, cytoxin, fludarabine, cyclosporin, FK506, rapamycin, mycophenolic acid, steroids, FR901228, cytokines, and irradiation. peptide vaccine, such as that described in Izumoto et al. 2008 J Neurosurg 108:963-971. 
     In one embodiment, the CAR-expressing cell described herein (optionally in combination with a B-cell inhibitor) can be used in combination with a chemotherapeutic agent. Exemplary chemotherapeutic agents include an anthracycline (e.g., doxorubicin (e.g., liposomal doxorubicin)); a vinca alkaloid (e.g., vinblastine, vincristine, vindesine, vinorelbine); an alkylating agent (e.g., cyclophosphamide, decarbazine, melphalan, ifosfamide, temozolomide); an immune cell antibody (e.g., alemtuzamab, gemtuzumab, rituximab, tositumomab); an antimetabolite (including, e.g., folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors (e.g., fludarabine)); a TNFR glucocorticoid induced TNFR related protein (GITR) agonist; a proteasome inhibitor (e.g., aclacinomycin A, gliotoxin or bortezomib); an immunomodulator such as thalidomide or a thalidomide derivative (e.g., lenalidomide). 
     General Chemotherapeutic agents considered for use in combination therapies include anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea), Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), nab-paclitaxel (Abraxane®), phoenix (Yttrium90/MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®). 
     Treatment with a combination of a chemotherapeutic agent and a cell expressing a CAR molecule described herein can be used to treat a hematologic cancer described herein, e.g., AML. In embodiments, the combination of a chemotherapeutic agent and a CAR-expressing cell is useful for targeting, e.g., killing, cancer stem cells, e.g., leukemic stem cells, e.g., in subjects with AML. In embodiments, the combination of a chemotherapeutic agent and a CAR-expressing cell is useful for treating minimal residual disease (MRD). MRD refers to the small number of cancer cells that remain in a subject during treatment, e.g., chemotherapy, or after treatment. MRD is often a major cause for relapse. The present invention provides a method for treating cancer, e.g., MRD, comprising administering a chemotherapeutic agent in combination with a CAR-expressing cell, e.g., as described herein. 
     In an embodiment, the chemotherapeutic agent is administered prior to administration of the cell expressing a CAR molecule, e.g., a CAR molecule described herein. In chemotherapeutic regimens where more than one administration of the chemotherapeutic agent is desired, the chemotherapeutic regimen is initiated or completed prior to administration of a cell expressing a CAR molecule, e.g., a CAR molecule described herein. In embodiments, the chemotherapeutic agent is administered at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 20 days, 25 days, or 30 days prior to administration of the cell expressing the CAR molecule. In embodiments, the chemotherapeutic regimen is initiated or completed at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 20 days, 25 days, or 30 days prior to administration of the cell expressing the CAR molecule. 
     Anti-cancer agents of particular interest for combinations with the compounds of the present invention include: antimetabolites; drugs that inhibit either the calcium dependent phosphatase calcineurin or the p70S6 kinase FK506) or inhibit the p70S6 kinase; alkylating agents; mTOR inhibitors; immunomodulators; anthracyclines;  vinca  alkaloids; proteosome inhibitors; GITR agonists; protein tyrosine phosphatase inhibitors; a CDK4 kinase inhibitor; a BTK kinase inhibitor; a MKN kinase inhibitor; a DGK kinase inhibitor; or an oncolytic virus. 
     Exemplary antimetabolites include, without limitation, folic acid antagonists (also referred to herein as antifolates), pyrimidine analogs, purine analogs and adenosine deaminase inhibitors): methotrexate (Rheumatrex, Trexall), 5-fluorouracil (Adrucil®, Efudex®, Fluoroplex®), floxuridine (FUDF®), cytarabine (Cytosar-U®, Tarabine PFS), 6-mercaptopurine (Puri-Nethol®)), 6-thioguanine (Thioguanine Tabloid®), fludarabine phosphate (Fludara®), pentostatin (Nipent®), pemetrexed (Alimta®), raltitrexed (Tomudex®), cladribine (Leustatin®), clofarabine (Clofarex®, Clolar®), mercaptopurine (Puri-Nethol®), capecitabine (Xeloda®), nelarabine (Arranon®), azacitidine (Vidaza®) and gemcitabine (Gemzar®). Preferred antimetabolites include, e.g., 5-fluorouracil (Adrucil®, Efudex®, Fluoroplex®), floxuridine (FUDF®), capecitabine (Xeloda®), pemetrexed (Alimta®), raltitrexed (Tomudex®) and gemcitabine (Gemzar®). 
     Exemplary alkylating agents include, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): uracil mustard (Aminouracil Mustard®, Chlorethaminacil®, Demethyldopan®, Desmethyldopan®, Haemanthamine®, Nordopan®, Uracil nitrogen Mustard®, Uracillost®, Uracilmostaza®, Uramustin®, Uramustine), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune™), ifosfamide (Mitoxana), melphalan (Alkeran®), Chlorambucil (Leukeran®), pipobroman (Amedel®, Vercyte®), triethylenemelamine (Hemel®, Hexalen®, Hexastat), triethylenethiophosphoramine, Temozolomide (Temodar®), thiotepa (Thioplex®), busulfan (Busilvex®, Myleran®), carmustine (BiCNU®), lomustine (CeeNU®), streptozocin (Zanosar®), and Dacarbazine (DTIC-Dome®). Additional exemplary alkylating agents include, without limitation, Oxaliplatin (Eloxatin®); Temozolomide (Temodar® and Temodal); Dactinomycin (also known as actinomycin-D, Cosmegen®); Melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, Alkeran®); Altretamine (also known as hexamethylmelamine (HMM), Hexalen®); Carmustine (BiCNU®); Bendamustine (Treanda); Busulfan (Busulfex® and Myleran®); Carboplatin (Paraplatin®); Lomustine (also known as CCNU, CeeNU®); Cisplatin (also known as CDDP, Platinol® and Platinol®-AQ); Chlorambucil (Leukeran®); Cyclophosphamide (Cytoxan® and Neosar®); Dacarbazine (also known as DTIC, DIC and imidazole carboxamide, DTIC-Dome®); Altretamine (also known as hexamethylmelamine (HMM), Hexalen®); Ifosfamide (Ifex®); Prednumustine; Procarbazine (Matulane); Mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, Mustargen); Streptozocin (Zanosar®); Thiotepa (also known as thiophosphoamide, TESPA and TSPA, Thioplex®); Cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune); and Bendamustine HCl (Treanda®). 
     In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with fludarabine, cyclophosphamide, and/or rituximab. In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with fludarabine, cyclophosphamide, and rituximab (FCR). In embodiments, the subject has CLL. For example, the subject has a deletion in the short arm of chromosome 17 (del(17p), e.g., in a leukemic cell). In other examples, the subject does not have a del(17p). In embodiments, the subject comprises a leukemic cell comprising a mutation in the immunoglobulin heavy-chain variable-region (IgV H ) gene. In other embodiments, the subject does not comprise a leukemic cell comprising a mutation in the immunoglobulin heavy-chain variable-region (IgV H ) gene. In embodiments, the fludarabine is administered at a dosage of about 10-50 mg/m2 (e.g., about 10-15, 15-20, 20-25, 25-30, 30-35, 35-40, 40-45, or 45-50 mg/m 2 ), e.g., intravenously. In embodiments, the cyclophosphamide is administered at a dosage of about 200-300 mg/m2 (e.g., about 200-225, 225-250, 250-275, or 275-300 mg/m 2 ), e.g., intravenously. In embodiments, the rituximab is administered at a dosage of about 400-600 mg/m2 (e.g., 400-450, 450-500, 500-550, or 550-600 mg/m 2 ), e.g., intravenously. 
     In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with bendamustine and rituximab. In embodiments, the subject has CLL. For example, the subject has a deletion in the short arm of chromosome 17 (del(17p), e.g., in a leukemic cell). In other examples, the subject does not have a del(17p). In embodiments, the subject comprises a leukemic cell comprising a mutation in the immunoglobulin heavy-chain variable-region (IgV H ) gene. In other embodiments, the subject does not comprise a leukemic cell comprising a mutation in the immunoglobulin heavy-chain variable-region (IgV H ) gene. In embodiments, the bendamustine is administered at a dosage of about 70-110 mg/m2 (e.g., 70-80, 80-90, 90-100, or 100-110 mg/m2), e.g., intravenously. In embodiments, the rituximab is administered at a dosage of about 400-600 mg/m2 (e.g., 400-450, 450-500, 500-550, or 550-600 mg/m 2 ), e.g., intravenously. 
     In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with rituximab, cyclophosphamide, doxorubicine, vincristine, and/or a corticosteroid (e.g., prednisone). In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with rituximab, cyclophosphamide, doxorubicine, vincristine, and prednisone (R-CHOP). In embodiments, the subject has diffuse large B-cell lymphoma (DLBCL). In embodiments, the subject has nonbulky limited-stage DLBCL (e.g., comprises a tumor having a size/diameter of less than 7 cm). In embodiments, the subject is treated with radiation in combination with the R-CHOP. For example, the subject is administered R-CHOP (e.g., 1-6 cycles, e.g., 1, 2, 3, 4, 5, or 6 cycles of R-CHOP), followed by radiation. In some cases, the subject is administered R-CHOP (e.g., 1-6 cycles, e.g., 1, 2, 3, 4, 5, or 6 cycles of R-CHOP) following radiation. 
     In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and/or rituximab. In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R). In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with dose-adjusted EPOCH-R (DA-EPOCH-R). In embodiments, the subject has a B cell lymphoma, e.g., a Myc-rearranged aggressive B cell lymphoma. 
     In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with rituximab and/or lenalidomide. Lenalidomide ((RS)-3-(4-Amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione) is an immunomodulator. In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with rituximab and lenalidomide. In embodiments, the subject has follicular lymphoma (FL) or mantle cell lymphoma (MCL). In embodiments, the subject has FL and has not previously been treated with a cancer therapy. In embodiments, lenalidomide is administered at a dosage of about 10-20 mg (e.g., 10-15 or 15-20 mg), e.g., daily. In embodiments, rituximab is administered at a dosage of about 350-550 mg/m 2  (e.g., 350-375, 375-400, 400-425, 425-450, 450-475, or 475-500 mg/m 2 ), e.g., intravenously. 
     Exemplary mTOR inhibitors include, e.g., temsirolimus; ridaforolimus (formally known as deferolimus, (1R,2R,4S)-4-[(2R)-2 [(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23, 29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0 4,9 ] hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethylphosphinate, also known as AP23573 and MK8669, and described in PCT Publication No. WO 03/064383); everolimus (Afinitor® or RAD001); rapamycin (AY22989, Sirolimus®); simapimod (CAS 164301-51-3); emsirolimus, (5-{2,4-Bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055); 2-Amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one (PF04691502, CAS 1013101-36-4); and N 2 -[1,4-dioxo-4-[[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-L-arginylglycyl-L-α-aspartylL-serine-, inner salt (SF1126, CAS 936487-67-1) (SEQ ID NO: 1316), and XL765. 
     Exemplary immunomodulators include, e.g., afutuzumab (available from Roche®); pegfilgrastim (Neulasta); lenalidomide (CC-5013, Revlimid®); thalidomide (Thalomid®), actimid (CC4047); and IRX-2 (mixture of human cytokines including interleukin 1, interleukin 2, and interferon γ, CAS 951209-71-5, available from IRX Therapeutics). 
     Exemplary anthracyclines include, e.g., doxorubicin (Adriamycin® and Rubex®); bleomycin (Lenoxane®); daunorubicin (dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, Cerubidine); daunorubicin liposomal (daunorubicin citrate liposome, DaunoXome®); mitoxantrone (DHAD, Novantrone); epirubicin (Ellence™); idarubicin (Idamycin®, Idamycin PFS®); mitomycin C (Mutamycin®); geldanamycin; herbimycin; ravidomycin; and desacetylravidomycin. 
     Exemplary vinca alkaloids include, e.g., vinorelbine tartrate (Navelbine®), Vincristine (Oncovin®), and Vindesine (Eldisine®)); vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, Alkaban-AQ® and Velban®); and vinorelbine (Navelbine®). 
     Exemplary proteosome inhibitors include bortezomib (Velcade); carfilzomib (PX-171-007, (S)-4-Methyl-N—((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-pentanamide); marizomib (NPI-0052); ixazomib citrate (MLN-9708); delanzomib (CEP-18770); and O-Methyl-N-[(2-methyl-5-thiazolyl)carbonyl]-L-seryl-O-methyl-N-[(1S)-2-[(2R)-2-methyl-2-oxiranyl]-2-oxo-1-(phenylmethyl)ethyl]-L-serinamide (ONX-0912). 
     In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with brentuximab. Brentuximab is an antibody-drug conjugate of anti-CD30 antibody and monomethyl auristatin E. In embodiments, the subject has Hodgkin&#39;s lymphoma (HL), e.g., relapsed or refractory HL. In embodiments, the subject comprises CD30+ HL. In embodiments, the subject has undergone an autologous stem cell transplant (ASCT). In embodiments, the subject has not undergone an ASCT. In embodiments, brentuximab is administered at a dosage of about 1-3 mg/kg (e.g., about 1-1.5, 1.5-2, 2-2.5, or 2.5-3 mg/kg), e.g., intravenously, e.g., every 3 weeks. 
     In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with brentuximab and dacarbazine or in combination with brentuximab and bendamustine. Dacarbazine is an alkylating agent with a chemical name of 5-(3,3-Dimethyl-1-triazenyl)imidazole-4-carboxamide. Bendamustine is an alkylating agent with a chemical name of 4-[5-[Bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid. In embodiments, the subject has Hodgkin&#39;s lymphoma (HL). In embodiments, the subject has not previously been treated with a cancer therapy. In embodiments, the subject is at least 60 years of age, e.g., 60, 65, 70, 75, 80, 85, or older. In embodiments, dacarbazine is administered at a dosage of about 300-450 mg/m 2  (e.g., about 300-325, 325-350, 350-375, 375-400, 400-425, or 425-450 mg/m 2 ), e.g., intravenously. In embodiments, bendamustine is administered at a dosage of about 75-125 mg/m2 (e.g., 75-100 or 100-125 mg/m 2 , e.g., about 90 mg/m 2 ), e.g., intravenously. In embodiments, brentuximab is administered at a dosage of about 1-3 mg/kg (e.g., about 1-1.5, 1.5-2, 2-2.5, or 2.5-3 mg/kg), e.g., intravenously, e.g., every 3 weeks. 
     In some embodiments, a CAR-expressing cell described herein is administered to a subject in combination with a CD20 inhibitor, e.g., an anti-CD20 antibody (e.g., an anti-CD20 mono- or bispecific antibody) or a fragment thereof. Exemplary anti-CD20 antibodies include but are not limited to rituximab, ofatumumab, ocrelizumab, veltuzumab, obinutuzumab, TRU-015 (Trubion Pharmaceuticals), ocaratuzumab, and Prol31921 (Genentech). See, e.g., Lim et al. Haematologica. 95.1(2010):135-43. 
     In some embodiments, the anti-CD20 antibody comprises rituximab. Rituximab is a chimeric mouse/human monoclonal antibody IgG1 kappa that binds to CD20 and causes cytolysis of a CD20 expressing cell, e.g., as described in www.accessdata.fda.gov/drugsatfda_docs/label/2010/103705s53111bl.pdf. In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with rituximab. In embodiments, the subject has CLL or SLL. 
     In some embodiments, rituximab is administered intravenously, e.g., as an intravenous infusion. For example, each infusion provides about 500-2000 mg (e.g., about 500-550, 550-600,600-650, 650-700, 700-750, 750-800, 800-850, 850-900, 900-950, 950-1000, 1000-1100, 1100-1200, 1200-1300, 1300-1400, 1400-1500, 1500-1600, 1600-1700, 1700-1800, 1800-1900, or 1900-2000 mg) of rituximab. In some embodiments, rituximab is administered at a dose of 150 mg/m 2  to 750 mg/m 2 , e.g., about 150-175 mg/m 2 , 175-200 mg/m 2 , 200-225 mg/m 2 , 225-250 mg/m 2 , 250-300 mg/m 2 , 300-325 mg/m 2 , 325-350 mg/m 2 , 350-375 mg/m 2 , 375-400 mg/m 2 , 400-425 mg/m 2 , 425-450 mg/m 2 , 450-475 mg/m 2 , 475-500 mg/m 2 , 500-525 mg/m 2 , 525-550 mg/m 2 , 550-575 mg/m 2 , 575-600 mg/m 2 , 600-625 mg/m 2 , 625-650 mg/m 2 , 650-675 mg/m 2 , or 675-700 mg/m 2 , where m 2  indicates the body surface area of the subject. In some embodiments, rituximab is administered at a dosing interval of at least 4 days, e.g., 4, 7, 14, 21, 28, 35 days, or more. For example, rituximab is administered at a dosing interval of at least 0.5 weeks, e.g., 0.5, 1, 2, 3, 4, 5, 6, 7, 8 weeks, or more. In some embodiments, rituximab is administered at a dose and dosing interval described herein for a period of time, e.g., at least 2 weeks, e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks, or greater. For example, rituximab is administered at a dose and dosing interval described herein for a total of at least 4 doses per treatment cycle (e.g., at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more doses per treatment cycle). 
     In some embodiments, the anti-CD20 antibody comprises ofatumumab. Ofatumumab is an anti-CD20 IgG1κ human monoclonal antibody with a molecular weight of approximately 149 kDa. For example, ofatumumab is generated using transgenic mouse and hybridoma technology and is expressed and purified from a recombinant murine cell line (NSO). See, e.g., www.accessdata.fda.gov/drugsatfda_docs/label/2009/125326lbl.pdf; and Clinical Trial Identifier number NCT01363128, NCT01515176, NCT01626352, and NCT01397591. In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with ofatumumab. In embodiments, the subject has CLL or SLL. 
     In some embodiments, ofatumumab is administered as an intravenous infusion. For example, each infusion provides about 150-3000 mg (e.g., about 150-200, 200-250, 250-300, 300-350, 350-400, 400-450, 450-500, 500-550, 550-600, 600-650, 650-700, 700-750, 750-800, 800-850, 850-900, 900-950, 950-1000, 1000-1200, 1200-1400, 1400-1600, 1600-1800, 1800-2000, 2000-2200, 2200-2400, 2400-2600, 2600-2800, or 2800-3000 mg) of ofatumumab. In embodiments, ofatumumab is administered at a starting dosage of about 300 mg, followed by 2000 mg, e.g., for about 11 doses, e.g., for 24 weeks. In some embodiments, ofatumumab is administered at a dosing interval of at least 4 days, e.g., 4, 7, 14, 21, 28, 35 days, or more. For example, ofatumumab is administered at a dosing interval of at least 1 week, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 26, 28, 20, 22, 24, 26, 28, 30 weeks, or more. In some embodiments, ofatumumab is administered at a dose and dosing interval described herein for a period of time, e.g., at least 1 week, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 40, 50, 60 weeks or greater, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or greater, or 1, 2, 3, 4, 5 years or greater. For example, ofatumumab is administered at a dose and dosing interval described herein for a total of at least 2 doses per treatment cycle (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, or more doses per treatment cycle). 
     In some cases, the anti-CD20 antibody comprises ocrelizumab. Ocrelizumab is a humanized anti-CD20 monoclonal antibody, e.g., as described in Clinical Trials Identifier Nos. NCT00077870, NCT01412333, NCT00779220, NCT00673920, NCT01194570, and Kappos et al. Lancet. 19.378(2011):1779-87. 
     In some cases, the anti-CD20 antibody comprises veltuzumab. Veltuzumab is a humanized monoclonal antibody against CD20. See, e.g., Clinical Trial Identifier No. NCT00547066, NCT00546793, NCT01101581, and Goldenberg et al. Leuk Lymphoma. 51(5)(2010):747-55. 
     In some cases, the anti-CD20 antibody comprises GA101. GA101 (also called obinutuzumab or RO5072759) is a humanized and glyco-engineered anti-CD20 monoclonal antibody. See, e.g., Robak. Curr. Opin. Investig. Drugs. 10.6(2009):588-96; Clinical Trial Identifier Numbers: NCT01995669, NCT01889797, NCT02229422, and NCT01414205; and www.accessdata.fda.gov/drugsatfda_docs/label/2013/125486s0001bl.pdf. 
     In some cases, the anti-CD20 antibody comprises AME-133v. AME-133v (also called LY2469298 or ocaratuzumab) is a humanized IgG1 monoclonal antibody against CD20 with increased affinity for the FcγRIIIa receptor and an enhanced antibody dependent cellular cytotoxicity (ADCC) activity compared with rituximab. See, e.g., Robak et al. BioDrugs 25.1(2011):13-25; and Forero-Torres et al. Clin Cancer Res. 18.5(2012):1395-403. 
     In some cases, the anti-CD20 antibody comprises PRO131921. PRO131921 is a humanized anti-CD20 monoclonal antibody engineered to have better binding to FcγRIIIa and enhanced ADCC compared with rituximab. See, e.g., Robak et al. BioDrugs 25.1(2011):13-25; and Casulo et al. Clin Immunol. 154.1(2014):37-46; and Clinical Trial Identifier No. NCT00452127. 
     In some cases, the anti-CD20 antibody comprises TRU-015. TRU-015 is an anti-CD20 fusion protein derived from domains of an antibody against CD20. TRU-015 is smaller than monoclonal antibodies, but retains Fc-mediated effector functions. See, e.g., Robak et al. BioDrugs 25.1(2011):13-25. TRU-015 contains an anti-CD20 single-chain variable fragment (scFv) linked to human IgG1 hinge, CH2, and CH3 domains but lacks CH1 and CL domains. 
     In some embodiments, an anti-CD20 antibody described herein is conjugated or otherwise bound to a therapeutic agent, e.g., a chemotherapeutic agent (e.g., cytoxan, fludarabine, histone deacetylase inhibitor, demethylating agent, peptide vaccine, anti-tumor antibiotic, tyrosine kinase inhibitor, alkylating agent, anti-microtubule or anti-mitotic agent), anti-allergic agent, anti-nausea agent (or anti-emetic), pain reliever, or cytoprotective agent described herein. 
     In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with a B-cell lymphoma 2 (BCL-2) inhibitor (e.g., venetoclax, also called ABT-199 or GDC-0199;) and/or rituximab. In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with venetoclax and rituximab. Venetoclax is a small molecule that inhibits the anti-apoptotic protein, BCL-2. Venetoclax has the following chemical name (4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide). 
     In embodiments, the subject has CLL. In embodiments, the subject has relapsed CLL, e.g., the subject has previously been administered a cancer therapy. In embodiments, venetoclax is administered at a dosage of about 15-600 mg (e.g., 15-20, 20-50, 50-75, 75-100, 100-200, 200-300, 300-400, 400-500, or 500-600 mg), e.g., daily. In embodiments, rituximab is administered at a dosage of about 350-550 mg/m2 (e.g., 350-375, 375-400, 400-425, 425-450, 450-475, or 475-500 mg/m2), e.g., intravenously, e.g., monthly. 
     In some embodiments, one or more CAR-expressing cells described herein is administered in combination with an oncolytic virus. In embodiments, oncolytic viruses are capable of selectively replicating in and triggering the death of or slowing the growth of a cancer cell. In some cases, oncolytic viruses have no effect or a minimal effect on non-cancer cells. An oncolytic virus includes but is not limited to an oncolytic adenovirus, oncolytic Herpes Simplex Viruses, oncolytic retrovirus, oncolytic parvovirus, oncolytic vaccinia virus, oncolytic Sinbis virus, oncolytic influenza virus, or oncolytic RNA virus (e.g., oncolytic reovirus, oncolytic Newcastle Disease Virus (NDV), oncolytic measles virus, or oncolytic vesicular stomatitis virus (VSV)). 
     In some embodiments, the oncolytic virus is a virus, e.g., recombinant oncolytic virus, described in US2010/0178684 A1, which is incorporated herein by reference in its entirety. In some embodiments, a recombinant oncolytic virus comprises a nucleic acid sequence (e.g., heterologous nucleic acid sequence) encoding an inhibitor of an immune or inflammatory response, e.g., as described in US2010/0178684 A1, incorporated herein by reference in its entirety. In embodiments, the recombinant oncolytic virus, e.g., oncolytic NDV, comprises a pro-apoptotic protein (e.g., apoptin), a cytokine (e.g., GM-CSF, interferon-gamma, interleukin-2 (IL-2), tumor necrosis factor-alpha), an immunoglobulin (e.g., an antibody against ED-B firbonectin), tumor associated antigen, a bispecific adapter protein (e.g., bispecific antibody or antibody fragment directed against NDV HN protein and a T cell co-stimulatory receptor, such as CD3 or CD28; or fusion protein between human IL-2 and single chain antibody directed against NDV HN protein). See, e.g., Zamarin et al. Future Microbiol. 7.3(2012):347-67, incorporated herein by reference in its entirety. In some embodiments, the oncolytic virus is a chimeric oncolytic NDV described in U.S. Pat. No. 8,591,881 B2, US 2012/0122185 A1, or US 2014/0271677 A1, each of which is incorporated herein by reference in their entireties. 
     In some embodiments, the oncolytic virus comprises a conditionally replicative adenovirus (CRAd), which is designed to replicate exclusively in cancer cells. See, e.g., Alemany et al. Nature Biotechnol. 18(2000):723-27. In some embodiments, an oncolytic adenovirus comprises one described in Table 1 on page 725 of Alemany et al., incorporated herein by reference in its entirety. 
     Exemplary oncolytic viruses include but are not limited to the following: 
     Group B Oncolytic Adenovirus (ColoAdl) (PsiOxus Therapeutics Ltd.) (see, e.g., Clinical Trial Identifier: NCT02053220); 
     ONCOS-102 (previously called CGTG-102), which is an adenovirus comprising granulocyte-macrophage colony stimulating factor (GM-CSF) (Oncos Therapeutics) (see, e.g., Clinical Trial Identifier: NCT01598129); 
     VCN-01, which is a genetically modified oncolytic human adenovirus encoding human PH20 hyaluronidase (VCN Biosciences, S.L.) (see, e.g., Clinical Trial Identifiers: NCT02045602 and NCT02045589); 
     Conditionally Replicative Adenovirus ICOVIR-5, which is a virus derived from wild-type human adenovirus serotype 5 (Had5) that has been modified to selectively replicate in cancer cells with a deregulated retinoblastoma/E2F pathway (Institut Catala d&#39;Oncologia) (see, e.g., Clinical Trial Identifier: NCT01864759); 
     Celyvir, which comprises bone marrow-derived autologous mesenchymal stem cells (MSCs) infected with ICOVIR5, an oncolytic adenovirus (Hospital Infantil Universitario Nino Jesns, Madrid, Spain/Ramon Alemany) (see, e.g., Clinical Trial Identifier: NCT01844661); 
     CG0070, which is a conditionally replicating oncolytic serotype 5 adenovirus (Ad5) in which human E2F-1 promoter drives expression of the essential Ela viral genes, thereby restricting viral replication and cytotoxicity to Rb pathway-defective tumor cells (Cold Genesys, Inc.) (see, e.g., Clinical Trial Identifier: NCT02143804); or 
     DNX-2401 (formerly named Delta-24-RGD), which is an adenovirus that has been engineered to replicate selectively in retinoblastoma (Rb)-pathway deficient cells and to infect cells that express certain RGD-binding integrins more efficiently (Clinica Universidad de Navarra, Universidad de Navarra/DNAtrix, Inc.) (see, e.g., Clinical Trial Identifier: NCT01956734). 
     In some embodiments, an oncolytic virus described herein is administering by injection, e.g., subcutaneous, intra-arterial, intravenous, intramuscular, intrathecal, or intraperitoneal injection. In embodiments, an oncolytic virus described herein is administered intratumorally, transdermally, transmucosally, orally, intranasally, or via pulmonary administration. 
     In an embodiment, cells expressing a CAR described herein are administered to a subject in combination with a molecule that decreases the Treg cell population. Methods that decrease the number of (e.g., deplete) Treg cells are known in the art and include, e.g., CD25 depletion, cyclophosphamide administration, modulating GITR function. Without wishing to be bound by theory, it is believed that reducing the number of Treg cells in a subject prior to apheresis or prior to administration of a CAR-expressing cell described herein reduces the number of unwanted immune cells (e.g., Tregs) in the tumor microenvironment and reduces the subject&#39;s risk of relapse. 
     In an embodiment, a CAR-expressing cell described herein is administered to a subject in combination with a molecule that decreases the Treg cell population. Methods that decrease the number of (e.g., deplete) Treg cells are known in the art and include, e.g., CD25 depletion, cyclophosphamide administration, and modulating GITR function. Without wishing to be bound by theory, it is believed that reducing the number of Treg cells in a subject prior to apheresis or prior to administration of a CAR-expressing cell described herein reduces the number of unwanted immune cells (e.g., Tregs) in the tumor microenvironment and reduces the subject&#39;s risk of relapse. In one embodiment, CAR-expressing cells described herein are administered to a subject in combination with a molecule targeting GITR and/or modulating GITR functions, such as a GITR agonist and/or a GITR antibody that depletes regulatory T cells (Tregs). In one embodiment, CAR-expressing cells described herein are administered to a subject in combination with cyclophosphamide. In one embodiment, the GITR binding molecule and/or molecule modulating GITR function (e.g., GITR agonist and/or Treg depleting GITR antibodies) is administered prior to the CAR-expressing cells. For example, in one embodiment, the GITR agonist can be administered prior to apheresis of the cells. In embodiments, cyclophosphamide is administered to the subject prior to administration (e.g., infusion or re-infusion) of the CAR-expressing cell or prior to apheresis of the cells. In embodiments, cyclophosphamide and an anti-GITR antibody are administered to the subject prior to administration (e.g., infusion or re-infusion) of the CAR-expressing cell or prior to apheresis of the cells. In one embodiment, the subject has cancer (e.g., a solid cancer or a hematological cancer such as ALL or CLL). In one embodiment, the subject has CLL. In embodiments, the subject has a solid cancer, e.g., a solid cancer described herein. 
     In one embodiment, the combination of a CD19 CAR expressing cell described herein and one or more B-cell inhibitor described herein is administered to a subject in combination with a GITR agonist, e.g., a GITR agonist described herein. In one embodiment, the GITR agonist is administered prior to the CAR-expressing cell, e.g., CD19 CAR-expressing cells. For example, in one embodiment, the GITR agonist can be administered prior to apheresis of the cells. In one embodiment, the subject has CLL. 
     In one embodiment, a CAR expressing cell described herein is administered to a subject in combination with a GITR agonist, e.g., a GITR agonist described herein. In one embodiment, the GITR agonist is administered prior to the CAR-expressing cell. For example, in one embodiment, the GITR agonist can be administered prior to apheresis of the cells. 
     Exemplary GITR agonists include, e.g., GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies) such as, e.g., a GITR fusion protein described in U.S. Pat. No. 6,111,090, European Patent No.: 090505B1, U.S. Pat. No. 8,586,023, PCT Publication Nos.: WO 2010/003118 and 2011/090754, or an anti-GITR antibody described, e.g., in U.S. Pat. No. 7,025,962, European Patent No.: 1947183B1, U.S. Pat. Nos. 7,812,135, 8,388,967, 8,591,886, European Patent No.: EP 1866339, PCT Publication No.: WO 2011/028683, PCT Publication No.: WO 2013/039954, PCT Publication No.: WO2005/007190, PCT Publication No.: WO 2007/133822, PCT Publication No.: WO2005/055808, PCT Publication No.: WO 99/40196, PCT Publication No.: WO 2001/03720, PCT Publication No.: WO99/20758, PCT Publication No.: WO2006/083289, PCT Publication No.: WO 2005/115451, U.S. Pat. No. 7,618,632, and PCT Publication No.: WO 2011/051726. 
     In one embodiment, a CAR expressing cell described herein is administered to a subject in combination with a protein tyrosine phosphatase inhibitor, e.g., a protein tyrosine phosphatase inhibitor described herein. In one embodiment, the protein tyrosine phosphatase inhibitor is an SHP-1 inhibitor, e.g., an SHP-1 inhibitor described herein, such as, e.g., sodium stibogluconate. In one embodiment, the protein tyrosine phosphatase inhibitor is an SHP-2 inhibitor, e.g., an SHP-2 inhibitor described herein. 
     In one embodiment, a CAR-expressing cell described herein optionally in combination with one or more B-cell inhibitor can be used in combination with a kinase inhibitor. In one embodiment, the kinase inhibitor is a CDK4 inhibitor, e.g., a CDK4 inhibitor described herein, e.g., a CD4/6 inhibitor, such as, e.g., 6-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, hydrochloride (also referred to as palbociclib or PD0332991). In one embodiment, the kinase inhibitor is a BTK inhibitor, e.g., a BTK inhibitor described herein, such as, e.g., ibrutinib. In one embodiment, the kinase inhibitor is an mTOR inhibitor, e.g., an mTOR inhibitor described herein, such as, e.g., rapamycin, a rapamycin analog, OSI-027. The mTOR inhibitor can be, e.g., an mTORC1 inhibitor and/or an mTORC2 inhibitor, e.g., an mTORC1 inhibitor and/or mTORC2 inhibitor described herein. In one embodiment, the kinase inhibitor is a MNK inhibitor, e.g., a MNK inhibitor described herein, such as, e.g., 4-amino-5-(4-fluoroanilino)-pyrazolo [3,4-d] pyrimidine. The MNK inhibitor can be, e.g., a MNKla, MNK1b, MNK2a and/or MNK2b inhibitor. 
     In one embodiment, the kinase inhibitor is a CDK4 inhibitor selected from aloisine A; flavopiridol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone; crizotinib (PF-02341066; 2-(2-Chlorophenyl)-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-one, hydrochloride (P276-00); 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-2-amine (RAF265); indisulam (E7070); roscovitine (CYC202); palbociclib (PD0332991); dinaciclib (SCH727965); N-[5-[[(5-tert-butyloxazol-2-yl)methyl]thio]thiazol-2-yl]piperidine-4-carboxamide (BMS 387032); 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzoic acid (MLN8054); 5-[3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-N-ethyl-4-methyl-3-pyridinemethanamine (AG-024322); 4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid N-(piperidin-4-yl)amide (AT7519); 4-[2-methyl-1-(1-methylethyl)-1H-imidazol-5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidinamine (AZD5438); and XL281 (BMS908662). 
     In one embodiment, the kinase inhibitor is a CDK4 inhibitor, e.g., palbociclib (PD0332991), and the palbociclib is administered at a dose of about 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg (e.g., 75 mg, 100 mg or 125 mg) daily for a period of time, e.g., daily for 14-21 days of a 28 day cycle, or daily for 7-12 days of a 21 day cycle. In one embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles of palbociclib are administered. 
     In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with a cyclin-dependent kinase (CDK) 4 or 6 inhibitor, e.g., a CDK4 inhibitor or a CDK6 inhibitor described herein. In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with a CDK4/6 inhibitor (e.g., an inhibitor that targets both CDK4 and CDK6), e.g., a CDK4/6 inhibitor described herein. In an embodiment, the subject has MCL. MCL is an aggressive cancer that is poorly responsive to currently available therapies, i.e., essentially incurable. In many cases of MCL, cyclin D1 (a regulator of CDK4/6) is expressed (e.g., due to chromosomal translocation involving immunoglobulin and Cyclin D1 genes) in MCL cells. Thus, without being bound by theory, it is thought that MCL cells are highly sensitive to CDK4/6 inhibition with high specificity (i.e., minimal effect on normal immune cells). CDK4/6 inhibitors alone have had some efficacy in treating MCL, but have only achieved partial remission with a high relapse rate. An exemplary CDK4/6 inhibitor is LEE011 (also called ribociclib). 
     Without being bound by theory, it is believed that administration of a CAR-expressing cell described herein with a CDK4/6 inhibitor (e.g., LEE011 or other CDK4/6 inhibitor described herein) can achieve higher responsiveness, e.g., with higher remission rates and/or lower relapse rates, e.g., compared to a CDK4/6 inhibitor alone. 
     In one embodiment, the kinase inhibitor is a BTK inhibitor selected from ibrutinib (PCI-32765); GDC-0834; RN-486; CGI-560; CGI-1764; HM-71224; CC-292; ONO-4059; CNX-774; and LFM-A13. In an embodiment, the BTK inhibitor does not reduce or inhibit the kinase activity of interleukin-2-inducible kinase (ITK), and is selected from GDC-0834; RN-486; CGI-560; CGI-1764; HM-71224; CC-292; ONO-4059; CNX-774; and LFM-A13. 
     In one embodiment, the kinase inhibitor is a BTK inhibitor, e.g., ibrutinib (PCI-32765). In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with a BTK inhibitor (e.g., ibrutinib). In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with ibrutinib (also called PCI-32765). The chemical name of ibrutinib is (1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one). 
     In embodiments, the subject has CLL, mantle cell lymphoma (MCL), or small lymphocytic lymphoma (SLL). For example, the subject has a deletion in the short arm of chromosome 17 (del(17p), e.g., in a leukemic cell). In other examples, the subject does not have a del(17p). In embodiments, the subject has relapsed CLL or SLL, e.g., the subject has previously been administered a cancer therapy (e.g., previously been administered one, two, three, or four prior cancer therapies). In embodiments, the subject has refractory CLL or SLL. In other embodiments, the subject has follicular lymphoma, e.g., relapse or refractory follicular lymphoma. In one embodiment, the kinase inhibitor is a BTK inhibitor, e.g., ibrutinib (PCI-32765), and the ibrutinib is administered at a dose of about 250 mg, 300 mg, 350 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg (e.g., 250 mg, 420 mg or 560 mg) daily for a period of time, e.g., daily for 21 day cycle, or daily for 28 day cycle. In one embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles of ibrutinib are administered. In some embodiments, ibrutinib is administered in combination with rituximab. See, e.g., Burger et al. (2013) Ibrutinib In Combination With Rituximab (iR) Is Well Tolerated and Induces a High Rate Of Durable Remissions In Patients With High-Risk Chronic Lymphocytic Leukemia (CLL): New, Updated Results Of a Phase II Trial In 40 Patients, Abstract 675 presented at 55 th ASH Annual Meeting and Exposition, New Orleans, La. 7-10 December Without being bound by theory, it is thought that the addition of ibrutinib enhances the T cell proliferative response and may shift T cells from a T-helper-2 (Th2) to T-helper-1 (Thl) phenotype. Th1 and Th2 are phenotypes of helper T cells, with Th1 versus Th2 directing different immune response pathways. A Th1 phenotype is associated with proinflammatory responses, e.g., for killing cells, such as intracellular pathogens/viruses or cancerous cells, or perpetuating autoimmune responses. A Th2 phenotype is associated with eosinophil accumulation and anti-inflammatory responses. In some embodiments of the methods, uses, and compositions herein, the BTK inhibitor is a BTK inhibitor described in International Application WO/2015/079417, which is herein incorporated by reference in its entirety. For instance, in some embodiments, the BTK inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; 
     
       
         
         
             
             
         
       
     
     wherein,
 
R1 is hydrogen, C1-C6 alkyl optionally substituted by hydroxy;
 
R2 is hydrogen or halogen;
 
R3 is hydrogen or halogen;
 
R4 is hydrogen;
 
R5 is hydrogen or halogen;
 
or R4 and R5 are attached to each other and stand for a bond, —CH2-, —CH2-CH2-, —CH═CH—, —CH═CH—CH2-; —CH2-CH═CH—; or —CH2-CH2-CH2-;
 
R6 and R7 stand independently from each other for H, C1-C6 alkyl optionally substituted by hydroxyl, C3-C6 cycloalkyl optionally substituted by halogen or hydroxy, or halogen;
 
R8, R9, R, R′, R10 and R11 independently from each other stand for H, or C1-C6 alkyl optionally substituted by C1-C6 alkoxy; or any two of R8, R9, R, R′, R10 and R11 together with the carbon atom to which they are bound may form a 3-6 membered saturated carbocyclic ring;
 
R12 is hydrogen or C1-C6 alkyl optionally substituted by halogen or C1-C6 alkoxy;
 
or R12 and any one of R8, R9, R, R′, R10 or R11 together with the atoms to which they are bound may form a 4, 5, 6 or 7 membered azacyclic ring, which ring may optionally be substituted by halogen, cyano, hydroxyl, C1-C6 alkyl or C1-C6 alkoxy;
 
     n is 0 or 1; and 
     R13 is C2-C6 alkenyl optionally substituted by C1-C6 alkyl, C1-C6 alkoxy or N,N-di-C1-C6 alkyl amino; C2-C6 alkynyl optionally substituted by C1-C6 alkyl or C1-C6 alkoxy; or C2-C6 alkylenyl oxide optionally substituted by C1-C6 alkyl. 
     In some embodiments, the BTK inhibitor of Formula I is chosen from: N-(3-(5-((1-Acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (E)-N-(3-(6-Amino-5-((1-(but-2-enoyl)azetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-Amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-Amino-5-((1-(but-2-ynoyl)azetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(5-((1-Acryloylpiperidin-4-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (E)-N-(3-(6-Amino-5-(2-(N-methylbut-2-enamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-Amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (E)-N-(3-(6-Amino-5-(2-(4-methoxy-N-methylbut-2-enamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(2-((4-Amino-6-(3-(4-cyclopropyl-2-fluorobenzamido)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)oxy)ethyl)-N-methyloxirane-2-carboxamide; N-(2-((4-Amino-6-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)phenyl)pyrimidin-5-yl)oxy)ethyl)-N-methylacrylamide; N-(3-(5-(2-Acrylamidoethoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-Amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-Amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(5-((1-Acrylamidocyclopropyl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)—N-(3-(5-(2-Acrylamidopropoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)—N-(3-(6-Amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)—N-(3-(6-Amino-5-(2-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)—N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-Amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)—N-(3-(5-((1-Acryloylpyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)—N-(3-(6-Amino-5-((1-(but-2-ynoyl)pyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-2-(3-(5-((1-Acryloylpyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-6-cyclopropyl-3,4-dihydroisoquinolin-1(2H)-one; N-(2-((4-Amino-6-(3-(6-cyclopropyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-5-fluoro-2-(hydroxymethyl)phenyl)pyrimidin-5-yl)oxy)ethyl)-N-methylacrylamide; N-(3-(5-(((2S,4R)-1-Acryloyl-4-methoxypyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-Amino-5-(((2S,4R)-1-(but-2-ynoyl)-4-methoxypyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; 2-(3-(5-(((2S,4R)-1-Acryloyl-4-methoxypyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-6-cyclopropyl-3,4-dihydroisoquinolin-1(2H)-one; N-(3-(5-(((2S,4S)-1-Acryloyl-4-methoxypyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-Amino-5-(((2S,4S)-1-(but-2-ynoyl)-4-methoxypyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(5-(((2S,4R)-1-Acryloyl-4-fluoropyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-Amino-5-(((2S,4R)-1-(but-2-ynoyl)-4-fluoropyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)—N-(3-(5-((1-Acryloylazetidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)—N-(3-(6-Amino-5-((1-propioloylazetidin-2-yl)methoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-2-(3-(5-((1-Acryloylazetidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-6-cyclopropyl-3,4-dihydroisoquinolin-1(2H)-one; (R)—N-(3-(5-((1-Acryloylazetidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (R)—N-(3-(5-((1-Acryloylpiperidin-3-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(5-(((2R,3S)-1-Acryloyl-3-methoxypyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(5-(((2S,4R)-1-Acryloyl-4-cyanopyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; or N-(3-(5-(((2S,4S)-1-Acryloyl-4-cyanopyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. 
     Unless otherwise provided, the chemical terms used above in describing the BTK inhibitor of Formula I are used according to their meanings as set out in International Application WO/2015/079417, which is herein incorporated by reference in its entirety. 
     In one embodiment, the kinase inhibitor is an mTOR inhibitor selected from temsirolimus; ridaforolimus (1R,2R,4S)-4-[(2R)-2 [(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23, 29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04-9] hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethylphosphinate, also known as AP23573 and MK8669; everolimus (RAD001); rapamycin (AY22989); simapimod; (5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055); 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one (PF04691502); and N 2 -[1,4-dioxo-4-[[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-L-arginylglycyl-L-α-aspartylL-serine-, inner salt (SF1126) (SEQ ID NO: 1316); and XL765. 
     In one embodiment, the kinase inhibitor is an mTOR inhibitor, e.g., rapamycin, and the rapamycin is administered at a dose of about 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg (e.g., 6 mg) daily for a period of time, e.g., daily for 21 day cycle cycle, or daily for 28 day cycle. In one embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles of rapamycin are administered. In one embodiment, the kinase inhibitor is an mTOR inhibitor, e.g., everolimus and the everolimus is administered at a dose of about 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg (e.g., 10 mg) daily for a period of time, e.g., daily for 28 day cycle. In one embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles of everolimus are administered. 
     In one embodiment, the kinase inhibitor is an MNK inhibitor selected from CGP052088; 4-amino-3-(p-fluorophenylamino)-pyrazolo [3,4-d] pyrimidine (CGP57380); cercosporamide; ETC-1780445-2; and 4-amino-5-(4-fluoroanilino)-pyrazolo [3,4-d] pyrimidine. 
     In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with a phosphoinositide 3-kinase (PI3K) inhibitor (e.g., a PI3K inhibitor described herein, e.g., idelalisib or duvelisib) and/or rituximab. In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with idelalisib and rituximab. In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with duvelisib and rituximab. Idelalisib (also called GS-1101 or CAL-101; Gilead) is a small molecule that blocks the delta isoform of PI3K. The chemical name for idelalisib is (5-Fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]-4(3H)-quinazolinone). 
     Duvelisib (also called IPI-145; Infinity Pharmaceuticals and Abbvie) is a small molecule that blocks PI3K-δ,γ. The chemical name for duvelisib is (8-Chloro-2-phenyl-3-[(1S)-1-(9H-purin-6-ylamino)ethyl]-1(2H)-isoquinolinone). 
     In embodiments, the subject has CLL. In embodiments, the subject has relapsed CLL, e.g., the subject has previously been administered a cancer therapy (e.g., previously been administered an anti-CD20 antibody or previously been administered ibrutinib). For example, the subject has a deletion in the short arm of chromosome 17 (del(17p), e.g., in a leukemic cell). In other examples, the subject does not have a del(17p). In embodiments, the subject comprises a leukemic cell comprising a mutation in the immunoglobulin heavy-chain variable-region (IgVH) gene. In other embodiments, the subject does not comprise a leukemic cell comprising a mutation in the immunoglobulin heavy-chain variable-region (IgVH) gene. In embodiments, the subject has a deletion in the long arm of chromosome 11 (del(11q)). In other embodiments, the subject does not have a del(11q). In embodiments, idelalisib is administered at a dosage of about 100-400 mg (e.g., 100-125, 125-150, 150-175, 175-200, 200-225, 225-250, 250-275, 275-300, 325-350, 350-375, or 375-400 mg), e.g., BID. In embodiments, duvelisib is administered at a dosage of about 15-100 mg (e.g., about 15-25, 25-50, 50-75, or 75-100 mg), e.g., twice a day. In embodiments, rituximab is administered at a dosage of about 350-550 mg/m2 (e.g., 350-375, 375-400, 400-425, 425-450, 450-475, or 475-500 mg/m 2 ), e.g., intravenously. 
     In one embodiment, the kinase inhibitor is a dual phosphatidylinositol 3-kinase (PI3K) and mTOR inhibitor selected from 2-Amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one (PF-04691502); N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-V-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea (PF-05212384, PKI-587); 2-Methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile (BEZ-235); apitolisib (GDC-0980, RG7422); 2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide (GSK2126458); 8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]quinolin-2(3H)-one Maleic acid (NVP-BGT226); 3-[4-(4-Morpholinylpyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl]phenol (PI-103); 5-(9-isopropyl-8-methyl-2-morpholino-9H-purin-6-yl)pyrimidin-2-amine (VS-5584, SB2343); and N-[2-[(3,5-Dimethoxyphenyl)amino]quinoxalin-3-yl]-4-[(4-methyl-3-methoxyphenyl)carbonyl]aminophenylsulfonamide (XL765). 
     In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with an anaplastic lymphoma kinase (ALK) inhibitor. Exemplary ALK kinases include but are not limited to crizotinib (Pfizer), ceritinib (Novartis), alectinib (Chugai), brigatinib (also called AP26113; Ariad), entrectinib (Ignyta), PF-06463922 (Pfizer), TSR-011 (Tesaro) (see, e.g., Clinical Trial Identifier No. NCT02048488), CEP-37440 (Teva), and X-396 (Xcovery). In some embodiments, the subject has a solid cancer, e.g., a solid cancer described herein, e.g., lung cancer. 
     The chemical name of crizotinib is 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine. The chemical name of ceritinib is 5-Chloro-N 2 -[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-N 4 -[2-(isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine. The chemical name of alectinib is 9-ethyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. The chemical name of brigatinib is 5-Chloro-N 2 -{4-[4-(dimethylamino)-1-piperidinyl]-2-methoxyphenyl}-N 4 -[2-(dimethylphosphoryl)phenyl]-2,4-pyrimidinediamine. The chemical name of entrectinib is N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-methylpiperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide. The chemical name of PF-06463922 is (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile. The chemical structure of CEP-37440 is (S)-2-((5-chloro-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-1-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide. The chemical name of X-396 is (R)-6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-N-(4-(4-methylpiperazine-1-carbonyl)phenyl)pyridazine-3-carboxamide. 
     In one embodiment, the kinase inhibitor is an ITK inhibitor selected from ibrutinib; N-(5-(5-(4-Acetylpiperazine-1-carbonyl)-4-methoxy-2-methylphenylthio)thiazol-2-yl)-4-((3,3-dimethylbutan-2-ylamino)methyl)benzamide (BMS-509744); 7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one (CTA056); R)-3-(1-(1-Acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(3-methyl-4-(1-methylethyl))benzamide (PF-06465469). 
     Drugs that inhibit either the calcium dependent phosphatase calcineurin (cyclosporine and FK506) or inhibit the p70S6 kinase that is important for growth factor induced signaling (rapamycin). (Liu et al., Cell 66:807-815, 1991; Henderson et al., Immun. 73:316-321, 1991; Bierer et al., Curr. Opin. Immun. 5:763-773, 1993) can also be used. In a further aspect, the cell compositions of the present invention may be administered to a patient in conjunction with (e.g., before, simultaneously or following) bone marrow transplantation, T cell ablative therapy using chemotherapy agents such as, fludarabine, external-beam radiation therapy (XRT), cyclophosphamide, and/or antibodies such as OKT3 or CAMPATH. In one aspect, the cell compositions of the present invention are administered following B-cell ablative therapy such as agents that react with CD20, e.g., Rituxan. For example, in one embodiment, subjects may undergo standard treatment with high dose chemotherapy followed by peripheral blood stem cell transplantation. In certain embodiments, following the transplant, subjects receive an infusion of the expanded immune cells of the present invention. In an additional embodiment, expanded cells are administered before or following surgery. 
     In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with an indoleamine 2,3-dioxygenase (IDO) inhibitor. IDO is an enzyme that catalyzes the degradation of the amino acid, L-tryptophan, to kynurenine. Many cancers overexpress IDO, e.g., prostatic, colorectal, pancreatic, cervical, gastric, ovarian, head, and lung cancer. pDCs, macrophages, and dendritic cells (DCs) can express IDO. Without being bound by theory, it is thought that a decrease in L-tryptophan (e.g., catalyzed by IDO) results in an immunosuppressive milieu by inducing T-cell anergy and apoptosis. Thus, without being bound by theory, it is thought that an IDO inhibitor can enhance the efficacy of a CAR-expressing cell described herein, e.g., by decreasing the suppression or death of a CAR-expressing immune cell. In embodiments, the subject has a solid tumor, e.g., a solid tumor described herein, e.g., prostatic, colorectal, pancreatic, cervical, gastric, ovarian, head, or lung cancer. Exemplary inhibitors of IDO include but are not limited to 1-methyl-tryptophan, indoximod (NewLink Genetics) (see, e.g., Clinical Trial Identifier Nos. NCT01191216; NCT01792050), and INCB024360 (Incyte Corp.) (see, e.g., Clinical Trial Identifier Nos. NCT01604889; NCT01685255) 
     In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with a modulator of myeloid-derived suppressor cells (MDSCs). MDSCs accumulate in the periphery and at the tumor site of many solid tumors. These cells suppress T cell responses, thereby hindering the efficacy of CAR-expressing cell therapy. Without being bound by theory, it is thought that administration of a MDSC modulator enhances the efficacy of a CAR-expressing cell described herein. In an embodiment, the subject has a solid tumor, e.g., a solid tumor described herein, e.g., glioblastoma. Exemplary modulators of MDSCs include but are not limited to MCS110 and BLZ945. MCS110 is a monoclonal antibody (mAb) against macrophage colony-stimulating factor (M-CSF). See, e.g., Clinical Trial Identifier No. NCT00757757. BLZ945 is a small molecule inhibitor of colony stimulating factor 1 receptor (CSF1R). See, e.g., Pyonteck et al. Nat. Med. 19(2013):1264-72. 
     In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with a CD19 CART cell (e.g., CTL019, e.g., as described in WO2012/079000, incorporated herein by reference). In embodiments, the subject has acute myeloid leukemia (AML), e.g., a CD19 positive AML or a CD19 negative AML. In embodiments, the subject has a CD19+ lymphoma, e.g., a CD19+ Non-Hodgkin&#39;s Lymphoma (NHL), a CD19+ FL, or a CD19+ DLBCL. In embodiments, the subject has a relapsed or refractory CD19+ lymphoma. In embodiments, a lymphodepleting chemotherapy is administered to the subject prior to, concurrently with, or after administration (e.g., infusion) of CD19 CART cells. In an example, the lymphodepleting chemotherapy is administered to the subject prior to administration of CD19 CART cells. For example, the lymphodepleting chemotherapy ends 1-4 days (e.g., 1, 2, 3, or 4 days) prior to CD19 CART cell infusion. In embodiments, multiple doses of CD19 CART cells are administered, e.g., as described herein. For example, a single dose comprises about 5×10 8  CD19 CART cells. In embodiments, a lymphodepleting chemotherapy is administered to the subject prior to, concurrently with, or after administration (e.g., infusion) of a CAR-expressing cell described herein, e.g., a non-CD19 CAR-expressing cell. In embodiments, a CD19 CART is administered to the subject prior to, concurrently with, or after administration (e.g., infusion) of a non-CD19 CAR-expressing cell, e.g., a non-CD19 CAR-expressing cell described herein. 
     In some embodiments, a CAR-expressing cell described herein is administered to a subject in combination with a CD19 CAR-expressing cell, e.g., CTL019, e.g., as described in WO2012/079000, incorporated herein by reference, for treatment of a disease associated with the expression of CLL-1, e.g., a cancer described herein. Without being bound by theory, it is believed that administering a CD19 CAR-expressing cell in combination with a CAR-expressing cell improves the efficacy of a CAR-expressing cell described herein by targeting early lineage cancer cells, e.g., cancer stem cells, modulating the immune response, depleting regulatory B cells, and/or improving the tumor microenvironment. For example, a CD19 CAR-expressing cell targets cancer cells that express early lineage markers, e.g., cancer stem cells and CD19-expressing cells, while the CAR-expressing cell described herein targets cancer cells that express later lineage markers, e.g., CLL-1. This preconditioning approach can improve the efficacy of the CAR-expressing cell described herein. In such embodiments, the CD19 CAR-expressing cell is administered prior to, concurrently with, or after administration (e.g., infusion) of a CAR-expressing cell described herein. 
     In embodiments, a CAR-expressing cell described herein also expresses a CAR targeting CD19, e.g., a CD19 CAR. In an embodiment, the cell expressing a CAR described herein and a CD19 CAR is administered to a subject for treatment of a cancer described herein, e.g., AML. In an embodiment, the configurations of one or both of the CAR molecules comprise a primary intracellular signaling domain and a costimulatory signaling domain. In another embodiment, the configurations of one or both of the CAR molecules comprise a primary intracellular signaling domain and two or more, e.g., 2, 3, 4, or 5 or more, costimulatory signaling domains. In such embodiments, the CAR molecule described herein and the CD19 CAR may have the same or a different primary intracellular signaling domain, the same or different costimulatory signaling domains, or the same number or a different number of costimulatory signaling domains. Alternatively, the CAR described herein and the CD19 CAR are configured as a split CAR, in which one of the CAR molecules comprises an antigen binding domain and a costimulatory domain (e.g., 4-1BB), while the other CAR molecule comprises an antigen binding domain and a primary intracellular signaling domain (e.g., CD3 zeta). 
     In some embodiments, a CAR-expressing cell described herein is administered to a subject in combination with a interleukin-15 (IL-15) polypeptide, a interleukin-15 receptor alpha (IL-15Ra) polypeptide, or a combination of both a IL-15 polypeptide and a IL-15Ra polypeptide e.g., hetIL-15 (Admune Therapeutics, LLC). hetIL-15 is a heterodimeric non-covalent complex of IL-15 and IL-15Ra. hetIL-15 is described in, e.g., U.S. Pat. No. 8,124,084, U.S. 2012/0177598, U.S. 2009/0082299, U.S. 2012/0141413, and U.S. 2011/0081311, incorporated herein by reference. In embodiments, het-IL-15 is administered subcutaneously. In embodiments, the subject has a cancer, e.g., solid cancer, e.g., melanoma or colon cancer. In embodiments, the subject has a metastatic cancer. 
     In embodiments, a subject having a disease described herein, e.g., a hematological disorder, e.g., AML or MDS, is administered a CAR-expressing cell described herein in combination with an agent, e.g., cytotoxic or chemotherapy agent, a biologic therapy (e.g., antibody, e.g., monoclonal antibody, or cellular therapy), or an inhibitor (e.g., kinase inhibitor). In embodiments, the subject is administered a CAR-expressing cell described herein in combination with a cytotoxic agent, e.g., CPX-351 (Celator Pharmaceuticals), cytarabine, daunorubicin, vosaroxin (Sunesis Pharmaceuticals), sapacitabine (Cyclacel Pharmaceuticals), idarubicin, or mitoxantrone. CPX-351 is a liposomal formulation comprising cytarabine and daunorubicin at a 5:1 molar ratio. In embodiments, the subject is administered a CAR-expressing cell described herein in combination with a hypomethylating agent, e.g., a DNA methyltransferase inhibitor, e.g., azacitidine or decitabine. In embodiments, the subject is administered a CAR-expressing cell described herein in combination with a biologic therapy, e.g., an antibody or cellular therapy, e.g., 225Ac-lintuzumab (Actimab-A; Actinium Pharmaceuticals), IPH2102 (Innate Pharma/Bristol Myers Squibb), SGN-CD33A (Seattle Genetics), or gemtuzumab ozogamicin (Mylotarg; Pfizer). SGN-CD33A is an antibody-drug conjugate (ADC) comprising a pyrrolobenzodiazepine dimer that is attached to an anti-CD33 antibody. Actimab-A is an anti-CD33 antibody (lintuzumab) labeled with actinium. IPH2102 is a monoclonal antibody that targets killer immunoglobulin-like receptors (KIRs). In embodiments, the subject is administered a CAR-expressing cell described herein in combination a FLT3 inhibitor, e.g., sorafenib (Bayer), midostaurin (Novartis), quizartinib (Daiichi Sankyo), crenolanib (Arog Pharmaceuticals), PLX3397 (Daiichi Sankyo), AKN-028 (Akinion Pharmaceuticals), or ASP2215 (Astellas). In embodiments, the subject is administered a CAR-expressing cell described herein in combination with an isocitrate dehydrogenase (IDH) inhibitor, e.g., AG-221 (Celgene/Agios) or AG-120 (Agios/Celgene). In embodiments, the subject is administered a CAR-expressing cell described herein in combination with a cell cycle regulator, e.g., inhibitor of polo-like kinase 1 (Plkl), e.g., volasertib (Boehringer Ingelheim); or an inhibitor of cyclin-dependent kinase 9 (Cdk9), e.g., alvocidib (Tolero Pharmaceuticals/Sanofi Aventis). In embodiments, the subject is administered a CAR-expressing cell described herein in combination with a B cell receptor signaling network inhibitor, e.g., an inihibitor of B-cell lymphoma 2 (Bcl-2), e.g., venetoclax (Abbvie/Roche); or an inhibitor of Bruton&#39;s tyrosine kinase (Btk), e.g., ibrutinib (Pharmacyclics/Johnson &amp; Johnson Janssen Pharmaceutical). In embodiments, the subject is administered a CAR-expressing cell described herein in combination with an inhibitor of M1 aminopeptidase, e.g., tosedostat (CTI BioPharma/Vernalis); an inhibitor of histone deacetylase (HDAC), e.g., pracinostat (MEI Pharma); a multi-kinase inhibitor, e.g., rigosertib (Onconova Therapeutics/Baxter/SymBio); or a peptidic CXCR4 inverse agonist, e.g., BL-8040 (BioLineRx). 
     In another embodiment, the subjects receive an infusion of the CAR expressing cell, e.g., CD19 CAR-expressing cell, compositions of the present invention prior to transplantation, e.g., allogeneic stem cell transplant, of cells. In a preferred embodiment, CAR expressing cells transiently express the CAR, e.g., by electroporation of an mRNA CAR, whereby the expression of the antigen targeted by the CAR, e.g., CD19 is terminated prior to infusion of donor stem cells to avoid engraftment failure. In one embodiment, the subject can be administered an agent which reduces or ameliorates a side effect associated with the administration of a CAR-expressing cell. Side effects associated with the administration of a CAR-expressing cell include, but are not limited to CRS, and hemophagocytic lymphohistiocytosis (HLH), also termed Macrophage Activation Syndrome (MAS). Symptoms of CRS include high fevers, nausea, transient hypotension, hypoxia, and the like. Accordingly, the methods described herein can comprise administering a CAR-expressing cell described herein to a subject and further administering an agent to manage elevated levels of a soluble factor resulting from treatment with a CAR-expressing cell. In one embodiment, the soluble factor elevated in the subject is one or more of IFN-γ, TNFα, IL-2 and IL-6. Therefore, an agent administered to treat this side effect can be an agent that neutralizes one or more of these soluble factors. Examples of such agents include, but are not limited to a steroid (e.g., corticosteroid), an inhibitor of TNFα, and an inhibitor of IL-6. An example of a TNFa inhibitor is an anti-TNFa antibody molecule such as, infliximab, adalimumab, certolizumab pegol, and golimumab. Another example of a TNFa inhibitor is a fusion protein such as entanercept. Small molecule inhibitor of TNFa include, but are not limited to, xanthine derivatives (e.g. pentoxifylline) and bupropion. An example of an IL-6 inhibitor is an anti-IL-6 antibody molecule such as tocilizumab (toc), sarilumab, elsilimomab, CNTO 328, ALD518/BMS-945429, CNTO 136, CPSI-2364, CDP6038, VX30, ARGX-109, FE301, and FM101. In one embodiment, the anti-IL-6 antibody molecule is tocilizumab. An example of an IL-1R based inhibitor is anakinra. 
     In embodiments, lymphodepletion is performed on a subject, e.g., prior to administering one or more cells that express a CAR described herein. In embodiments, the lymphodepletion comprises administering one or more of melphalan, cytoxan, cyclophosphamide, and fludarabine. In embodiments, the lymphodepletion comprises administering bendamustine (e.g., at about 90 mg/m 2 , e.g., daily×2), cyclophosphamide and fludarabine (e.g., at about 200 mg/m2 cyclophosphamide and about 20 mg/m2 fludarabine, e.g., daily×3), XRT and cyclophosphamide (e.g., at about 400 cGy XRT and about 1 g/m 2 cyclophosphamide), cyclophosphamide (e.g., about 1 g/m 2  or 1.2 g/m 2  cyclophosphamide, e.g., over 4 days), carboplatin and gemcitabine, or modified EPOCH. 
     In embodiments, a lymphodepleting chemotherapy is administered to the subject prior to, concurrently with, or after administration (e.g., infusion) of CAR cells, e.g., cells described herein. In an example, the lymphodepleting chemotherapy is administered to the subject prior to administration of CAR cells. For example, the lymphodepleting chemotherapy ends 1-4 days (e.g., 1, 2, 3, or 4 days) prior to CAR cell infusion. In embodiments, multiple doses of CAR cells are administered, e.g., as described herein. For example, a single dose comprises about 5×10 8  CAR cells. In embodiments, a lymphodepleting chemotherapy is administered to the subject prior to, concurrently with, or after administration (e.g., infusion) of a CAR-expressing cell described herein. 
     In some embodiments, CAR-expressing cells described herein are administered to a subject in combination with a CD19 CAR-expressing cell, e.g., CTL019, e.g., as described in WO2012/079000, incorporated herein by reference, for treatment of a disease associated with the expression of cancer antigen, e.g., a cancer described herein. Without being bound by theory, it is believed that administering a CD19 CAR-expressing cell in combination with another CAR-expressing cell improves the efficacy of a CAR-expressing cell described herein by targeting early lineage cancer cells, e.g., cancer stem cells, modulating the immune response, depleting regulatory B cells, and/or improving the tumor microenvironment. For example, a CD19 CAR-expressing cell targets cancer cells that express early lineage markers, e.g., cancer stem cells and CD19-expressing cells, while some other CAR-expressing cells described herein target cancer cells that express later lineage markers. This preconditioning approach can improve the efficacy of the CAR-expressing cell described herein. In such embodiments, the CD19 CAR-expressing cell is administered prior to, concurrently with, or after administration (e.g., infusion) of the second CAR-expressing cell. 
     In embodiments, a CAR-expressing cell which expresses a CAR targeting a cancer antigen other than CD19 also expresses a CAR targeting CD19, e.g., a CD19 CAR. In an embodiment, the cell expressing a non-CD19 CAR and a CD19 CAR is administered to a subject for treatment of a cancer described herein, e.g., AML. In an embodiment, the configurations of one or both of the CAR molecules comprise a primary intracellular signaling domain and a costimulatory signaling domain. In another embodiment, the configurations of one or both of the CAR molecules comprise a primary intracellular signaling domain and two or more, e.g., 2, 3, 4, or 5 or more, costimulatory signaling domains. In such embodiments, the non-CD19 CAR molecule and the CD19 CAR may have the same or a different primary intracellular signaling domain, the same or different costimulatory signaling domains, or the same number or a different number of costimulatory signaling domains. Alternatively, the non-CD19 CAR and the CD19 CAR are configured as a split CAR, in which one of the CAR molecules comprises an antigen binding domain and a costimulatory domain (e.g., 4-1BB), while the other CAR molecule comprises an antigen binding domain and a primary intracellular signaling domain (e.g., CD3 zeta). 
     Inhibitory Molecule Inhibitors/Checkpoint Inhibitors 
     In one embodiment, the subject can be administered an agent which enhances the activity of a CAR-expressing cell. For example, in one embodiment, the agent can be an agent which inhibits an inhibitory molecule, e.g., the agent is a checkpoint inhibitor. Inhibitory or checkpoint molecules, e.g., Programmed Death 1 (PD1), can, in some embodiments, decrease the ability of a CAR-expressing cell to mount an immune effector response. Examples of inhibitory molecules include PD1, PD-L1, PD-L2, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GAL9, adenosine, and TGF (e.g., TGF beta). In embodiments, the CAR-expressing cell described herein comprises a switch costimulatory receptor, e.g., as described in WO 2013/019615, which is incorporated herein by reference in its entirety. 
     The methods described herein can include administration of a CAR-expressing cell in combination with a checkpoint inhibitor. In one embodiment, the subject is a complete responder. In another embodiment, the subject is a partial responder or non-responder, and, e.g., in some embodiments, the checkpoint inhibitor is administered prior to the CAR-expressing cell, e.g., two weeks, 12 days, 10 days, 8 days, one week, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day before administration of the CAR-expressing cell. In some embodiments, the checkpoint inhibitor is administered concurrently with the CAR-expressing cell. 
     Inhibition of an inhibitory molecule, e.g., by inhibition at the DNA, RNA or protein level, can optimize a CAR-expressing cell performance. In embodiments, an inhibitory nucleic acid, e.g., an inhibitory nucleic acid, e.g., a dsRNA, e.g., an siRNA or shRNA, or a clustered regularly interspaced short palindromic repeats (CRISPR), a transcription-activator like effector nuclease (TALEN), or a zinc finger endonuclease (ZFN), can be used to inhibit expression of an inhibitory molecule in the CAR-expressing cell. In an embodiment the inhibitor is an shRNA. In an embodiment, the inhibitory molecule is inhibited within a CAR-expressing cell. In these embodiments, a dsRNA molecule that inhibits expression of the inhibitory molecule is linked to the nucleic acid that encodes a component, e.g., all of the components, of the CAR. 
     In an embodiment, a nucleic acid molecule that encodes a dsRNA molecule that inhibits expression of the molecule that modulates or regulates, e.g., inhibits, T-cell function is operably linked to a promoter, e.g., a H1- or a U6-derived promoter such that the dsRNA molecule that inhibits expression of the molecule that modulates or regulates, e.g., inhibits, T-cell function is expressed, e.g., is expressed within a CAR-expressing cell. See e.g., Tiscornia G., “Development of Lentiviral Vectors Expressing siRNA,” Chapter 3, in Gene Transfer: Delivery and Expression of DNA and RNA (eds. Friedmann and Rossi). Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA, 2007; Brummelkamp T R, et al. (2002) Science 296: 550-553; Miyagishi M, et al. (2002) Nat. Biotechnol. 19: 497-500. In an embodiment the nucleic acid molecule that encodes a dsRNA molecule that inhibits expression of the molecule that modulates or regulates, e.g., inhibits, T-cell function is present on the same vector, e.g., a lentiviral vector, that comprises a nucleic acid molecule that encodes a component, e.g., all of the components, of the CAR. In such an embodiment, the nucleic acid molecule that encodes a dsRNA molecule that inhibits expression of the molecule that modulates or regulates, e.g., inhibits, T-cell function is located on the vector, e.g., the lentiviral vector, 5′- or 3′- to the nucleic acid that encodes a component, e.g., all of the components, of the CAR. The nucleic acid molecule that encodes a dsRNA molecule that inhibits expression of the molecule that modulates or regulates, e.g., inhibits, T-cell function can be transcribed in the same or different direction as the nucleic acid that encodes a component, e.g., all of the components, of the CAR. In an embodiment the nucleic acid molecule that encodes a dsRNA molecule that inhibits expression of the molecule that modulates or regulates, e.g., inhibits, T-cell function is present on a vector other than the vector that comprises a nucleic acid molecule that encodes a component, e.g., all of the components, of the CAR. In an embodiment, the nucleic acid molecule that encodes a dsRNA molecule that inhibits expression of the molecule that modulates or regulates, e.g., inhibits, T-cell function it transiently expressed within a CAR-expressing cell. In an embodiment, the nucleic acid molecule that encodes a dsRNA molecule that inhibits expression of the molecule that modulates or regulates, e.g., inhibits, T-cell function is stably integrated into the genome of a CAR-expressing cell. In an embodiment, the molecule that modulates or regulates, e.g., inhibits, T-cell function is PD-1. 
     In one embodiment, the inhibitor of an inhibitory signal can be, e.g., an antibody or antibody fragment that binds to an inhibitory molecule. For example, the agent can be an antibody or antibody fragment that binds to PD1, PD-L1, PD-L2 or CTLA4 (e.g., ipilimumab (also referred to as MDX-010 and MDX-101, and marketed as Yervoy®; Bristol-Myers Squibb; Tremelimumab (IgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675,206)). In an embodiment, the agent is an antibody or antibody fragment that binds to TIM3. In an embodiment, the agent is an antibody or antibody fragment that binds to LAG3. In an embodiment, the agent is an antibody or antibody fragment that binds to CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5). In embodiments, the agent that enhances the activity of a CAR-expressing cell, e.g., inhibitor of an inhibitory molecule, is administered in combination with an allogeneic CAR, e.g., an allogeneic CAR described herein (e.g., described in the Allogeneic CAR section herein). 
     PD1 is an inhibitory member of the CD28 family of receptors that also includes CD28, CTLA-4, ICOS, and BTLA. PD1 is expressed on activated B cells, T cells and myeloid cells (Agata et al. 1996 Int. Immunol 8:765-75). Two ligands for PD1, PD-L1 and PD-L2 have been shown to downregulate T cell activation upon binding to PD1 (Freeman et a. 2000 J Exp Med 192:1027-34; Latchman et al. 2001 Nat Immunol 2:261-8; Carter et al. 2002 Eur J Immunol 32:634-43). PD-L1 is abundant in human cancers (Dong et al. 2003 J Mol Med 81:281-7; Blank et al. 2005 Cancer Immunol. Immunother 54:307-314; Konishi et al. 2004 Clin Cancer Res 10:5094). Immune suppression can be reversed by inhibiting the local interaction of PD1 with PD-L1. 
     Antibodies, antibody fragments, and other inhibitors of PD1, PD-L1 and PD-L2 are available in the art and may be used combination with a CD19 CAR described herein. For example, nivolumab (also referred to as BMS-936558 or MDX1106; Bristol-Myers Squibb) is a fully human IgG4 monoclonal antibody which specifically blocks PD1. Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD1 are disclosed in U.S. Pat. No. 8,008,449 and WO2006/121168. Pidilizumab (CT-011; Cure Tech) is a humanized IgG1k monoclonal antibody that binds to PD1. Pidilizumab and other humanized anti-PD1 monoclonal antibodies are disclosed in WO2009/101611. Pembrolizumab (formerly known as lambrolizumab, and also referred to as Keytruda, MK03475; Merck) is a humanized IgG4 monoclonal antibody that binds to PD1. Pembrolizumab and other humanized anti-PD1 antibodies are disclosed in U.S. Pat. No. 8,354,509 and WO2009/114335. MEDI4736 (Medimmune) is a human monoclonal antibody that binds to PDL1, and inhibits interaction of the ligand with PD1. MDPL3280A (Genentech/Roche) is a human Fc optimized IgG1 monoclonal antibody that binds to PD-L1. MDPL3280A and other human monoclonal antibodies to PD-L1 are disclosed in U.S. Pat. No. 7,943,743 and U.S Publication No.: 20120039906. Other anti-PD-L1 binding agents include YW243.55.S70 (heavy and light chain variable regions are shown in SEQ ID NOs 20 and 21 in WO2010/077634) and MDX-1 105 (also referred to as BMS-936559, and, e.g., anti-PD-L1 binding agents disclosed in WO2007/005874). AMP-224 (B7-DCIg; Amplimmune; e.g., disclosed in WO2010/027827 and WO2011/066342), is a PD-L2 Fc fusion soluble receptor that blocks the interaction between PD1 and B7-H1. Other anti-PD1 antibodies include AMP 514 (Amplimmune), among others, e.g., anti-PD1 antibodies disclosed in U.S. Pat. No. 8,609,089, US 2010028330, and/or US 20120114649. 
     In some embodiments, a PD1 inhibitor described herein (e.g., a PD1 antibody, e.g., a PD1 antibody described herein) is used combination with a CD19 CAR described herein to treat a disease associated with expression of CD19. In some embodiments, a PD-L1 inhibitor described herein (e.g., a PD-L1 antibody, e.g., a PD-L1 antibody described herein) is used combination with a CD19 CAR described herein to treat a disease associated with expression of CD19. In some embodiments, the CD19 CAR therapy is administered prior to, simultaneously with or after the PD-1 inhibitor. In one embodiment, the CD19 CAR therapy is administered prior to the PD-1 inhibitor. For example, one or more doses of the PD-1 inhibitor can be administered post-CD19 CAR therapy (e.g., starting 5 days to 4 months, e.g., 10 day to 3 months, e.g., 14 days to 2 months post-CD19 CAR therapy). In some embodiments, the combination of the CD19 CAR therapy and PD-1 inhibitor therapy is repeated. 
     The disease may be, e.g., a lymphoma such as DLBCL including primary DLBCL or secondary DLBCL. In some embodiments, the subject has, or is identified as having, at least 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cancer cells, e.g., DLBCL cells, which are CD3+/PD1+. In some embodiments, the subject has, or is identified as having, substantially non-overlapping populations of CD19+ cells and PD-L1+ cells in a cancer, e.g., the cancer microenvironment. For instance, in some embodiments, less than 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of cells in the cancer, e.g., cancer microenvironment, are double positive for CD19 and PD-L1. 
     In embodiments of the CD19 CAR therapy-PD1 inhibitor therapy, the CD19 CAR therapy comprises one or more treatments with cells that express a murine CAR molecule described herein, e.g., a murine CD19 CAR molecule of Tables 3, 4 and 5 on pages 359-363 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     In another embodiment of the CD19 CAR therapy-PD1 inhibitor therapy, the CD19 CAR therapy comprises one or more treatments with cells that express a humanized CD19 CAR, e.g., a humanized CD19 CAR according to Tables 2, 4 and 5 on page 339-363 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     In some embodiments, the subject is treated with a combination of a CD19 CAR, a PD1 inhibitor, and a PD-L1 inhibitor. In some embodiments, the subject is treated with a combination of a CD19 CAR, a PD1 inhibitor, and a CD3 inhibitor. In some embodiments, the subject is treated with a combination of a CD19 CAR, a PD1 inhibitor, a PD-L1 inhibitor, and a CD3 inhibitor. Optionally, the subject has, or is identified as having, at least 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cancer cells, e.g., DLBCL cells, which are CD3 + /PD1+. 
     In some embodiments, the methods herein include a step of assaying cells in a biological sample, e.g., a sample comprising DLBCL cells, for CD3 and/or PD-1 (e.g., CD3 and/or PD-1 expression). In some embodiments, the methods include a step of assaying cells in a biological sample, e.g., a sample comprising DLBCL cells, for CD19 and/or PD-L1 (e.g., CD19 and/or PD-L1 expression). In some embodiments, the methods include, e.g., providing a sample comprising cancer cells and performing a detection step, e.g., by immunohistochemistry, for one or more of CD3, PD-1, CD19, or PD-L1. The methods may comprise a further step of recommending or administering a treatment, e.g., a treatment comprising a CD19 CAR. 
     In one embodiment, the anti-PD-1 antibody or fragment thereof is an anti-PD-1 antibody molecule as described in US 2015/0210769, entitled “Antibody Molecules to PD-1 and Uses Thereof,” incorporated by reference in its entirety. In one embodiment, the anti-PD-1 antibody molecule includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region from an antibody chosen from any of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP49-Clone-E; or as described in Table 1 of US 2015/0210769, or encoded by the nucleotide sequence in Table 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or closely related CDRs, e.g., CDRs which are identical or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions). 
     In yet another embodiment, the anti-PD-1 antibody molecule comprises at least one, two, three or four variable regions from an antibody described herein, e.g., an antibody chosen from any of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP49-hum04, BAP49-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP49-Clone-E; or as described in Table 1 of US 2015/0210769, or encoded by the nucleotide sequence in Table 1; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences. 
     In one embodiment of the CD19 CAR therapy-PD1 inhibitor therapy, the PD-1 inhibitor, e.g., pembrolizumab, is administered post-CD19 CAR therapy (e.g., starting 5 days to 4 months, e.g., 10 day to 3 months, e.g., 14 days to 2 months post-CTL019 or post-CTL119 therapy, or post-a combination of CTL019 and CTL119 therapies). In embodiments, administration of the therapy is to a subject with B-ALL, e.g., relapsed or refractory B-ALL. 
     In yet another embodiment of the CD19 CAR therapy-PD1 inhibitor therapy, the hematologic cancer is B-ALL, e.g., relapsed or refractory B-ALL. 
     In one embodiment, the subject has a hematologic malignancy, e.g., B-ALL, and may not respond to the CAR T therapy or may relapse, e.g., due to poor CAR T cell persistence. 
     In one embodiment of the CD19 CAR therapy-PD1 inhibitor therapy, the subject shows an improved therapeutic outcome, e.g., the subject achieves one or more of partial remission, complete remission, or prolonged CAR T cell persistence, in response to the CD19 CAR therapy-PD1 inhibitor therapy, e.g., one or more cycles of the CD19 CAR therapy-PD1 inhibitor therapy. 
     In one embodiment of the CD19 CAR therapy-PD1 inhibitor therapy, prior to administration of the PD-1 inhibitor, the subject has relapsed or refractory B-ALL to a prior treatment with a CD19 CAR therapy, e.g., a prior treatment with one or both of CTL019 and CTL119. In some embodiments, the subject shows decreased or poor CAR T cell persistence. In some embodiments, the subject shows CD19+ relapse. 
     In some embodiments, the subject, e.g., a subject showing CD19+ relapse after a CD19CAR therapy, is administered a further CD19 CAR therapy, in combination with the PD-1 inhibitor, e.g., pembrolizumab. In embodiments, the further administration of the combination therapy results in an improved therapeutic outcome, e.g., the subject achieves one or more of partial remission, complete remission, or a prolonged CAR T cell persistence. 
     TIM3 (T cell immunoglobulin-3) also negatively regulates T cell function, particularly in IFN-g-secreting CD4+ T helper 1 and CD8+ T cytotoxic 1 cells, and plays a critical role in T cell exhaustion. Inhibition of the interaction between TIM3 and its ligands, e.g., galectin-9 (Gal9), phosphatidylserine (PS), and HMGB1, can increase immune response. Antibodies, antibody fragments, and other inhibitors of TIM3 and its ligands are available in the art and may be used combination with a CD19 CAR described herein. For example, antibodies, antibody fragments, small molecules, or peptide inhibitors that target TIM3 binds to the IgV domain of TIM3 to inhibit interaction with its ligands. Antibodies and peptides that inhibit TIM3 are disclosed in WO2013/006490 and US20100247521. Other anti-TIM3 antibodies include humanized versions of RMT3-23 (disclosed in Ngiow et al., 2011, Cancer Res, 71:3540-3551), and clone 8B.2C12 (disclosed in Monney et al., 2002, Nature, 415:536-541). Bi-specific antibodies that inhibit TIM3 and PD-1 are disclosed in US20130156774. In one embodiment, the anti-TIM3 antibody or fragment thereof is an anti-TIM3 antibody molecule as described in US 2015/0218274, entitled “Antibody Molecules to TIM3 and Uses Thereof,” incorporated by reference in its entirety. In one embodiment, the anti-TIM3 antibody molecule includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region from an antibody chosen from any of ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-hum10, ABTIM3-hum11, ABTIM3-hum12, ABTIM3-hum13, ABTIM3-hum14, ABTIM3-hum15, ABTIM3-hum16, ABTIM3-hum17, ABTIM3-hum18, ABTIM3-hum19, ABTIM3-hum20, ABTIM3-hum21, ABTIM3-hum22, ABTIM3-hum23; or as described in Tables 1-4 of US 2015/0218274; or encoded by the nucleotide sequence in Tables 1-4; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences, or closely related CDRs, e.g., CDRs which are identical or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions). 
     In yet another embodiment, the anti-TIM3 antibody molecule comprises at least one, two, three or four variable regions from an antibody described herein, e.g., an antibody chosen from any of ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-hum10, ABTIM3-hum11, ABTIM3-hum12, ABTIM3-hum13, ABTIM3-hum14, ABTIM3-hum15, ABTIM3-hum16, ABTIM3-hum17, ABTIM3-hum18, ABTIM3-hum19, ABTIM3-hum20, ABTIM3-hum21, ABTIM3-hum22, ABTIM3-hum23; or as described in Tables 1-4 of US 2015/0218274; or encoded by the nucleotide sequence in Tables 1-4; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences. 
     In other embodiments, the agent which enhances the activity of a CAR-expressing cell is a CEACAM inhibitor (e.g., CEACAM-1, CEACAM-3, and/or CEACAM-5 inhibitor). In one embodiment, the inhibitor of CEACAM is an anti-CEACAM antibody molecule. Exemplary anti-CEACAM-1 antibodies are described in WO 2010/125571, WO 2013/082366 WO 2014/059251 and WO 2014/022332, e.g., a monoclonal antibody 34B1, 26H7, and 5F4; or a recombinant form thereof, as described in, e.g., US 2004/0047858, U.S. Pat. No. 7,132,255 and WO 99/052552. In other embodiments, the anti-CEACAM antibody binds to CEACAM-5 as described in, e.g., Zheng et al. PLoS One. 2010 Sep. 2; 5(9). pii: e12529 (DOI:10:1371/journal.pone.0021146), or crossreacts with CEACAM-1 and CEACAM-5 as described in, e.g., WO 2013/054331 and US 2014/0271618. 
     Without wishing to be bound by theory, carcinoembryonic antigen cell adhesion molecules (CEACAM), such as CEACAM-1 and CEACAM-5, are believed to mediate, at least in part, inhibition of an anti-tumor immune response (see e.g., Markel et al. J Immunol. 2002 Mar. 15; 168(6):2803-10; Markel et al. J Immunol. 2006 Nov. 1; 177(9):6062-71; Markel et al. Immunology. 2009 February; 126(2):186-200; Markel et al. Cancer Immunol Immunother. 2010 February; 59(2):215-30; Ortenberg et al. Mol Cancer Ther. 2012 June; 11(6):1300-10; Stern et al. J Immunol. 2005 Jun. 1; 174(11):6692-701; Zheng et al. PLoS One. 2010 Sep. 2; 5(9). pii: e12529). For example, CEACAM-1 has been described as a heterophilic ligand for TIM-3 and as playing a role in TIM-3-mediated T cell tolerance and exhaustion (see e.g., WO 2014/022332; Huang, et al. (2014) Nature doi:10.1038/nature13848). In embodiments, co-blockade of CEACAM-1 and TIM-3 has been shown to enhance an anti-tumor immune response in xenograft colorectal cancer models (see e.g., WO 2014/022332; Huang, et al. (2014), supra). In other embodiments, co-blockade of CEACAM-1 and PD-1 reduce T cell tolerance as described, e.g., in WO 2014/059251. Thus, CEACAM inhibitors can be used with the other immunomodulators described herein (e.g., anti-PD-1 and/or anti-TIM-3 inhibitors) to enhance an immune response against a cancer, e.g., a melanoma, a lung cancer (e.g., NSCLC), a bladder cancer, a colon cancer, an ovarian cancer, and other cancers as described herein. 
     LAG3 (lymphocyte activation gene-3 or CD223) is a cell surface molecule expressed on activated T cells and B cells that has been shown to play a role in CD8+ T cell exhaustion. Antibodies, antibody fragments, and other inhibitors of LAG3 and its ligands are available in the art and may be used combination with a CD19 CAR described herein. For example, BMS-986016 (Bristol-Myers Squib) is a monoclonal antibody that targets LAG3. IMP701 (Immutep) is an antagonist LAG3 antibody and IMP731 (Immutep and GlaxoSmithKline) is a depleting LAG3 antibody. Other LAG3 inhibitors include IMP321 (Imrnutep), which is a recombinant fusion protein of a soluble portion of LAG3 and Ig that binds to MHC class II molecules and activates antigen presenting cells (APC). Other antibodies are disclosed, e.g., in WO2010/019570. 
     In one embodiment, the anti-LAG3 antibody or fragment thereof is an anti-LAG3 antibody molecule as described in US 2015/0259420, entitled “Antibody Molecules to LAG3 and Uses Thereof,” incorporated by reference in its entirety. In one embodiment, the anti-LAG3 antibody molecule includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region from an antibody chosen from any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J; or as described in Table 1 of US 2015/0259420; or encoded by the nucleotide sequence in Table 1; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences, or closely related CDRs, e.g., CDRs which are identical or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions). 
     In yet another embodiment, the anti-LAG3 antibody molecule comprises at least one, two, three or four variable regions from an antibody described herein, e.g., an antibody chosen from any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J; or as described in Table 1 of US 2015/0259420; or encoded by the nucleotide sequence in Tables 1; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences. 
     In embodiments, the subject is administered an additional agent (in further combination with a CAR-expressing cell, e.g., a CD19 CAR-expressing cell), where the additional agent is an inhibitor of an inhibitory molecule, e.g., checkpoint molecule, e.g., PD-1, PD-L1, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GAL9, adenosine, or TGF beta. In embodiments, the additional agent is an inhibitor of PD-L1, e.g., FAZ053 (a hIgG4 humanized anti-PD-L1 monoclonal antibody), MPDL3280A, durvalumab (DEMI-4736), avelumab (MSB-0010718C), or BMS-936559. In embodiments, the additional agent is an additional inhibitor of PD-1, e.g., pembrolizumab, nivolumab, PDR001, MEDI-0680 (AMP-514), AMP-224, REGN-2810, or BGB-A317. In embodiments, the additional agent is an inhibitor of CTLA-4, e.g., ipilimumab. In embodiments, the additional agent is an inhibitor of LAG-3, e.g., LAG525 (a hIgG4 humanized anti-LAG-3 monoclonal antibody). In embodiments, the additional agent is an inhibitor of TIM-3, e.g., MBG453 (a hIgG4 humanized anti-TIM-3 monoclonal antibody). In embodiments, the additional agent is an inhibitor of the enzyme, B-Raf, e.g., dabrafenib (GSK2118436; N-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide). In embodiments, the additional agent is an inhibitor of MEK1 and/or MEK2, e.g., trametinib (N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide). In embodiments, the additional agent comprises dabrafenib and trametinib. In embodiments, the additional agent is an inhibitor of GITR, e.g., GWN323. In embodiments, the additional agent is an agonist of STING (Stimulator of Interferon Genes), e.g., MIW815. In embodiments, the additional agent is an IL-15 agonist, e.g., NIZ985. In embodiments, the additional agent an inhibitor of adenosine receptor, e.g., NIR178. In embodiments, the additional agent is an inhibitor of macrophage colony stimulating factor (CSF-1), e.g., MCS110. In embodiments, the additional agent is an inhibitor of cMet, e.g., INC280. In embodiments, the additional agent is an inhibitor of porcupine (PORCN), e.g., WNT974. In embodiments, the additional agent is a histone deacetylase inhibitor, e.g., panobinost. In embodiments, the additional agent is an mTOR inhibitor, e.g., everolimus. In embodiments, the additional agent is a second mitochondrial-derived activator of caspases (SMAC) mimetic and/or an inhibitor of IAP (inhibiotor of apoptosis protein) family of proteins, e.g., LCL161. In embodiments, the additional agent is an inhibitor epidermal growth factor receptor (EGFR), e.g., EGF816. In embodiments, the additional agent is an inhibitor of IL-17, e.g., CJM112. In embodiments, the additional agent is an inhibitor of IL-1beta, e.g., ILARIS. 
     While not wishing to be bound by theory, in some embodiments, a tumor microenvironment is not conducive to CART cells attacking cancer cells, due to direct or indirect inhibitory effects exerted by the presence of PD-L1+ expressing cells or PD1+ T cells within the tumor microenvironment. More specifically, a tumor microenvironment can comprise tumor cells (which are generally CD19+), immune effector cells (which can be CD3+ T cells and can be PD1+ or PD1-, and which can be endogenous cells or CAR-expressing cells), and activated myeloid cells (which are generally PD-L1+). PD1+ T cells can create a “barrier” around the tumor microenvironment by preventing entry of CART cells the tumor. According to the non-limiting theory herein, pre-administration of a PD1 inhibitor and/or PD-L1 inhibitor makes the tumor microenvironment more favorable to entry of CAR-expressing cells into the tumor microenvironment and effectively clear the target positive cancer cells. 
     Accordingly, in certain aspects, the present disclosure provides methods of combination therapy comprising administering to a subject a cell that expresses a CAR molecule that binds CD19, e.g., a CD19 CAR, in combination with a PD1 inhibitor, a PD-L1 inhibitor, or both. In some embodiments, the PD1 inhibitor and/or PD-L1 inhibitor is administered before the CAR therapy. In other embodiments, the PD1 inhibitor and/or PD-L1 inhibitor is administered concurrently with or after the CAR therapy. In some aspects, the subject is a subject having a disease associated with expression of CD19, e.g., a hematologic malignancy, e.g., a leukemia or lymphoma, e.g., DLBCL, e.g. primary DLBCL. In some embodiments, the patient has, or is identified as having, elevated levels of PD1, PDL1, or CD3, or any combination thereof. In some embodiments, the patient has, or is identified as having, or at least 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of DLBCL cells which are positive for CD3 and PD1. 
     Also provided herein are methods for monitoring the efficacy of a CAR therapy, e.g., a CD19 CAR therapy. CAR-expressing cells can be administered to a patient&#39;s bloodstream with the intent that the cells home to a tumor cell, e.g., infiltrate a tumor. Accordingly, in some embodiments, the method comprises assaying a tumor sample for the presence of CAR-expressing cells. In embodiments, the method comprises detecting a tumor marker, e.g., CD19. In embodiments, the method comprises detecting a marker of a CAR-expressing cell, e.g., a CAR construct or nucleic acid encoding the CAR construct. In embodiments, the method further comprises detecting a T cell marker, e.g., CD3. In some aspects, the subject is a subject having a disease associated with expression of CD19, e.g., a hematologic malignancy, e.g., a leukemia or lymphoma, e.g., DLBCL, e.g. primary DLBCL. In some embodiments, if the CAR-expressing cells show poor infiltration of the tumor, the subject is identified as at an elevated risk of relapse compared to a subject with good infiltration of the tumor. In some embodiments, if the CAR-expressing cells show poor infiltration of the tumor, the subject is administered a PD1 inhibitor and/or PD-L1 inhibitor, e.g., in combination with a second dose of CAR-expressing cells. 
     In some embodiments, the agent which enhances the activity of a CAR-expressing cell can be, e.g., a fusion protein comprising a first domain and a second domain, wherein the first domain is an inhibitory molecule, or fragment thereof, and the second domain is a polypeptide that is associated with a positive signal, e.g., a polypeptide comprising an intracellular signaling domain as described herein. In some embodiments, the polypeptide that is associated with a positive signal can include a costimulatory domain of CD28, CD27, ICOS, e.g., an intracellular signaling domain of CD28, CD27 and/or ICOS, and/or a primary signaling domain, e.g., of CD3 zeta, e.g., described herein. In one embodiment, the fusion protein is expressed by the same cell that expressed the CAR. In another embodiment, the fusion protein is expressed by a cell, e.g., a T cell that does not express an anti-CD19 CAR. 
     In an embodiment, the method further comprises administering a checkpoint inhibitor. In embodiments, the subject receives a pre-treatment of with an agent, e.g., an mTOR inhibitor, and/or a checkpoint inhibitor, prior to the initiation of a CART therapy. In embodiments, the subject receives concurrent treatment with an agent, e.g., an mTOR inhibitor, and/or a checkpoint inhibitor. In embodiments, the subject receives treatment with an agent, e.g., an mTOR inhibitor, and/or a checkpoint inhibitor, post-CART therapy. 
     In embodiments, the determined level or determined characteristic is acquired before, at the same time, or during a course of CART therapy. 
     In one embodiment, the agent which enhances activity of a CAR-expressing cell described herein is miR-17-92. 
     In one embodiment, the agent which enhances activity of a CAR-described herein is a cytokine. Cytokines have important functions related to T cell expansion, differentiation, survival, and homeostasis. Cytokines that can be administered to the subject receiving a CAR-expressing cell described herein include: IL-2, IL-4, IL-7, IL-9, IL-15, IL-18, and IL-21, or a combination thereof. In embodiments, the cytokine administered is IL-7, IL-15, or IL-21, or a combination thereof. The cytokine can be administered once a day or more than once a day, e.g., twice a day, three times a day, or four times a day. The cytokine can be administered for more than one day, e.g. the cytokine is administered for 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, or 4 weeks. For example, the cytokine is administered once a day for 7 days. 
     In embodiments, the cytokine is administered in combination with CAR-expressing cells. The cytokine can be administered simultaneously or concurrently with the CAR-expressing cells, e.g., administered on the same day. The cytokine may be prepared in the same pharmaceutical composition as the CAR-expressing cells, or may be prepared in a separate pharmaceutical composition. Alternatively, the cytokine can be administered shortly after administration of the CAR-expressing T cells, e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration of the CAR-expressing cells. In embodiments where the cytokine is administered in a dosing regimen that occurs over more than one day, the first day of the cytokine dosing regimen can be on the same day as administration with the CAR-expressing cells, or the first day of the cytokine dosing regimen can be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration of the CAR-expressing T cells. In one embodiment, on the first day, the CAR-expressing cells are administered to the subject, and on the second day, a cytokine is administered once a day for the next 7 days. In an embodiment, the cytokine to be administered in combination with the CAR-expressing cells is IL-7, IL-15, and/or IL-21. 
     In other embodiments, the cytokine is administered a sufficient period of time after administration of the CAR-expressing cells, e.g., at least 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year or more after administration of CAR-expressing cells. In one embodiment, the cytokine is administered after assessment of the subject&#39;s response to the CAR-expressing cells. For example, the subject is administered CAR-expressing cells according to the dosage and regimens described herein. The response of the subject to CART therapy is assessed at 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year or more after administration of CAR-expressing cells, using any of the methods described herein, including inhibition of tumor growth, reduction of circulating tumor cells, or tumor regression. Subjects that do not exhibit a sufficient response to CART therapy can be administered a cytokine. Administration of the cytokine to the subject that has sub-optimal response to the CART therapy improves CART efficacy and/or anti-tumor activity. In an embodiment, the cytokine administered after administration of CAR-expressing cells is IL-7. 
     Further combination therapies may include anti-allergenic agents, anti-emetics, analgesics, adjunct therapies, 
     Some patients may experience allergic reactions to the therapeutics described herein and/or other anti-cancer agent(s) during or after administration; therefore, anti-allergic agents are often administered to minimize the risk of an allergic reaction. Suitable anti-allergic agents include corticosteroids, such as dexamethasone (e.g., Decadron®), beclomethasone (e.g., Beclovent®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala-Cort®, hydrocortisone phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), prednisolone (sold under the tradenames Delta-Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (sold under the tradenames Deltasone®, Liquid Red®, Meticorten® and Orasone), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, sold under the tradenames Duralone®, Medralone®, Medrol®, M-Prednisol® and Solu-Medrol®); antihistamines, such as diphenhydramine (e.g., Benadryl®), hydroxyzine, and cyproheptadine; and bronchodilators, such as the beta-adrenergic receptor agonists, albuterol (e.g., Proventil), and terbutaline (Brethine®). 
     Some patients may experience nausea during and after administration of the therapeutics described herein and/or other anti-cancer agent(s); therefore, anti-emetics are used in preventing nausea (upper stomach) and vomiting. Suitable anti-emetics include aprepitant (Emend®), ondansetron (Zofran®), granisetron HCl (Kytril®), lorazepam (Ativan®. dexamethasone (Decadron®), prochlorperazine (Compazine®), casopitant (Rezonic® and Zunrisa®), and combinations thereof. 
     Medication to alleviate the pain experienced during the treatment period is often prescribed to make the patient more comfortable. Common over-the-counter analgesics, such Tylenol®, are often used. However, opioid analgesic drugs such as hydrocodone/paracetamol or hydrocodone/acetaminophen (e.g., Vicodin®), morphine (e.g., Astramorph® or Avinza®), oxycodone (e.g., OxyContin® or Percocet®), oxymorphone hydrochloride (Opana), and fentanyl (e.g., Duragesic®) are also useful for moderate or severe pain. 
     In an effort to protect normal cells from treatment toxicity and to limit organ toxicities, cytoprotective agents (such as neuroprotectants, free-radical scavengers, cardioprotectors, anthracycline extravasation neutralizers, nutrients and the like) may be used as an adjunct therapy. Suitable cytoprotective agents include Amifostine (Ethyol®), glutamine, dimesna (Tavocept®), mesna (Mesnex®), dexrazoxane (Zinecard® or Totect®), xaliproden (Xaprila®), and leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid). 
     The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium “The Merck Index” or from databases, e.g. Patents International (e.g. IMS World Publications). 
     The above-mentioned compounds, which can be used in combination with a compound of the present invention, can be prepared and administered as described in the art, such as in the documents cited above. 
     In one embodiment, the present invention provides pharmaceutical compositions comprising at least one compound of the present invention (e.g., a compound of the present invention) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject, either alone or together with other anti-cancer agents. 
     In one embodiment, the present invention provides methods of treating human or animal subjects suffering from a cellular proliferative disease, such as cancer. The present invention provides methods of treating a human or animal subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of the present invention (e.g., a compound of the present invention) or a pharmaceutically acceptable salt thereof, either alone or in combination with other anti-cancer agents. 
     In particular, compositions will either be formulated together as a combination therapeutic or administered separately. 
     In combination therapy, the compound of the present invention and other anti-cancer agent(s) may be administered either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. 
     In a preferred embodiment, the compound of the present invention and the other anti-cancer agent(s) is generally administered sequentially in any order by infusion or orally. The dosing regimen may vary depending upon the stage of the disease, physical fitness of the patient, safety profiles of the individual drugs, and tolerance of the individual drugs, as well as other criteria well-known to the attending physician and medical practitioner(s) administering the combination. The compound of the present invention and other anti-cancer agent(s) may be administered within minutes of each other, hours, days, or even weeks apart depending upon the particular cycle being used for treatment. In addition, the cycle could include administration of one drug more often than the other during the treatment cycle and at different doses per administration of the drug. 
     In another aspect of the present invention, kits that include one or more compound of the present invention and a combination partner as disclosed herein are provided. Representative kits include (a) a compound of the present invention or a pharmaceutically acceptable salt thereof, (b) at least one combination partner, e.g., as indicated above, whereby such kit may comprise a package insert or other labeling including directions for administration. 
     A compound of the present invention may also be used to advantage in combination with known therapeutic processes, for example, the administration of hormones or especially radiation. A compound of the present invention may in particular be used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy. 
     Combination with a Low, Immune-Enhancing Dose of an mTOR Inhibitor 
     In one embodiment, the cells expressing a CAR molecule, e.g., a CAR molecule described herein, are administered in combination with a low, immune enhancing dose of an mTOR inhibitor. For instance, in an embodiment, the combination therapy includes: CD19 CAR expressing cells, a B-cell inhibitor (inhibitor of one or more of CD10, CD20, CD22, CD34, CD123, FLT-3, or ROR1, e.g., a CAR-expressing cell targeting one or more of CD10, CD20, CD22, CD34, CD123, FLT-3, or ROR1), and an mTOR inhibitor. Methods described herein use low, immune enhancing, doses of mTOR inhibitors, e.g., allosteric mTOR inhibitors, including rapalogs such as RAD001. Administration of a low, immune enhancing, dose of an mTOR inhibitor (e.g., a dose that is insufficient to completely suppress the immune system, but sufficient to improve immune function) can optimize the performance of immune effector cells, e.g., T cells or CAR-expressing cells, in the subject. While not wishing to be bound by theory, it is believed that treatment with a low, immune enhancing, dose (e.g., a dose that is insufficient to completely suppress the immune system but sufficient to improve immune function) is accompanied by a decrease in PD-1 positive T cells or an increase in PD-1 negative cells. PD-1 positive T cells, but not PD-1 negative T cells, can be exhausted by engagement with cells which express a PD-1 ligand, e.g., PD-L1 or PD-L2. Additional methods of administering low, immune enhancing dose of an mTOR inhibitor and effects on T cells, e.g., T cells to be endingeered to express a CAR, are described on pages 62-63, 69, 112, and 313-315 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     Methods for measuring mTOR inhibition, dosages, treatment regimens, and suitable pharmaceutical compositions are described in U.S. Patent Application No. 2015/01240036, hereby incorporated by reference. 
     In an embodiment, administration of a low, immune enhancing, dose of an mTOR inhibitor can result in one or more of the following:
         i) a decrease in the number of PD-1 positive immune effector cells;   ii) an increase in the number of PD-1 negative immune effector cells;   iii) an increase in the ratio of PD-1 negative immune effector cells/PD-1 positive immune effector cells;   iv) an increase in the number of naïve T cells;   v) an increase in the expression of one or more of the following markers: CD62L high , CD127 high , CD27, and BCL2, e.g., on memory T cells, e.g., memory T cell precursors; vi) a decrease in the expression of KLRG1, e.g., on memory T cells, e.g., memory T cell precursors; or   vii) an increase in the number of memory T cell precursors, e.g., cells with any one or combination of the following characteristics: increased CD62L high  increased CD127 high  increased CD27 + , decreased KLRG1, and increased BCL2;       

     and wherein any of the foregoing, e.g., i), ii), iii), iv), v), vi), or vii), occurs e.g., at least transiently, e.g., as compared to a non-treated subject. 
     In another embodiment, administration of a low, immune enhancing, dose of an mTOR inhibitor results in increased or prolonged proliferation or persistence of CAR-expressing cells, e.g., in culture or in a subject, e.g., as compared to non-treated CAR-expressing cells or a non-treated subject. In embodiments, increased proliferation or persistence is associated with in an increase in the number of CAR-expressing cells. The effect of a low dose of RAD001 on CAR T cell proliferation is described, e.g., in Example 18 on pages 557-558 of of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety, and the effect of low dose RAD001 on CAR T cell expansion in vivo is described, e.g., in Example 19 on pages 558-560 of of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     In another embodiment, administration of a low, immune enhancing, dose of an mTOR inhibitor results in increased killing of cancer cells by CAR-expressing cells, e.g., in culture or in a subject, e.g., as compared to non-treated CAR-expressing cells or a non-treated subject. In embodiments, increased killing of cancer cells is associated with in a decrease in tumor volume. 
     In one embodiment, the cells expressing a CAR molecule, e.g., a CAR molecule described herein, are administered in combination with a low, immune enhancing dose of an mTOR inhibitor, e.g., an allosteric mTOR inhibitor, e.g., RAD001, or a catalytic mTOR inhibitor. For example, administration of the low, immune enhancing, dose of the mTOR inhibitor can be initiated prior to administration of a CAR-expressing cell described herein; completed prior to administration of a CAR-expressing cell described herein; initiated at the same time as administration of a CAR-expressing cell described herein; overlapping with administration of a CAR-expressing cell described herein; or continuing after administration of a CAR-expressing cell described herein. 
     Alternatively or in addition, administration of a low, immune enhancing, dose of an mTOR inhibitor can optimize immune effector cells to be engineered to express a CAR molecule described herein. In such embodiments, administration of a low, immune enhancing, dose of an mTOR inhibitor, e.g., an allosteric inhibitor, e.g., RAD001, or a catalytic inhibitor, is initiated or completed prior to harvest of immune effector cells, e.g., T cells or NK cells, to be engineered to express a CAR molecule described herein, from a subject. 
     In another embodiment, immune effector cells, e.g., T cells or NK cells, to be engineered to express a CAR molecule described herein, e.g., after harvest from a subject, or CAR-expressing immune effector cells, e.g., T cells or NK cells, e.g., prior to administration to a subject, can be cultured in the presence of a low, immune enhancing, dose of an mTOR inhibitor. 
     In an embodiment, administering to the subject a low, immune enhancing, dose of an mTOR inhibitor comprises administering, e.g., once per week, e.g., in an immediate release dosage form, 0.1 to 20, 0.5 to 10, 2.5 to 7.5, 3 to 6, or about 5, mgs of RAD001, or a bioequivalent dose thereof. In an embodiment, administering to the subject a low, immune enhancing, dose of an mTOR inhibitor comprises administering, e.g., once per week, e.g., in a sustained release dosage form, 0.3 to 60, 1.5 to 30, 7.5 to 22.5, 9 to 18, or about 15 mgs of RAD001, or a bioequivalent dose thereof. 
     In an embodiment, a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 5 but no more than 90%, at least 10 but no more than 90%, at least 15, but no more than 90%, at least 20 but no more than 90%, at least 30 but no more than 90%, at least but no more than 90%, at least 50 but no more than 90%, at least 60 but no more than 90%, at least 70 but no more than 90%, at least 5 but no more than 80%, at least 10 but no more than 80%, at least 15, but no more than 80%, at least 20 but no more than 80%, at least 30 but no more than 80%, at least 40 but no more than 80%, at least 50 but no more than 80%, at least 60 but no more than 80%, at least 5 but no more than 70%, at least 10 but no more than 70%, at least 15, but no more than 70%, at least 20 but no more than 70%, at least 30 but no more than 70%, at least 40 but no more than 70%, at least 50 but no more than 70%, at least 5 but no more than 60%, at least 10 but no more than 60%, at least 15, but no more than 60%, at least 20 but no more than 60%, at least 30 but no more than 60%, at least 40 but no more than 60%, at least 5 but no more than 50%, at least 10 but no more than 50%, at least 15, but no more than 50%, at least 20 but no more than 50%, at least 30 but no more than 50%, at least 40 but no more than 50%, at least 5 but no more than 40%, at least 10 but no more than 40%, at least 15, but no more than 40%, at least 20 but no more than 40%, at least 30 but no more than 40%, at least 35 but no more than 40%, at least 5 but no more than 30%, at least 10 but no more than 30%, at least 15, but no more than 30%, at least 20 but no more than 30%, or at least 25 but no more than 30%. 
     The extent of mTOR inhibition can be conveyed as, or corresponds to, the extent of P70 S6 kinase inhibition, e.g., the extent of mTOR inhibition can be determined by the level of decrease in P70 S6 kinase activity, e.g., by the decrease in phosphorylation of a P70 S6 kinase substrate. The level of mTOR inhibition can be evaluated by various methods, such as measuring P70 S6 kinase activity by the Boulay assay, as described in U.S. Patent Application No. 2015/01240036, hereby incorporated by reference, or as described in U.S. Pat. No. 7,727,950, hereby incorporated by reference; measuring the level of phosphorylated S6 by western blot; or evaluating a change in the ratio of PD1 negative immune effector cells to PD1 positive immune effector cells. 
     As used herein, the term “mTOR inhibitor” refers to a compound or ligand, or a pharmaceutically acceptable salt thereof, which inhibits the mTOR kinase in a cell. In an embodiment, an mTOR inhibitor is an allosteric inhibitor. Allosteric mTOR inhibitors include the neutral tricyclic compound rapamycin (sirolimus), rapamycin-related compounds, that is compounds having structural and functional similarity to rapamycin including, e.g., rapamycin derivatives, rapamycin analogs (also referred to as rapalogs) and other macrolide compounds that inhibit mTOR activity. In an embodiment, an mTOR inhibitor is a catalytic inhibitor. 
     Rapamycin is a known macrolide antibiotic produced by  Streptomyces hygroscopicus .See, e.g., McAlpine, J. B., et al., J. Antibiotics (1991) 44: 688; Schreiber, S. L., et al., J. Am. Chem. Soc. (1991) 113: 7433; U.S. Pat. No. 3,929,992. There are various numbering schemes proposed for rapamycin. To avoid confusion, when specific rapamycin analogs are named herein, the names are given with reference to rapamycin using the numbering scheme of formula A. 
     Rapamycin analogs useful in the invention are, for example, 0-substituted analogs in which the hydroxyl group on the cyclohexyl ring of rapamycin is replaced by OR 1  in which R 1  is hydroxyalkyl, hydroxyalkoxyalkyl, acylaminoalkyl, or aminoalkyl; e.g. RAD001, also known as everolimus, as described in U.S. Pat. No. 5,665,772 and WO94/09010, the contents of each are incorporated by reference. 
     Other suitable rapamycin analogs include those substituted at the 26- or 28-position. The rapamycin analog may be an epimer of an analog mentioned above, particularly an epimer of an analog substituted in position 40, 28 or 26, and may optionally be further hydrogenated, e.g. as described in U.S. Pat. No. 6,015,815, WO95/14023 and WO99/15530 the contents of which are incorporated by reference, e.g. ABT578 also known as zotarolimus or a rapamycin analog described in U.S. Pat. No. 7,091,213, WO98/02441 and WO01/14387 the contents of which are incorporated by reference, e.g. AP23573 also known as ridaforolimus. 
     Examples of rapamycin analogs suitable for use in the present invention from U.S. Pat. No. 5,665,772 include, but are not limited to, 40-O-benzyl-rapamycin, 40-O-(4′-hydroxymethyl)benzyl-rapamycin, 40-O-[4′-(1,2-dihydroxyethyl)]benzyl-rapamycin, 40-O-allyl-rapamycin, 40-O-[3′-(2,2-dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin, (2′E,4′S)-40-O-(4′,5′-dihydroxypent-2′-en-1′-yl)-rapamycin, 40-O-(2-hydroxy)ethoxycarbonylmethyl-rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-(6-hydroxy)hexyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-[(3S)-2,2-dimethyldioxolan-3-yl]methyl-rapamycin, 40-O-[(2S)-2,3-dihydroxyprop-1-yl]-rapamycin, 40-O-(2-acetoxy)ethyl-rapamycin, 40-O-(2-nicotinoyloxy)ethyl-rapamycin, 40-O-[2-(N-morpholino)acetoxy]ethyl-rapamycin, 40-O-(2-N-imidazolylacetoxy)ethyl-rapamycin, 40-O-[2-(N-methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin, 39-O-desmethyl-39, 40-O,O-ethylene-rapamycin, (26R)-26-dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(2-aminoethyl)-rapamycin, 40-O-(2-acetaminoethyl)-rapamycin, 40-O-(2-nicotinamidoethyl)-rapamycin, 40-O-(2-(N-methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin, 40-O-(2-ethoxycarbonylaminoethyl)-rapamycin, 40-O-(2-tolylsulfonamidoethyl)-rapamycin and 40-O-[2-(4′,5′-dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin. 
     Other rapamycin analogs useful in the present invention are analogs where the hydroxyl group on the cyclohexyl ring of rapamycin and/or the hydroxy group at the 28 position is replaced with an hydroxyester group are known, for example, rapamycin analogs found in U.S. RE44,768, e.g. temsirolimus. 
     Other rapamycin analogs useful in the preset invention include those wherein the methoxy group at the 16 position is replaced with another substituent, e.g., (optionally hydroxy-substituted) alkynyloxy, benzyl, orthomethoxybenzyl or chlorobenzyl and/or wherein the mexthoxy group at the 39 position is deleted together with the 39 carbon so that the cyclohexyl ring of rapamycin becomes a cyclopentyl ring lacking the 39 position methyoxy group; e.g. as described in WO95/16691 and WO96/41807, the contents of which are incorporated by reference. The analogs can be further modified such that the hydroxy at the 40-position of rapamycin is alkylated and/or the 32-carbonyl is reduced. 
     Rapamycin analogs from WO95/16691 include, but are not limited to, 16-demthoxy-16-(pent-2-ynyl)oxy-rapamycin, 16-demthoxy-16-(but-2-ynyl)oxy-rapamycin, 16-demthoxy-16-(propargyl)oxy-rapamycin, 16-demethoxy-16-(4-hydroxy-but-2-ynyl)oxy-rapamycin, 16-demthoxy-16-benzyloxy-40-O-(2-hydroxyethyl)-rapamycin, 16-demthoxy-16-benzyloxy-rapamycin, 16-demethoxy-16-ortho-methoxybenzyl-rapamycin, 16-demethoxy-40-O-(2-methoxyethyl)-16-pent-2-ynyl)oxy-rapamycin, 39-demethoxy-40-desoxy-39-formyl-42-nor-rapamycin, 39-demethoxy-40-desoxy-39-hydroxymethyl-42-nor-rapamycin, 39-demethoxy-40-desoxy-39-carboxy-42-nor-rapamycin, 39-demethoxy-40-desoxy-39-(4-methyl-piperazin-1-yl)carbonyl-42-nor-rapamycin, 39-demethoxy-40-desoxy-39-(morpholin-4-yl)carbonyl-42-nor-rapamycin, 39-demethoxy-40-desoxy-39-[N-methyl, N-(2-pyridin-2-yl-ethyl)]carbamoyl-42-nor-rapamycin and 39-demethoxy-40-desoxy-39-(p-toluenesulfonylhydrazonomethyl)-42-nor-rapamycin. Rapamycin analogs from WO96/41807 include, but are not limited to, 32-deoxo-rapamycin, 16-O-pent-2-ynyl-32-deoxo-rapamycin, 16-O-pent-2-ynyl-32-deoxo-40-O-(2-hydroxy-ethyl)-rapamycin, 16-O-pent-2-ynyl-32-(S)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, 32(S)-dihydro-40-O-(2-methoxy)ethyl-rapamycin and 32(S)-dihydro-40-O-(2-hydroxyethyl)-rapamycin. 
     Another suitable rapamycin analog is umirolimus as described in US2005/0101624 the contents of which are incorporated by reference. 
     RAD001, otherwise known as everolimus (Afinitor®), has the chemical name (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(1R)- 2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone, as described in U.S. Pat. No. 5,665,772 and WO94/09010, the contents of each are incorporated by reference. 
     Further examples of allosteric mTOR inhibitors include sirolimus (rapamycin, AY-22989), 40-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]-rapamycin (also called temsirolimus or CCI-779) and ridaforolimus (AP-23573/MK-8669). Other examples of allosteric mTor inhibitors include zotarolimus (ABT578) and umirolimus. 
     Alternatively or additionally, catalytic, ATP-competitive mTOR inhibitors have been found to target the mTOR kinase domain directly and target both mTORC1 and mTORC2. These are also more effective inhibitors of mTORC1 than such allosteric mTOR inhibitors as rapamycin, because they modulate rapamycin-resistant mTORC1 outputs such as 4EBP1-T37/46 phosphorylation and cap-dependent translation. 
     Catalytic inhibitors include: BEZ235 or 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile, or the monotosylate salt form (the synthesis of BEZ235 is described in WO2006/122806); CCG168 (otherwise known as AZD-8055, Chresta, C. M., et al., Cancer Res, 2010, 70(1), 288-298) which has the chemical name {5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3d]pyrimidin-7-yl]-2-methoxy-phenyl}-methanol; 3-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-N-methylbenzamide (WO09104019); 3-(2-aminobenzo[d]oxazol-5-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (WO10051043 and WO2013023184); A N-(3-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxaline-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide (WO07044729 and WO12006552); PKI-587 (Venkatesan, A. M., J. Med. Chem., 2010, 53, 2636-2645) which has the chemical name 1-[4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl]-3-[4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl]urea; GSK-2126458 (ACS Med. Chem. Lett., 2010, 1, 39-43) which has the chemical name 2,4-difluoro-N-{2-methoxy-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide; 5-(9-isopropyl-8-methyl-2-morpholino-9H-purin-6-yl)pyrimidin-2-amine (WO10114484); and (E)-N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-iH-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (WO12007926). 
     Further examples of catalytic mTOR inhibitors include 8-(6-methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (WO2006/122806) and Ku-0063794 (Garcia-Martinez J M, et al., Biochem J., 2009, 421(1), 29-42. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR).) WYE-354 is another example of a catalytic mTOR inhibitor (Yu K, et al. (2009). Biochemical, Cellular, and In vivo Activity of Novel ATP-Competitive and Selective Inhibitors of the Mammalian Target of Rapamycin. Cancer Res. 69(15): 6232-6240). 
     mTOR inhibitors useful according to the present invention also include prodrugs, derivatives, pharmaceutically acceptable salts, or analogs thereof of any of the foregoing. mTOR inhibitors, such as RAD001, may be formulated for delivery based on well-established methods in the art based on the particular dosages described herein. In particular, U.S. Pat. No. 6,004,973 (incorporated herein by reference) provides examples of formulations useable with the mTOR inhibitors described herein. 
     Methods and Biomarkers for Evaluating CAR-Effectiveness or Sample Suitability 
     The present disclosure provides, among other things, gene signatures that indicate whether a cancer patient treated with a CAR therapy is likely to relapse, or has relapsed. Without wishing to be bound by theory, an experimental basis for this gene signature is set out in Example 12 on pages 528-532 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     In an embodiment, novel transcriptional gene signatures described e.g., in Table 29 (on page 530 International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety), are used to enable manufactured product improvements, thereby reducing the likelihood of patient relapse. In an embodiment, gene signatures described herein are used to modify therapeutic application of manufactured product, thereby reducing the likelihood of patient relapse. 
     In an embodiment, gene signatures described e.g., in Table 29 (on page 530 International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety) are identified in a subject prior to treatment with a CAR-expressing cell, e.g., CART treatment (e.g., a CART19 treatment, e.g., CTL019 therapy) that predict relapse to CAR treatment. In an embodiment, gene signatures described herein are identified in an apheresis sample or bone marrow sample. In an embodiment, gene signatures described herein are identified in a manufactured CAR-expressing cell product, e.g., CART product (e.g., a CART19 product, e.g., CTL019) prior to infusion. 
     In embodiments, a method of using the compositions described herein comprises assaying a gene signature that indicates whether a subject treated with the cell is likely to relapse, or has relapsed. In embodiments, the method comprises assaying the gene signature in the cell prior to infusion into the subject. In embodiments, the method further comprises decreasing the T REG  signature of a population of cells comprising the transduced cell. In embodiments, decreasing the T REG  signature comprises performing CD25-depletion on the population of cells. 
     In embodiments, a method comprises assaying a gene signature that indicates whether the subject is likely to relapse, or has relapsed. In embodiments, the method comprises assaying a gene signature in a subject prior to treatment with a CAR-expressing cell, e.g., CART treatment (e.g., a CART19 treatment, e.g., CTL019 therapy) that predicts relapse to CAR treatment. In embodiments, the level of one or more markers is the level of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 markers listed in Table 29 (on page 530 International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety). In embodiments, the level of the marker comprises an mRNA level or a level of a soluble protein. 
     This disclosure also provides evidence, for instance in Example 12, on pages 528-532 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety, that (without wishing to be bound by theory) decreasing the T REG  signature in the patient prior to apheresis or during manufacturing of the CART product reduces the risk of patient relapse. 
     In an embodiment, a patient is pre-treated with one or more therapies that reduce T REG  cells prior to collection of cells for CAR product manufacturing, e.g., CART product manufacturing, thereby reducing the risk of patient relapse to CAR-expressing cell treatment (e.g., CTL019 treatment). Methods of decreasing T REG  cells include, but are not limited to, cyclophosphamide, anti-GITR antibody, CD25-depletion, and combinations thereof. 
     In an embodiment, a patient is pre-treated with cyclophosphamide or an anti-GITR antibody prior to collection of cells for CAR-expressing cell product manufacturing, thereby reducing the risk of patient relapse to CAR-expressing cell treatment (e.g., CTL019 treatment). 
     In an embodiment, the CAR-expressing cell manufacturing process is modified to deplete T REG  cells prior to manufacturing of the CAR-expressing cell product (e.g., a CTL019 product). In an embodiment, CD25-depletion is used to deplete T REG  cells prior to manufacturing of the CAR-expressing cell product (e.g., a CTL019 product). 
     In an embodiment, after treating a patient or a CAR-expressing cell product with a treatment that reduces T REG  cells, the patient is treated with a combination therapy. The combination therapy may comprise, e.g., a CD19 inhibitor such as a CD19 CAR-expressing cell, and one or more B-cell inhibitors, e.g., B-cell inhibitors as described herein. 
     In an embodiment, a patient is assayed for the level of T REG  cells in a patient sample, e.g., a sample comprising cancer cells and/or a sample representing a tumor microenvironment. In an embodiment, this information is used to determine a course of treatment for the patient. For instance, in an embodiment, if the patient is identified as having elevated levels of T REG  cells compared to a control, the therapy comprises administering a treatment other than a CAR-expressing cell. For instance, the therapy may comprise administration of an antibody molecule, administration of a small molecule therapeutic, surgery, or radiation therapy, or any combination thereof. This therapy may target one or more B-cell antigens. 
     In embodiments, the characteristic of CD19 is a mutation in exon 2, e.g., a mutation causing a frameshift or a premature stop codon or both. In embodiments, the level of T REG  cells is determined by staining a sample for a marker expressed by T REG  cells. In embodiments, the level of T REG  cells is the level of Treg cells in a relevant location in the subject&#39;s body, e.g., in a cancer microenvironment. 
     In an embodiment, a relapser is a patient having, or who is identified as having, an increased level of expression (e.g., increase in RNA levels) of one or more of (e.g., 2, 3, 4, or all of) the following genes, compared to non relapsers: MIR199A1, MIR1203, uc02lovp, ITM2C, and HLA-DQB1 and/or a decreased levels of expression (e.g., decrease in RNA levels) of one or more of (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or all of) the following genes, compared to non relapsers: PPIAL4D, TTTY10, TXLNG2P, MIR4650-1, KDM5D, USP9Y, PRKY, RPS4Y2, RPS4Y1, NCRNA00185, SULTiE1, and EIF1AY. 
     In another aspect, the invention features a method of evaluating or monitoring the effectiveness of a CAR-expressing cell therapy, in a subject (e.g., a subject having a cancer), or the suitability of a sample (e.g., an apheresis sample) for a CAR therapy, e.g., therapy including administration of a low, immune-enhancing dose of an mTOR inhibitor. The method includes acquiring a value of effectiveness to the CAR therapy, or sample suitability, wherein said value is indicative of the effectiveness or suitability of the CAR-expressing cell therapy. 
     In embodiments, the value of effectiveness to the CAR therapy, or sample suitability, comprises a measure of one, two, three, four, five, six or more (all) of the following: 
     (i) the level or activity of one, two, three, or more (e.g., all) of resting T EFF  cells, resting T REG  cells, younger T cells (e.g., younger CD4 or CD8 cells, or gamma/delta T cells), or early memory T cells, or a combination thereof, in a sample (e.g., an apheresis sample or a manufactured CAR-expressing cell product sample); 
     (ii) the level or activity of one, two, three, or more (e.g., all) of activated T EFF  Cells, activated T REG  ells, older T cells (e.g., older CD4 or CD8 cells), or late memory T cells, or a combination thereof, in a sample (e.g., an apheresis sample or a manufactured CAR-expressing cell product sample); 
     (iii) the level or activity of an immune cell exhaustion marker, e.g., one, two or more immune checkpoint inhibitors (e.g., PD-1, PD-L1, TIM-3 and/or LAG-3) in a sample (e.g., an apheresis sample or a manufactured CAR-expressing cell product sample). In one embodiment, an immune cell has an exhausted phenotype, e.g., co-expresses at least two exhaustion markers, e.g., co-expresses PD-1 and TIM-3. In other embodiments, an immune cell has an exhausted phenotype, e.g., co-expresses at least two exhaustion markers, e.g., co-expresses PD-1 and LAG-3; 
     (iv) the level or activity of CD27 and/or CD45RO− (e.g., CD27+CD45RO−) immune effector cells, e.g., in a CD4+ or a CD8+ T cell population, in a sample (e.g., an apheresis sample or a manufactured CAR-expressing cell product sample); 
     (v) the level or activity of one, two, three, four, five, ten, twelve or more of the biomarkers chosen from CCL20, IL-17a and/or IL-6, PD-1, PD-L1, LAG-3, TIM-3, CD57, CD27, CD122, CD62L, KLRG1; 
     (vi) a cytokine level or activity (e.g., quality of cytokine repertoire) in a CAR-expressing cell product sample; or 
     (vii) a transduction efficiency of a CAR-expressing cell in a manufactured CAR-expressing cell product sample. 
     In some embodiments of any of the methods disclosed herein, the CAR-expressing cell therapy comprises a plurality (e.g., a population) of CAR-expressing immune effector cells, e.g., a plurality (e.g., a population) of T cells or NK cells, or a combination thereof. In one embodiment, the CAR-expressing cell therapy includes administration of a low, immune-enhancing dose of an mTOR inhibitor. 
     In some embodiments of any of the methods disclosed herein, the measure of one or more of (i)-(vii) is obtained from an apheresis sample acquired from the subject. The apheresis sample can be evaluated prior to infusion or re-infusion. 
     In some embodiments of any of the methods disclosed herein, the measure of one or more of (i)-(vii) is obtained from a manufactured CAR-expressing cell product sample. The manufactured CAR-expressing cell product can be evaluated prior to infusion or re-infusion. 
     In some embodiments of any of the methods disclosed herein, the subject is evaluated prior to receiving, during, or after receiving, the CAR-expressing cell therapy. 
     In some embodiments of any of the methods disclosed herein, the measure of one or more of (i)-(vii) evaluates a profile for one or more of gene expression, flow cytometry or protein expression. 
     In some embodiments of any of the methods disclosed herein, the method further comprises identifying the subject as a responder, a non-responder, a relapser or a non-relapser, based on a measure of one or more of (i)-(vii). 
     In some embodiments of any of the methods disclosed herein, a responder (e.g., a complete responder) has, or is identified as having, a greater level or activity of one, two, or more (all) of GZMK, PPF1BP2, or naïve T cells as compared to a non-responder. 
     In some embodiments of any of the methods disclosed herein, a non-responder has, or is identified as having, a greater level or activity of one, two, three, four, five, six, seven, or more (e.g., all) of IL22, IL-2RA, IL-21, IRF8, IL8, CCL17, CCL22, effector T cells, or regulatory T cells, as compared to a responder. 
     In an embodiment, a relapser is a patient having, or who is identified as having, an increased level of expression of one or more of (e.g., 2, 3, 4, or all of) the following genes, compared to non relapsers: MIR199A1, MIR1203, uc02lovp, ITM2C, and HLA-DQB1 and/or a decreased levels of expression of one or more of (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or all of) the following genes, compared to non relapsers: PPIAL4D, TTTY10, TXLNG2P, MIR4650-1, KDM5D, USP9Y, PRKY, RPS4Y2, RPS4Y1, NCRNA00185, SULTiE1, and EIF1AY. 
     In some embodiments of any of the methods disclosed herein, a complete responder has, or is identified as having, a greater, e.g., a statistically significant greater, percentage of CD8+ T cells compared to a reference value, e.g., a non-responder percentage of CD8+ T cells. 
     In some embodiments of any of the methods disclosed herein, a complete responder has, or is identified as having, a greater percentage of CD27+CD45RO− immune effector cells, e.g., in the CD8+ population, compared to a reference value, e.g., a non-responder number of CD27+CD45RO− immune effector cells. 
     In some embodiments of any of the methods disclosed herein, a complete responder or a partial responder has, or is identified as having, a greater, e.g., a statistically significant greater, percentage of CD4+ T cells compared to a reference value, e.g., a non-responder percentage of CD4+ T cells. 
     In some embodiments of any of the methods disclosed herein, a complete responder has, or is identified as having, a greater percentage of one, two, three, or more (e.g., all) of resting TEFF cells, resting T REG  cells, younger T cells (e.g., younger CD4 or CD8 cells, or gamma/delta T cells), or early memory T cells, or a combination thereof, compared to a reference value, e.g., a non-responder number of resting T EFF  cells, resting T REG  cells, younger T cells (e.g., younger CD4 or CD8 cells), or early memory T cells. 
     In some embodiments of any of the methods disclosed herein, a non-responder has, or is identified as having, a greater percentage of one, two, three, or more (e.g., all) of activated T EFF  cells, activated T REG  ells, older T cells (e.g., older CD4 or CD8 cells), or late memory T cells, or a combination thereof, compared to a reference value, e.g., a responder number of activated T EFF  cells, activated T REG  ells, older T cells (e.g., older CD4 or CD8 cells), or late memory T cells. 
     In some embodiments of any of the methods disclosed herein, a non-responder has, or is identified as having, a greater percentage of an immune cell exhaustion marker, e.g., one, two or more immune checkpoint inhibitors (e.g., PD-1, PD-L1, TIM-3 and/or LAG-3). In one embodiment, a non-responder has, or is identified as having, a greater percentage of PD-1, PD-L1, or LAG-3 expressing immune effector cells (e.g., CD4+ T cells and/or CD8+ T cells) (e.g., CAR-expressing CD4+ cells and/or CD8+ T cells) compared to the percentage of PD-1 or LAG-3 expressing immune effector cells from a responder. 
     In one embodiment, a non-responder has, or is identified as having, a greater percentage of immune cells having an exhausted phenotype, e.g., immune cells that co-express at least two exhaustion markers, e.g., co-expresses PD-1, PD-L1 and/or TIM-3. In other embodiments, a non-responder has, or is identified as having, a greater percentage of immune cells having an exhausted phenotype, e.g., immune cells that co-express at least two exhaustion markers, e.g., co-expresses PD-1 and LAG-3. 
     In some embodiments of any of the methods disclosed herein, a non-responder has, or is identified as having, a greater percentage of PD-1/PD-L1+/LAG-3+ cells in the CAR-expressing cell population compared to a responder (e.g., a complete responder) to the CAR-expressing cell therapy. 
     In some embodiments of any of the methods disclosed herein, a partial responder has, or is identified as having, a higher percentages of PD-1/PD-L1+/LAG-3+ cells, than a responder, in the CAR-expressing cell population. 
     In some embodiments of any of the methods disclosed herein, a non-responder has, or is identified as having, an exhausted phenotype of PD1/PD-L1+ CAR+ and co-expression of LAG3 in the CAR-expressing cell population. 
     In some embodiments of any of the methods disclosed herein, a non-responder has, or is identified as having, a greater percentage of PD-1/PD-L1+/TIM-3+ cells in the CAR-expressing cell population compared to the responder (e.g., a complete responder). 
     In some embodiments of any of the methods disclosed herein, a partial responders has, or is identified as having, a higher percentage of PD-1/PD-L1+/TIM-3+ cells, than responders, in the CAR-expressing cell population. 
     In some embodiments of any of the methods disclosed herein, the presence of CD8+CD27+CD45RO− T cells in an apheresis sample is a positive predictor of the subject response to a CAR-expressing cell therapy. 
     In some embodiments of any of the methods disclosed herein, a high percentage of PD1+ CAR+ and LAG3+ or TIM3+ T cells in an apheresis sample is a poor prognostic predictor of the subject response to a CAR-expressing cell therapy. 
     In some embodiments of any of the methods disclosed herein, the responder (e.g., the complete or partial responder) has one, two, three or more (or all) of the following profile: 
     (i) has a greater number of CD27+ immune effector cells compared to a reference value, e.g., a non-responder number of CD27+ immune effector cells; 
     (ii) has a greater number of CD8+ T cells compared to a reference value, e.g., a non-responder number of CD8+ T cells; 
     (iii) has a lower number of immune cells expressing one or more checkpoint inhibitors, e.g., a checkpoint inhibitor chosen from PD-1, PD-L1, LAG-3, TIM-3, or KLRG-1, or a combination, compared to a reference value, e.g., a non-responder number of cells expressing one or more checkpoint inhibitors; or 
     (iv) has a greater number of one, two, three, four or more (all) of resting TEFF cells, resting T REG  cells, naïve CD4 cells, unstimulated memory cells or early memory T cells, or a combination thereof, compared to a reference value, e.g., a non-responder number of resting TEFF cells, resting T REG  cells, naïve CD4 cells, unstimulated memory cells or early memory T cells. 
     In some embodiments of any of the methods disclosed herein, the cytokine level or activity of (vi) is chosen from one, two, three, four, five, six, seven, eight, or more (or all) of cytokine CCL20/MIP3a, IL17A, IL6, GM-CSF, IFNγ, IL10, IL13, IL2, IL21, IL4, IL5, IL9 or TNFα, or a combination thereof. The cytokine can be chosen from one, two, three, four or more (all) of IL-17a, CCL20, IL2, IL6, or TNFα. In one embodiment, an increased level or activity of a cytokine is chosen from one or both of IL-17a and CCL20, is indicative of increased responsiveness or decreased relapse. 
     In some embodiments of any of the methods disclosed herein, a transduction efficiency of 15% or higher in (vii) is indicative of increased responsiveness or decreased relapse. 
     In some embodiments of any of the methods disclosed herein, a transduction efficiency of less than 15% in (vii) is indicative of decreased responsiveness or increased relapse. 
     In embodiments, the responder, a non-responder, a relapser or a non-relapser identified by the methods herein can be further evaluated according to clinical criteria. For example, a complete responder has, or is identified as, a subject having a disease, e.g., a cancer, who exhibits a complete response, e.g., a complete remission, to a treatment. A complete response may be identified, e.g., using the NCCN Guidelines® (which are incorporated by reference herein in their entireties), as described herein. A partial responder has, or is identified as, a subject having a disease, e.g., a cancer, who exhibits a partial response, e.g., a partial remission, to a treatment. A partial response may be identified, e.g., using the NCCN Guidelines®, as described herein. A non-responder has, or is identified as, a subject having a disease, e.g., a cancer, who does not exhibit a response to a treatment, e.g., the patient has stable disease or progressive disease. A non-responder may be identified, e.g., using the NCCN Guidelines®, as described herein. 
     Alternatively, or in combination with the methods disclosed herein, responsive to said value, performing one, two, three, four or more of: 
     administering e.g., to a responder or a non-relapser, a CAR-expressing cell therapy; 
     administered an altered dosing of a CAR-expressing cell therapy; 
     altering the schedule or time course of a CAR-expressing cell therapy; 
     administering, e.g., to a non-responder or a partial responder, an additional agent in combination with a CAR-expressing cell therapy, e.g., a checkpoint inhibitor, e.g., a checkpoint inhibitor described herein; 
     administering to a non-responder or partial responder a therapy that increases the number of younger T cells in the subject prior to treatment with a CAR-expressing cell therapy; 
     modifying a manufacturing process of a CAR-expressing cell therapy, e.g., enriching for younger T cells prior to introducing a nucleic acid encoding a CAR, or increasing the transduction efficiency, e.g., for a subject identified as a non-responder or a partial responder; 
     administering an alternative therapy, e.g., for a non-responder or partial responder or relapser; or 
     if the subject is, or is identified as, a non-responder or a relapser, decreasing the T REG  cell population and/or T REG  gene signature, e.g., by one or more of CD25 depletion, administration of cyclophosphamide, anti-GITR antibody, or a combination thereof. 
     In certain embodiments, the subject is pre-treated with an anti-GITR antibody. In certain embodiment, the subject is treated with an anti-GITR antibody prior to infusion or re-infusion. 
     In some embodiments of the methods described herein, imaging with FDG-PET/CT (PET/CT) is performed on a subject who has been treated with a CAR therapy. This measurement can predict response to the therapy. For instance, in embodiments, metabolically active tumor volume (MTV) and/or [11F]-2-fluoro-2-deoxy-D-glucose (FDG) uptake are measured. In embodiments, a decrease in MTV is indicative of response, e.g., CR (complete response) or PR (partial response), e.g., a post-treatment MTV value of about 0 is indicative of CR, while an increase in MTV is indicative of PD (progressive disease). In embodiments, a decrease in FDG uptake is indicative of response, e.g., CR or PR, while an increase in FDG uptake is indicative of PD. In embodiments, the imaging is performed after administration of the CAR therapy, e.g., about 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months after administration of the CAR therapy. In embodiments, the imaging is performed on a subject who does not have symptoms of CRS (cytokine release syndrome), e.g., a patient who suffered from CRS and whose symptoms resolved prior to imaging. In embodiments, the imaging is performed on a subject who has symptoms of CRS. In embodiments, imaging is performed prior to CAR therapy, and the pre-therapy image is compared to a post-therapy image. In embodiments, the subject has a cancer, e.g., lymphoma, e.g., diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). In some embodiments, the CAR therapy comprises a CAR19-expressing cell, e.g., murine CTL019 or humanized CTL119 as described herein, e.g., Tables 2-3. In some embodiments, the CAR therapy comprises a CAR therapy described herein, e.g., a CAR20-expressing cell, a CAR22-expressing cell, or a CAR19-expressing cell, optionally in combination with a B-cell therapy. 
     Personalized Medicine (Theranostics) 
     CD19 Characteristics, e.g. Mutations 
     Without wishing to be bound by theory, some cancer patients show an initial response to a CD19 inhibitor such as a CD19 CAR-expressing cell, and then relapse. In some embodiments, the relapse is caused (at least in part) by a frameshift and/or premature stop codon in CD19 in the cancer cells, or other change in the expression (including expression levels) of CD19 which reduces the ability of a CD19 CAR-expressing cell to target the cancer cells. Such a mutation can reduce the effectiveness of the CD19 therapy and contribute to the patient&#39;s relapse. Accordingly, in some embodiments, it can be beneficial when a CD19 therapy is supplemented or replaced with a therapy directed to a second, different target, e.g., a target expressed in B-cells, e.g., one or more of CD10, CD20, CD22, CD34, CD123, FLT-3, or ROR1. Various exemplary combination therapies of this type are disclosed herein. 
     This application discloses, among other things, methods for treating a subject having cancer comprising one or more of: (1) determining if a subject has a difference, e.g., statistically significant difference, in a characteristic of CD19 relative to a reference characteristic, and (2) if there is a difference between the determined characteristic and reference characteristic, administering to the subject a therapeutically effective dose of a CAR therapy, e.g., CART, thereby treating the subject. The patient may be, e.g., a patient who has relapsed after treatment with a CD19 inhibitor, e.g., a CD19 CAR expressing cell. The patient may be a patient who has received or is receiving a CD19 CAR therapy and is at risk of relapse. The patient may be a non-responder to a CD19 CAR therapy. 
     In embodiments, the one or more cells that express a CAR molecule that binds CD19 are administered concurrently with, before, or after the one or more B-cell inhibitors. 
     In embodiments, the subject has or is identified as having a difference, e.g., a statistically significant difference, between a determined level compared to a reference level of one or more markers listed in Table 29 (on page 530 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety) in a biological sample. 
     In embodiments, the subject has or is identified as having a difference between a determined characteristic compared to a reference characteristic, in a characteristic of CD19, e.g., a mutation causing a frameshift or a premature stop codon or both, in a biological sample. 
     In embodiments, the subject has or is identified as having a difference, e.g., a statistically significant difference, between a determined level compared to a reference level of Treg cells in a biological sample. 
     Additional characteristics that can be measured to determine a therapeutically effective dose of CAR therapy are described in pages 8-13, and 64-65 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety 
     The characteristic can be, e.g., a CD19 sequence, e.g., protein or nucleic acid sequence. The sequence can be determined, e.g., as described in the Examples, by high throughput nucleic acid sequencing, or by mass spectrometry of proteins. As described in the Example herein, a patient may relapse after CD19 CART therapy because of mutations in CD19, e.g., in exon 2 of CD19, e.g., a mutation that causes a frameshift and a premature stop codon in CD19. In embodiments, the insertion or deletion does not cause one or both of a frameshift and a premature stop codon. The mutation may be, e.g., an insertion, a deletion, a substitution, a translocation, or a combination of any of the foregoing. The insertion, deletion, or substitution may involve, e.g., at least 1, 2, 3, 4, 5, 10, 15, 20, 20, or 50 nucleotides. The insertion, deletion, or substitution may involve, e.g., at most 2, 3, 4, 5, 10, 15, 20, 20, 50, or 100 nucleotides. In some cases, a population of cells will comprise more than one mutation. In such cases, the mutations can be in overlapping or non-overlapping sub-populations of cells. 
     In some cases a patient is identified as having a CD19 characteristic that reduces CD19&#39;s ability to engage with a CD19 inhibitor such as a CD19 CAR expressing cell. Such a characteristic may be, e.g., a frameshift mutation, a premature stop codon, an alteration in nucleic acid sequence or an alteration in the structure of the primary mRNA transcript. The characteristic may be, e.g., a departure from normal production of CD19 that occurs earlier than splicing. The characteristic may be, e.g., a characteristic other than exon skipping. Such patients may be treated with an inhibitor of another target, e.g., a B-cell inhibitor, for example a CAR expressing cell directed against another epitope, e.g., an epitope within one or more of CD10, CD20, CD22, CD34, CD123, FLT-3, or ROR1. 
     In some cases, a patient is identified as having a CD19 characteristic that reduces CD19&#39;s ability to engage with a CD19 inhibitor, such as a CD19 CAR expressing cell, but does not reduce or abrogate CD19&#39;s ability to engage with a second CD19 inhibitor, such as a CD19 inhibitor that binds to a different region on CD19. Such a characteristic may be, e.g., a mutation that does not cause one or both of a frameshift mutation or a premature stop codon. Such a characteristic may be, e.g., an alteration in nucleic acid sequence or an alteration in the structure of the primary mRNA transcript, a departure from normal production of CD19 that occurs earlier than splicing, or a characteristic other than exon skipping. Such patients may be treated with an inhibitor of CD19, e.g., a B-cell inhibitor directed against an intact region of CD19, e.g., a wild-type portion of CD19. For instance, if a mutation is present in exon 2, the second CD19 inhibitor may bind to an exon other than exon 2, or a part of exon 2 that lacks the mutation. The second CD19 inhibitor may be, e.g., a CD19 inhibitor described herein. 
     T EFF  AND T REG  Signatures 
     Methods herein can include steps of determining a T REG  signature or determining the levels of T EFF  cells or T REG  ells, e.g., in a patient or in a population of cells e.g., immune cells. Methods herein can also include steps of reducing the level of T REG  cells, or decreasing a T REG  signature, in a patient or in a population of cells. In some embodiments, a T EFF  is a cell with upregulated expression of one or more (e.g., at least 10, 20, 30, 40, 50, 60, 70, 80, or all) of the following genes: AIM2, ALAS1, B4GALT5, BATF, C3orf26, C4orf43, CCL3, CCL4, CCT3, CCT7, CD40LG, CHAC2, CSF2, CTNNA1, EBNA1BP2, EDARADD, EEF1E1, EIF2B3, EIF2S1, FABP5, FAM40B, FKBP4, FOSL1, GFOD1, GLRX2, HSPD1, HSPE1, IFNG, IL15RA, IL21, IL2RA, IL3, KCNK5, KIAA0020, LARP4, LRP8, LTA, MANF, MIR1182, MIR155, MIR155HG, MTCH2, MYOF, NDUFAF1, NLN, NME1, NME1-NME2, OTUD7B, PAM, PDIA6, PEA15, PFKM, PGAM1, PGAM4, PPIL1, PRDX4, PRSS23, PSMD1, PSMD11, PSMD14, PTRH2, PUS7, RBBP8, RPF2, RPP25, SFXN1, SLC27A2, SLC39A14, SLC43A3, SORD, SPR, SRXN1, STIP1, STT3A, TBX21, TMCC2, TMEM165, TNFRSF9, TXN, TXNDC5, UCK2, VDR, WDR12, YWHAG, and ZDHHC16. In some embodiments, a T RE G cell is a cell with upregulated expression of one or more (e.g., at least 10, 20, 30, 40, 50, 60, 70, or all) of the following genes: AIM2, ALAS1, BATF, C5orf32, CCL17, CD40LG, CHAC2, CSF1, CTSL1, EBNA1BP2, EDARADD, EMP1, EPAS1, FABP5, FAM40B, FKBP4, FOSL1, GCLM, GK, GPR56, HMOX1, HSPD1, HSPE1, IKBIP, IL10, IL13, IL15RA, IL1RN, IL2RA, IL3, IL4, IL5, IL9, KCNK5, LTA, MANF, MIR1182, MIR155, MIR155HG, MYOF, NDUFAF1, NLN, NME1, NME1-NME2, PANX2, PDIA6, PGAM4, PPIL1, PPPDE2, PRDX4, PRKAR1B, PSMD1, PSMD11, PUS7, RBBP8, SLC27A2, SLC39A14, SLC43A3, SRXN1, STIP1, STT3A, TBX21, TNFRSF11A, TNFRSFlB, TNFRSF8, TNFRSF9, TXN, UCK2, VDR, VTRNAl-3, WDR12, YWHAG, ZDHHC16, and ZNF282. The upregulated expression may be, e.g., measured 16 hours after stimulation. The upregulated expression may be determined, e.g., by measuring RNA levels for the indicated genes. 
     In embodiments, the method comprises decreasing the T REG  signature in the subject prior to apheresis. In embodiments, the method further comprises decreasing the T REG  signature in the subject, e.g., by administering cyclophosphamide, an anti-GITR antibody, or both to the subject. In embodiments, the method comprises pre-treating a subject with cyclophosphamide, an anti-GITR antibody, or both, prior to collection of cells for CAR-expressing cell product manufacturing. In embodiments, the method further comprises obtaining a sample from the subject, wherein the sample comprises a cellular fraction (e.g., which comprises blood), a tissue fraction, an apheresis sample, or a bone marrow sample. 
     Pharmaceutical Compositions and Treatments 
     Pharmaceutical compositions of the present invention may comprise, in some aspects, a CAR-expressing cell, e.g., a plurality of CAR-expressing cells, as described herein, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients. Such compositions may comprise buffers such as neutral buffered saline, phosphate buffered saline and the like; carbohydrates such as glucose, mannose, sucrose or dextrans, mannitol; proteins; polypeptides or amino acids such as glycine; antioxidants; chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); and preservatives. Compositions of the present invention are in one aspect formulated for intravenous administration. 
     Pharmaceutical compositions of the present invention may be administered in a manner appropriate to the disease to be treated (or prevented). The quantity and frequency of administration will be determined by such factors as the condition of the patient, and the type and severity of the patient&#39;s disease, although appropriate dosages may be determined by clinical trials. 
     In one embodiment, the pharmaceutical composition is substantially free of, e.g., there are no detectable levels of a contaminant, e.g., selected from the group consisting of endotoxin, mycoplasma, replication competent lentivirus (RCL), p24, VSV-G nucleic acid, HIV gag, residual anti-CD3/anti-CD28 coated beads, mouse antibodies, pooled human serum, bovine serum albumin, bovine serum, culture media components, vector packaging cell or plasmid components, a bacterium and a fungus. In one embodiment, the bacterium is at least one selected from the group consisting of  Alcaligenes faecalis, Candida albicans, Escherichia coli, Haemophilus influenza, Neisseria meningitides, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumonia , and  Streptococcus pyogenes  group A. 
     When “an immunologically effective amount,” “an anti-tumor effective amount,” “a tumor-inhibiting effective amount,” or “therapeutic amount” is indicated, the precise amount of the compositions of the present invention to be administered can be determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the patient (subject). In some embodiments, a pharmaceutical composition comprising the cells, e.g., T cells described herein may be administered at a dosage of 10 4  to 10 9  cells/kg body weight, in some instances 10 5  to 10 6  cells/kg body weight, including all integer values within those ranges. In some embodiments, the cells, e.g., T cells described herein may be administered at 3×10 4 , 1×10 6 , 3×10 6 , or 1×10 7  cells/kg body weight. The cell compositions may also be administered multiple times at these dosages. The cells can be administered by using infusion techniques that are commonly known in immunotherapy (see, e.g., Rosenberg et al., New Eng. J. of Med. 319:1676, 1988). 
     In some embodiments, a dose of CAR cells (e.g., CD19 or BCMA CAR cells) comprises about 1×10 5 , 2×10 5 , 5×10 5 , 1×10 6 , 1.1×10 6 , 2×10 6 , 3.6×10 6 , 5×10 6 , 1×10 7 , 1.8×10 7 , 2×10 7 , 5×10 7 , 1×10 8 , 2×10 8 , or 5×10 8  cells/kg. In some embodiments, a dose of CAR cells (e.g., CD19 or BCMA CAR cells) comprises at least about 1×10 5 , 2×10 5 , 5×10 5 , 1×10 6 , 11×10 6 , 2×10 6 , 3.6×10 6 , 5×10 6 , 1×10 7 , 1.8×10 7 , 2×10 7 , 5×10 7 , 1×10 8 , 2×10 8 , or 5×10 8  cells/kg. In some embodiments, a dose of CAR cells (e.g., CD19 or BCMA CAR cells) comprises up to about 1×10 5 , 2×10 5 , 5×10 5 , 1×10 6 , 1.1×10 6 , 2×10 6 , 3.6×10 6 , 5×10 6 , 1×10 7 , 1.8×10 7 , 2×10 7 , 5×10 7 , 1×10 8 , 2×10 8 , or 5×10 8  cells/kg. In some embodiments, a dose of CAR cells (e.g., CD19 or BCMA CAR cells) comprises about 1.1×10 6 -1.8×10 7  cells/kg or about 8×10 5 -1.5×10 6  cells/kg. In some embodiments, a dose of CAR cells (e.g., CD19 or BCMA CAR cells) comprises about 1×10 7 , 2×10 7 , 5×10 7 , 1×10 8 , 2×10 8 , 5×10 8 , 1×10 9 , 2×10 9 , or 5×10 9  cells. In some embodiments, a dose of CAR cells (e.g., CD19 or BCMA CAR cells) comprises at least about 1×10 7 , 2×10 7 , 5×10 7 , 1×10 8 , 2×10 8 , 5×10 8 , 1×10 9 , 2×10 9 , or 5×10 9  cells. In some embodiments, a dose of CAR cells (e.g., CD19 or BCMA CAR cells) comprises up to about 1×10 7 , 2×10 7 , 5×10 7 , 1×10 8 , 2×10 8 , 5×10 8 , 1×10 9 , 2×10 9 , or 5×10 9  cells. 
     In certain aspects, it may be desired to administer activated cells, e.g., T cells or NK cells, to a subject and then subsequently redraw blood (or have an apheresis performed), activate the cells therefrom according to the present invention, and reinfuse the patient with these activated and expanded cells. This process can be carried out multiple times every few weeks. In certain aspects, cells, e.g., T cells or NK cells, can be activated from blood draws of from 10 cc to 400 cc. In certain aspects, cells, e.g., T cells or NK cells, are activated from blood draws of 20 cc, 30 cc, 40 cc, 50 cc, 60 cc, 70 cc, 80 cc, 90 cc, or 100 cc. 
     The administration of the subject compositions may be carried out in any convenient manner, including by aerosol inhalation, injection, ingestion, transfusion, implantation or transplantation. The compositions described herein may be administered to a patient trans arterially, subcutaneously, intradermally, intratumorally, intranodally, intramedullary, intramuscularly, by intravenous (i.v.) injection, or intraperitoneally. In one aspect, the cell compositions, e.g., T cell or NK cell compositions, of the present invention are administered to a patient by intradermal or subcutaneous injection. In one aspect, the cell compositions e.g., T cell or NK cell compositions, of the present invention are administered by i.v. injection. The compositions of cells e.g., T cell or NK cell compositions, may be injected directly into a tumor, lymph node, or site of infection. 
     In a particular exemplary aspect, subjects may undergo leukapheresis, wherein leukocytes are collected, enriched, or depleted ex vivo to select and/or isolate the cells of interest, e.g., T cells. These cell isolates, e.g., T cell or NK cell isolates, may be expanded by methods known in the art and treated such that one or more CAR constructs of the invention may be introduced, thereby creating a CAR-expressing cell, e.g., CAR T cell of the invention. Subjects in need thereof may subsequently undergo standard treatment with high dose chemotherapy followed by peripheral blood stem cell transplantation. In certain aspects, following or concurrent with the transplant, subjects receive an infusion of the expanded CAR-expressing cells of the present invention. In an additional aspect, expanded cells are administered before or following surgery. 
     The dosage of the above treatments to be administered to a patient will vary with the precise nature of the condition being treated and the recipient of the treatment. The scaling of dosages for human administration can be performed according to art-accepted practices. The dose for a therapeutic, e.g., an antibody, e.g., CAMPATH, for example, may be, e.g., in the range 1 to about 100 mg for an adult patient, e.g., administered daily for a period between 1 and 30 days. A suitable daily dose is 1 to 10 mg per day although in some instances larger doses of up to 40 mg per day may be used (described in U.S. Pat. No. 6,120,766). 
     In one embodiment, the CAR is introduced into cells, e.g., T cells or NK cells, e.g., using in vitro transcription, and the subject (e.g., human) receives an initial administration of CAR-expressing cells, e.g., CAR T cells of the invention, and one or more subsequent administrations of the CAR-expressing cells, e.g., CAR T cells of the invention, wherein the one or more subsequent administrations are administered less than 15 days, e.g., 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 days after the previous administration. In one embodiment, more than one administration of the CAR-expressing cells, e.g., CAR T cells of the invention are administered to the subject (e.g., human) per week, e.g., 2, 3, or 4 administrations of the CAR-expressing cells, e.g., CAR T cells of the invention are administered per week. In one embodiment, the subject (e.g., human subject) receives more than one administration of the CAR-expressing cells, e.g., CAR T cells per week (e.g., 2, 3 or 4 administrations per week) (also referred to herein as a cycle), followed by a week of no CAR-expressing cells, e.g., CAR T cells administrations, and then one or more additional administration of the CAR-expressing cells, e.g., CAR T cells (e.g., more than one administration of the CAR-expressing cells, e.g., CAR T cells per week) is administered to the subject. In another embodiment, the subject (e.g., human subject) receives more than one cycle of CAR-expressing cells, e.g., CAR T cells, and the time between each cycle is less than 10, 9, 8, 7, 6, 5, 4, or 3 days. In one embodiment, the CAR-expressing cells, e.g., CAR T cells are administered every other day for 3 administrations per week. In one embodiment, the CAR-expressing cells, e.g., CAR T cells of the invention are administered for at least two, three, four, five, six, seven, eight or more weeks. 
     In some embodiments, subjects may be adult subjects (i.e., 18 years of age and older). In certain embodiments, subjects may be between 1 and 30 years of age. In some embodiments, the subjects are 16 years of age or older. In certain embodiments, the subjects are between 16 and 30 years of age. In some embodiments, the subjects are child subjects (i.e., between 1 and 18 years of age). 
     In one aspect, CAR-expressing cells, e.g., CARTs are generated using lentiviral viral vectors, such as lentivirus. CAR-expressing cells, e.g., CARTs generated that way will have stable CAR expression. 
     In one aspect, CAR-expressing cells, e.g., CARTs, are generated using a viral vector such as a gammaretroviral vector, e.g., a gammaretroviral vector described herein. CARTs generated using these vectors can have stable CAR expression. 
     In one aspect, CAR-expressing cells, e.g., CARTs transiently express CAR vectors for 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 days after transduction. Transient expression of CARs can be effected by RNA CAR vector delivery. In one aspect, the CAR RNA is transduced into the cell, e.g., NK cell or T cell, by electroporation. 
     A potential issue that can arise in patients being treated using transiently expressing CAR T cells (particularly with murine scFv bearing CARTs) is anaphylaxis after multiple treatments. 
     Without being bound by this theory, it is believed that such an anaphylactic response might be caused by a patient developing humoral anti-CAR response, i.e., anti-CAR antibodies having an anti-IgE isotype. It is thought that a patient&#39;s antibody producing cells undergo a class switch from IgG isotype (that does not cause anaphylaxis) to IgE isotype when there is a ten to fourteen day break in exposure to antigen. 
     If a patient is at high risk of generating an anti-CAR antibody response during the course of transient CAR therapy (such as those generated by RNA transductions), CART infusion breaks should not last more than ten to fourteen days. 
     CAR22 
     Design, function and sequences of CAR22 constructs, and exemplary CAR22 constructs, are described, e.g., in pages 363-422 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     The sequences of the human CARs are provided in Table 6A and 6B on pages 364-404 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. The clones, which are incorporated by reference herein, all contained a Q/K residue change in the signal domain of the co-stimulatory domain derived from CD3zeta chain. Several CD22 scFv sequences were generated and are described in Table 6B on pages 403-404 of International Application WO 2016/164731. 
     In some embodiments, the antigen binding domain of a CD22 CAR construct comprises a HC CDR1, a HC CDR2, and a HC CDR3 of any heavy chain binding domain amino acid sequences listed in Table 6A or 6B on pages 364-404 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety and further comprises a LC CDR1, a LC CDR2, and a LC CDR3 of any light chain binding domain amino acid sequences listed in Table 6A or 6B on pages 364-404 of International Application WO 2016/164731. 
     In some embodiments, the antigen binding domain of a CD22 CAR construct comprises one, two or all of LC CDR1, LC CDR2, and LC CDR3 of any light chain binding domain amino acid sequences listed in Table 6A or 6B on pages 364-404 of International Application WO 2016/164731, and one, two or all of HC CDR1, HC CDR2, and HC CDR3 of any heavy chain binding domain amino acid sequences listed in Table 6A or 6B on pages 364-404 of International Application WO 2016/164731. 
     The sequences of human CDR sequences of the scFv domains of a CD22 CAR construct are shown in Table 7A, 7B, or 7C on pages 406-411 of International Application WO 2016/164731 for the heavy chain variable domains and in Table 8A or 8B for the light chain variable domains on pages 412-414 of International Application WO 2016/164731. 
     In some embodiments, the antigen binding domain of a CD22 CAR construct comprises a HC CDR1, a HC CDR2, and a HC CDR3 of any heavy chain binding domain amino acid sequences listed in Table 9A or 9B on pages 414-418 of International Application WO 2016/164731. In embodiments, the antigen binding domain further comprises a LC CDR1, a LC CDR2, and a LC CDR3. In embodiments, the antigen binding domain comprises a LC CDR1, a LC CDR2, and a LC CDR3 of any light chain binding domain amino acid sequences listed in Table 10A or 10B on pages 418-421 of International Application WO 2016/164731. 
     In some embodiments, the antigen binding domain of a CD22 CAR construct comprises one, two or all of LC CDR1, LC CDR2, and LC CDR3 of any light chain binding domain amino acid sequences listed in Table 10A or 10B on pages 418-421 of International Application WO 2016/164731, and one, two or all of HC CDR1, HC CDR2, and HC CDR3 of any heavy chain binding domain amino acid sequences listed in Table 9A or 9B on pages 414-418 of International Application WO 2016/164731. 
     The order of the VL and VH domains in the scFv, the presence of a linker, and mutations in the CD3 zeta chain are described, e.g., on lines 8-15 on page 422 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety 
     CAR20 Constructs 
     Design, function and sequences of CAR20 constructs, and exemplary CAR20 constructs, are described, e.g., in pages 422-454 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     Isolated anti-CD20 single chain variable fragments and sequences of exemplary CD20 CARs are described in Table 11A and 11B on pages 422-446 of International Application WO 2016/164731. 
     In some embodiments, the antigen binding domain of a CD20 CAR construct comprises a HC CDR1, a HC CDR2, and a HC CDR3 of any heavy chain binding domain amino acid sequences listed in Table 11A and 11B on pages 422-446 of International Application WO 2016/164731. In embodiments, the antigen binding domain further comprises a LC CDR1, a LC CDR2, and a LC CDR3. In embodiments, the antigen binding domain of a CD20 CAR construct comprises a LC CDR1, a LC CDR2, and a LC CDR3 of any light chain binding domain amino acid sequences listed in Table 11A and 11B on pages 422-446 of International Application WO 2016/164731. 
     In some embodiments, the antigen binding domain of a CD20 CAR construct comprises one, two or all of LC CDR1, LC CDR2, and LC CDR3 of any light chain binding domain amino acid sequences listed in Table 11A and 11B on pages 422-446 of International Application WO 2016/164731, and one, two or all of HC CDR1, HC CDR2, and HC CDR3 of any heavy chain binding domain amino acid sequences listed in Table 11A and 11B on pages 422-446 of International Application WO 2016/164731. 
     The sequences of human CDR sequences of the scFv domains of a CD20 CAR construct are shown in Table 12A, Table 12B or Table 13 on pages 447-449 of International Application WO 2016/164731. 
     In some embodiments, the antigen binding domain of a CD20 CAR construct comprises a HC CDR1, a HC CDR2, and a HC CDR3 of any heavy chain binding domain amino acid sequences listed in Table 14A or 14B on pages 450-452 of International Application WO 2016/164731, and further comprises a LC CDR1, a LC CDR2, and a LC CDR3 of any light chain binding domain amino acid sequences listed in Table 15A or 15B on pages 452-454 of International Application WO 2016/164731. 
     In some embodiments, the antigen binding domain comprises one, two or all of LC CDR1, LC CDR2, and LC CDR3 of any light chain binding domain amino acid sequences listed in Table 15A or 15B on pages 452-454 of International Application WO 2016/164731, and one, two or all of HC CDR1, HC CDR2, and HC CDR3 of any heavy chain binding domain amino acid sequences listed in Table 14A or 14B on pages 450-452 of International Application WO 2016/164731. 
     CAR123 Constructs 
     Design, function and sequences of CAR123 constructs, and exemplary CAR123 constructs, are described, e.g., in pages 454-501 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     The sequences of exemplary human CD123 CARs are provided in Table 16 on pages 455-459 of International Application WO 2016/164731. 
     The order of the VL and VH domains in the scFv, the presence of a linker, and mutations in the CD3 zeta chain are described, e.g., on lines 27-29 on page 454, and lines 5-9 on page 455 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     In some embodiments, the antigen binding domain of a CD123 CAR construct comprises a HC CDR1, a HC CDR2, and a HC CDR3 of any heavy chain binding domain amino acid sequences listed in Table 16 on pages 455-459 of International Application WO 2016/164731, and further comprises a LC CDR1, a LC CDR2, and a LC CDR3 of any light chain binding domain amino acid sequences listed in Table 16 on pages 455-459 of International Application WO 2016/164731. 
     In some embodiments, the antigen binding domain of a CD123 CAR construct comprises one, two or all of LC CDR1, LC CDR2, and LC CDR3 of any light chain binding domain amino acid sequences listed in Table 16 on pages 455-459 of International Application WO 2016/164731, and one, two or all of HC CDR1, HC CDR2, and HC CDR3 of any heavy chain binding domain amino acid sequences listed in Table 16 on pages 455-459 of International Application WO 2016/164731. 
     The sequences of human CDR sequences of the scFv domains of a CD123 CAR construct are shown in Table 17 and Table 18 on page 460 of International Application WO 2016/164731. 
     In an embodiment, the B-cell inhibitor comprises a CD123 CAR which comprises an antibody or antibody fragment which includes a CD123 binding domain, wherein said CD123 binding domain comprises one or more of light chain complementary determining region 1 (LC CDR1), light chain complementary determining region 2 (LC CDR2), and light chain complementary determining region 3 (LC CDR3) amino acid sequence listed in Table 18, Table 20, Table 22, or Table 24 of International Application WO 2016/164731, and one or more of heavy chain complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary determining region 3 (HC CDR3) of any CD123 heavy chain binding domain amino acid sequence listed in Table 17, Table 19, Table 21, or Table 23 of International Application WO 2016/164731. 
     Additional CD123 CDR sequences of the scFv domains are described in Tables 19-24 on pages 461-463 of International Application WO 2016/164731. 
     Additional description of these CD123 CARs is provided, for instance, in PCT/CN2014/090508, which is incorporated by reference herein in its entirety. 
     Generation of CART-CD123, evaluation of cytolytic activity of CART-CD123, T cell transduction, degranulation, cytotoxicity and in vivo efficacy are described, e.g., in  FIGS. 42-48  on pages 647-656 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     Humanized anti-CD123 single chain variable fragments (scFv) are described, e.g., on lines 8-11 on page 467 of International Application WO 2016/164731, and the sequence of the humanized CARs are provided in Table 25 on page 467-500 of International Application WO 2016/164731. The sequences of humanized CDR sequences of the scFv domains of hzCD123 CAR 1-32 are shown in Table 26 and Table 27 on pages 500-501 of International Application WO 2016/164731. In some embodiments, the CAR123 has a HCDR3 having the sequence YCARGNWDDY, as described e.g., on lines 8-9 on page 501 of International Application WO 2016/164731. 
     The order of the VL and VH domains in the scFv, the presence of a linker, and mutations in the CD3 zeta chain are described, e.g., on lines 12-19 on page 467 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. 
     Bispecific CAR19/CAR22 Constructs and Function Thereof 
     The production and function of bispecific CAR19/CAR22 constructs is described, e.g., on pages 501-506 of International Application WO 2016/164731, filed Apr. 8, 2016, which is incorporated by reference in its entirety. The anti-CD19 base molecule is a humanized anti-CD19 sequence, provided as construct ID 104876 of Table 2, which uses the LH orientation. 
     The nucleotide and amino acid sequences of CAR19/CAR22 constructs, are provided in Table 28 on pages 501-508 of International Application WO 2016/164731. 
     In some embodiments, the antigen binding domain comprises a HC CDR1, a HC CDR2, and a HC CDR3 of any heavy chain binding domain amino acid sequences listed in Table 28 on pages 501-508 of International Application WO 2016/164731, and further comprises a LC CDR1, a LC CDR2, and a LC CDR3 of any light chain binding domain amino acid sequences listed in Table 28 on pages 501-508 of International Application WO 2016/164731. 
     In some embodiments, the antigen binding domain comprises one, two or all of LC CDR1, LC CDR2, and LC CDR3 of any light chain binding domain amino acid sequences listed in Table 28 on pages 501-508 of International Application WO 2016/164731, and one, two or all of HC CDR1, HC CDR2, and HC CDR3 of any heavy chain binding domain amino acid sequences listed in Table 28 on pages 501-508 of International Application WO 2016/164731. 
     Activity of CD19 and CD22 scFvs against their targets is described, e.g., on lines 6-9 on page 506 of International Application WO 2016/164731. 
     Additional CARs and Binding Domains 
     In other embodiments, the CAR-expressing cells can specifically bind to CD123, e.g., can include a CAR molecule (e.g., any of the CAR1-CAR8), or an antigen binding domain according to Tables 1-2 of WO 2014/130635, incorporated herein by reference. In an embodiment, the CAR molecule comprises a CD123 CAR described herein, e.g., a 
     CD123 CAR described in US2014/0322212A1 or US2016/0068601A1, both incorporated herein by reference. In embodiments, the CD123 CAR comprises an amino acid, or has a nucleotide sequence shown in US2014/0322212A1 or US2016/0068601A1, both incorporated herein by reference. 
     In other embodiments, the CAR-expressing cells can specifically bind to EGFRvIII, e.g., can include a CAR molecule, or an antigen binding domain according to Table 2 or SEQ ID NO:11 of WO 2014/130657, incorporated herein by reference. 
     In an embodiment, the CAR molecule comprises an EGFRvIII CAR molecule described herein, e.g., an EGFRvIII CAR described US2014/0322275A1, incorporated herein by reference. In embodiments, the EGFRvIII CAR comprises an amino acid, or has a nucleotide sequence shown in US2014/0322275A1, incorporated herein by reference. 
     In other embodiments, the CAR-expressing cells can specifically bind to mesothelin, e.g., can include a CAR molecule, or an antigen binding domain according to Tables 2-3 of WO 2015/090230, incorporated herein by reference. 
     In an embodiment, the CAR molecule comprises a mesothelin CAR described herein, e.g., a mesothelin CAR described in WO 2015/090230, incorporated herein by reference. In embodiments, the mesothelin CAR comprises an amino acid, or has a nucleotide sequence shown in WO 2015/090230, incorporated herein by reference. 
     In one embodiment, CAR molecule comprises a BCMA CAR molecule described herein, e.g., a BCMA CAR described in US-2016-0046724-A1. In embodiments, the BCMA CAR comprises an amino acid, or has a nucleotide sequence shown in US-2016-0046724-A1, incorporated herein by reference. 
     In an embodiment, the CAR molecule comprises a CLL1 CAR described herein, e.g., a CLL1 CAR described in US2016/0051651A1, incorporated herein by reference. In embodiments, the CLL1 CAR comprises an amino acid, or has a nucleotide sequence shown in US2016/0051651A1, incorporated herein by reference. 
     In an embodiment, the CAR molecule comprises a CD33 CAR described herein, e.ga CD33 CAR described in US2016/0096892A1, incorporated herein by reference. In embodiments, the CD33 CAR comprises an amino acid, or has a nucleotide sequence shown in US2016/0096892A1, incorporated herein by reference. 
     In accordance with any method or composition described herein, in embodiments, a CAR molecule comprises a CD123 CAR described herein, e.g., a CD123 CAR described in US2014/0322212A1 or US2016/0068601A1, both incorporated herein by reference. In embodiments, the CD123 CAR comprises an amino acid, or has a nucleotide sequence shown in US2014/0322212A1 or US2016/0068601A1, both incorporated herein by reference. In other embodiments, a CAR molecule comprises a CD19 CAR molecule described herein, e.g., a CD19 CAR molecule described in US-2015-0283178-A1, e.g., CTL019. In embodiments, the CD19 CAR comprises an amino acid, or has a nucleotide sequence shown in US-2015-0283178-A1, incorporated herein by reference. In one embodiment, CAR molecule comprises a BCMA CAR molecule described herein, e.g., a BCMA CAR described in US-2016-0046724-A1. In embodiments, the BCMA CAR comprises an amino acid, or has a nucleotide sequence shown in US-2016-0046724-A1, incorporated herein by reference. In an embodiment, the CAR molecule comprises a CLL1 CAR described herein, e.g., a CLL1 CAR described in US2016/0051651A1, incorporated herein by reference. In embodiments, the CLL1 CAR comprises an amino acid, or has a nucleotide sequence shown in US2016/0051651A1, incorporated herein by reference. In an embodiment, the CAR molecule comprises a CD33 CAR described herein, e.g., a CD33 CAR described in US2016/0096892A1, incorporated herein by reference. In embodiments, the CD33 CAR comprises an amino acid, or has a nucleotide sequence shown in US2016/0096892A1, incorporated herein by reference. In an embodiment, the CAR molecule comprises an EGFRvIII CAR molecule described herein, e.g., an EGFRvIII CAR described US2014/0322275A1, incorporated herein by reference. In embodiments, the EGFRvIII CAR comprises an amino acid, or has a nucleotide sequence shown in US2014/0322275A1, incorporated herein by reference. In an embodiment, the CAR molecule comprises a mesothelin CAR described herein, e.g., a mesothelin CAR described in WO 2015/090230, incorporated herein by reference. In embodiments, the mesothelin CAR comprises an amino acid, or has a nucleotide sequence shown in WO 2015/090230, incorporated herein by reference. 
     Exemplary CD19 CARs include CD19 CARs described herein, e.g., in one or more tables described herein, or an anti-CD19 CAR described in Xu et al. Blood 123.24(2014):3750-9; Kochenderfer et al. Blood 122.25(2013):4129-39, Cruz et al. Blood 122.17(2013):2965-73, NCT00586391, NCT01087294, NCT02456350, NCT00840853, NCT02659943, NCT02650999, NCT02640209, NCT01747486, NCT02546739, NCT02656147, NCT02772198, NCT00709033, NCT02081937, NCT00924326, NCT02735083, NCT02794246, NCT02746952, NCT01593696, NCT02134262, NCT01853631, NCT02443831, NCT02277522, NCT02348216, NCT02614066, NCT02030834, NCT02624258, NCT02625480, NCT02030847, NCT02644655, NCT02349698, NCT02813837, NCT02050347, NCT01683279, NCT02529813, NCT02537977, NCT02799550, NCT02672501, NCT02819583, NCT02028455, NCT01840566, NCT01318317, NCT01864889, NCT02706405, NCT01475058, NCT01430390, NCT02146924, NCT02051257, NCT02431988, NCT01815749, NCT02153580, NCT01865617, NCT02208362, NCT02685670, NCT02535364, NCT02631044, NCT02728882, NCT02735291, NCT01860937, NCT02822326, NCT02737085, NCT02465983, NCT02132624, NCT02782351, NCT01493453, NCT02652910, NCT02247609, NCT01029366, NCT01626495, NCT02721407, NCT01044069, NCT00422383, NCT01680991, NCT02794961, or NCT02456207, each of which is incorporated herein by reference in its entirety. 
     In one embodiment, the antigen binding domain comprises one, two three (e.g., all three) heavy chain CDRs, HC CDR1, HC CDR2 and HC CDR3, from an antibody described herein (e.g., an antibody described in WO2015/142675, US-2015-0283178-A1, US-2016-0046724-A1, US2014/0322212A1, US2016/0068601A1, US2016/0051651A1, US2016/0096892A1, US2014/0322275A1, or WO2015/090230, incorporated herein by reference), and/or one, two, three (e.g., all three) light chain CDRs, LC CDR1, LC CDR2 and LC CDR3, from an antibody described herein (e.g., an antibody described in WO2015/142675, US-2015-0283178-A1, US-2016-0046724-A1, US2014/0322212A1, US2016/0068601A1, US2016/0051651A1, US2016/0096892A1, US2014/0322275A1, or WO2015/090230, incorporated herein by reference). In one embodiment, the antigen binding domain comprises a heavy chain variable region and/or a variable light chain region of an antibody listed above. 
     In embodiments, the antigen binding domain is an antigen binding domain described in WO2015/142675, US-2015-0283178-A1, US-2016-0046724-A1, US2014/0322212A1, US2016/0068601A1, US2016/0051651A1, US2016/0096892A1, US2014/0322275A1, or WO2015/090230, incorporated herein by reference. 
     In embodiments, the antigen binding domain targets BCMA and is described in US-2016-0046724-A1. 
     In embodiments, the antigen binding domain targets CD19 and is described in US-2015-0283178-A1. 
     In embodiments, the antigen binding domain targets CD123 and is described in US2014/0322212A1, US2016/0068601A1. 
     In embodiments, the antigen binding domain targets CLL and is described in US2016/0051651A1. 
     In embodiments, the antigen binding domain targets CD33 and is described in US2016/0096892A1. 
     Exemplary target antigens that can be targeted using the CAR-expressing cells, include, but are not limited to, CD19, CD123, EGFRvIII, CD33, mesothelin, BCMA, and GFR ALPHA-4, among others, as described in, for example, WO2014/153270, WO 2014/130635, WO2016/028896, WO 2014/130657, WO2016/014576, WO 2015/090230, WO2016/014565, WO2016/014535, and WO2016/025880, each of which is herein incorporated by reference in its entirety. 
     In other embodiments, the CAR-expressing cells can specifically bind to humanized CD19, e.g., can include a CAR molecule, or an antigen binding domain (e.g., a humanized antigen binding domain) according to Table 3 of WO2014/153270, incorporated herein by reference. The amino acid and nucleotide sequences encoding the CD19 CAR molecules and antigen binding domains (e.g., including one, two, three VH CDRs; and one, two, three VL CDRs according to Kabat or Chothia), are specified in WO2014/153270. 
     In other embodiments, the CAR-expressing cells can specifically bind to CD123, e.g., can include a CAR molecule (e.g., any of the CAR1 to CAR8), or an antigen binding domain according to Tables 1-2 of WO 2014/130635, incorporated herein by reference. The amino acid and nucleotide sequences encoding the CD123 CAR molecules and antigen binding domains (e.g., including one, two, three VH CDRs; and one, two, three VL CDRs according to Kabat or Chothia), are specified in WO 2014/130635. 
     In other embodiments, the CAR-expressing cells can specifically bind to CD123, e.g., can include a CAR molecule (e.g., any of the CAR123-1 ro CAR123-4 and hzCAR123-1 to hzCAR123-32), or an antigen binding domain according to Tables 2, 6, and 9 of WO2016/028896, incorporated herein by reference. The amino acid and nucleotide sequences encoding the CD123 CAR molecules and antigen binding domains (e.g., including one, two, three VH CDRs; and one, two, three VL CDRs according to Kabat or Chothia), are specified in WO2016/028896. 
     In other embodiments, the CAR-expressing cells can specifically bind to EGFRvIII, e.g., can include a CAR molecule, or an antigen binding domain according to Table 2 or SEQ ID NO:11 of WO 2014/130657, incorporated herein by reference. The amino acid and nucleotide sequences encoding the EGFRvIII CAR molecules and antigen binding domains (e.g., including one, two, three VH CDRs; and one, two, three VL CDRs according to Kabat or Chothia), are specified in WO 2014/130657. 
     In other embodiments, the CAR-expressing cells can specifically bind to CD33, e.g., can include a CAR molecule (e.g., any of CAR33-1 to CAR-33-9), or an antigen binding domain according to Table 2 or 9 of WO2016/014576, incorporated herein by reference. The amino acid and nucleotide sequences encoding the CD33 CAR molecules and antigen binding domains (e.g., including one, two, three VH CDRs; and one, two, three VL CDRs according to Kabat or Chothia), are specified in WO2016/014576. 
     In other embodiments, the CAR-expressing cells can specifically bind to mesothelin, e.g., can include a CAR molecule, or an antigen binding domain according to Tables 2-3 of WO 2015/090230, incorporated herein by reference. The amino acid and nucleotide sequences encoding the mesothelin CAR molecules and antigen binding domains (e.g., including one, two, three VH CDRs; and one, two, three VL CDRs according to Kabat or Chothia), are specified in WO 2015/090230. 
     In other embodiments, the CAR-expressing cells can specifically bind to BCMA, e.g., can include a CAR molecule, or an antigen binding domain according to Table 1 or 16, SEQ ID NO: 271 or SEQ ID NO: 273 of WO2016/014565, incorporated herein by reference. The amino acid and nucleotide sequences encoding the BCMA CAR molecules and antigen binding domains (e.g., including one, two, three VH CDRs; and one, two, three VL CDRs according to Kabat or Chothia), are specified in WO2016/014565. 
     In other embodiments, the CAR-expressing cells can specifically bind to CLL-1, e.g., can include a CAR molecule, or an antigen binding domain according to Table 2 of WO2016/014535, incorporated herein by reference. The amino acid and nucleotide sequences encoding the CLL-1 CAR molecules and antigen binding domains (e.g., including one, two, three VH CDRs; and one, two, three VL CDRs according to Kabat or Chothia), are specified in WO2016/014535. 
     In other embodiments, the CAR-expressing cells can specifically bind to GFR ALPHA-4, e.g., can include a CAR molecule, or an antigen binding domain according to Table 2 of WO2016/025880, incorporated herein by reference. The amino acid and nucleotide sequences encoding the GFR ALPHA-4 CAR molecules and antigen binding domains (e.g., including one, two, three VH CDRs; and one, two, three VL CDRs according to Kabat or Chothia), are specified in WO2016/025880. 
     In one embodiment, the antigen binding domain of any of the CAR molecules described herein (e.g., any of CD19, CD123, EGFRvIII, CD33, mesothelin, BCMA, and GFR ALPHA-4) comprises one, two three (e.g., all three) heavy chain CDRs, HC CDR1, HC CDR2 and HC CDR3, from an antibody listed above, and/or one, two, three (e.g., all three) light chain CDRs, LC CDR1, LC CDR2 and LC CDR3, from an antigen binding domain listed above. In one embodiment, the antigen binding domain comprises a heavy chain variable region and/or a variable light chain region of an antibody listed or described above. 
     CRS Therapies 
     Therapies for CRS include IL-6 inhibitor or IL-6 receptor (IL-6R) inhibitors (e.g., tocilizumab or siltuximab), bazedoxifene, sgp130 blockers, vasoactive medications, corticosteroids, immunosuppressive agents, and mechanical ventilation. Exemplary therapies for CRS are described in International Application WO2014011984, which is hereby incorporated by reference. 
     Tocilizumab is a humanized, immunoglobulin G1kappa anti-human IL-6R monoclonal antibody. See, e.g., id. Tocilizumab blocks binding of IL-6 to soluble and membrane bound IL-6 receptors (IL-6Rs) and thus inhibitos classical and trans-IL-6 signaling. In embodiments, tocilizumab is administered at a dose of about 4-12 mg/kg, e.g., about 4-8 mg/kg for adults and about 8-12 mg/kg for pediatric subjects, e.g., administered over the course of 1 hour. 
     In some embodiments, the CRS therapeutic is an inhibitor of IL-6 signalling, e.g., an inhibitor of IL-6 or IL-6 receptor. In one embodiment, the inhibitor is an anti-IL-6 antibody, e.g., an anti-IL-6 chimeric monoclonal antibody such as siltuximab. In other embodiments, the inhibitor comprises a soluble gp130 (sgp130) or a fragment thereof that is capable of blocking IL-6 signalling. In some embodiments, the sgp130 or fragment thereof is fused to a heterologous domain, e.g., an Fc domain, e.g., is a gp130-Fc fusion protein such as FE301. In embodiments, the inhibitor of IL-6 signalling comprises an antibody, e.g., an antibody to the IL-6 receptor, such as sarilumab, olokizumab (CDP6038), elsilimomab, sirukumab (CNTO 136), ALD518/BMS-945429, ARGX-109, or FM101. In some embodiments, the inhibitor of IL-6 signalling comprises a small molecule such as CPSI-2364. 
     Exemplary vasoactive medications include but are not limited to angiotensin-11, endothelin-1, alpha adrenergic agonists, rostanoids, phosphodiesterase inhibitors, endothelin antagonists, inotropes (e.g., adrenaline, dobutamine, isoprenaline, ephedrine), vasopressors (e.g., noradrenaline, vasopressin, metaraminol, vasopressin, methylene blue), inodilators (e.g., milrinone, levosimendan), and dopamine. 
     Exemplary vasopressors include but are not limited to norepinephrine, dopamine, phenylephrine, epinephrine, and vasopressin. In some embodiments, a high-dose vasopressor includes one or more of the following: norpepinephrine monotherapy at &gt;20 ug/min, dopamine monotherapy at &gt;10 ug/kg/min, phenylephrine monotherapy at &gt;200 ug/min, and/or epinephrine monotherapy at &gt;10 ug/min. In some embodiments, if the subject is on vasopressin, a high-dose vasopressor includes vasopressin+norepinephrine equivalent of &gt;10 ug/min, where the norepinephrine equivalent dose=[norepinephrine (ug/min)]+[dopamine (ug/kg/min)/2]+[epinephrine (ug/min)]+[phenylephrine (ug/min)/10]. In some embodiments, if the subject is on combination vasopressors (not vasopressin), a high-dose vasopressor includes norepinephrine equivalent of ≥20 ug/min, where the norepinephrine equivalent dose=[norepinephrine (ug/min)]+[dopamine (ug/kg/min)/2]+[epinephrine (ug/min)]+[phenylephrine (ug/min)/10]. See e.g., Id. 
     In some embodiments, a low-dose vasopressor is a vasopressor administered at a dose less than one or more of the doses listed above for high-dose vasopressors. 
     Exemplary corticosteroids include but are not limited to dexamethasone, hydrocortisone, and methylprednisolone. In embodiments, a dose of dexamethasone of 0.5 mg/kg is used. In embodiments, a maximum dose of dexamethasone of 10 mg/dose is used. In embodiments, a dose of methylprednisolone of 2 mg/kg/day is used. 
     Exemplary immunosuppressive agents include but are not limited to an inhibitor of TNFα or an inhibitor of IL-1. In embodiments, an inhibitor of TNFα comprises an anti-TNFα antibody, e.g., monoclonal antibody, e.g., infliximab. In embodiments, an inhibitor of TNFα comprises a soluble TNFα receptor (e.g., etanercept). In embodiments, an IL-1 or IL-1R inhibitor comprises anakinra. 
     In some embodiments, the subject at risk of developing severe CRS is administered an anti-IFN-gamma or anti-sIL2Ra therapy, e.g., an antibody molecule directed against IFN-gamma or sIL2Ra. 
     In embodiments, a subject who has CRS or is at risk of developing CRS is treated with a fever reducing medication such as acetaminophen. 
     In embodiments, a subject herein is administered or provided one or more therapies for CRS described herein, e.g., one or more of IL-6 inhibitors or IL-6 receptor (IL-6R) inhibitors (e.g., tocilizumab), vasoactive medications, corticosteroids, immunosuppressive agents, or mechanical ventilation, in any combination, e.g., in combination with a CAR-expressing cell described herein. 
     In embodiments, a subject is administered one or more therapies for CRS described herein, e.g., one or more of IL-6 inhibitor or IL-6 receptor (IL-6R) inhibitors (e.g., tocilizumab), vasoactive medications, corticosteroids, immunosuppressive agents, or mechanical ventilation, in any combination, e.g., in combination with a CAR-expressing cell described herein. 
     In embodiments, a subject herein is transferred to an intensive care unit. In some embodiments, a subject herein is monitored for one ore more symptoms or conditions associated with CRS, such as fever, elevated heart rate, coagulopathy, MODS (multiple organ dysfunction syndrome), cardiovascular dysfunction, distributive shock, cardiomyopathy, hepatic dysfunction, renal dysfunction, encephalopathy, clinical seizures, respiratory failure, or tachycardia. In some embodiments, the methods herein comprise administering a therapy for one of the symptoms or conditions associated with CRS. For instance, in embodiments, e.g., if the subject develops coagulopathy, the method comprises administering cryoprecipitate. In some embodiments, e.g., if the subject develops cardiovascular dysfunction, the method comprises administering vasoactive infusion support. In some embodiments, e.g., if the subject develops distributive shock, the method comprises administering alpha-agonist therapy. In some embodiments, e.g., if the subject develops cardiomyopathy, the method comprises administering milrinone therapy. In some embodiments, e.g., if the subject develops respiratory failure, the method comprises performing mechanical ventilation (e.g., invasive mechanical ventilation or noninvasive mechanical ventilation). In some embodiments, e.g., if the subject develops shock, the method comprises administering crystalloid and/or colloid fluids. 
     In embodiments, the CAR-expressing cell is administered prior to, concurrently with, or subsequent to administration of one or more therapies for CRS described herein, e.g., one or more of IL-6 inhibitor or IL-6 receptor (IL-6R) inhibitors (e.g., tocilizumab), vasoactive medications, corticosteroids, immunosuppressive agents, or mechanical ventilation. In embodiments, the CAR-expressing cell is administered within 2 weeks (e.g., within 2 or 1 week, or within 14 days, e.g., within 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 day or less) of administration of one or more therapies for CRS described herein, e.g., one or more of IL-6 inhibitors or IL-6 receptor (IL-6R) inhibitors (e.g., tocilizumab), vasoactive medications, corticosteroids, immunosuppressive agents, or mechanical ventilation. In embodiments, the CAR-expressing cell is administered at least 1 day (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1, week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 3 months, or more) before or after administration of one or more therapies for CRS described herein, e.g., one or more of IL-6 inhibitors or IL-6 receptor (IL-6R) inhibitors (e.g., tocilizumab), vasoactive medications, corticosteroids, immunosuppressive agents, or mechanical ventilation. 
     In embodiments, a subject herein is administered a single dose of an IL-6 inhibitor or IL-6 receptor (IL-6R) inhibitor (e.g., tocilizumab). In embodiments, the subject is administered a plurality of doses (e.g., 2, 3, 4, 5, 6, or more doses) of an IL-6 inhibitor or IL-6 receptor (IL-6R) inhibitor (e.g., tocilizumab). 
     In embodiments, CRS is graded according to Table 28B: 
     
       
         
           
               
             
               
                 TABLE 28B 
               
               
                   
               
               
                 CRS grading 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Gr1 
                 Supportive care only 
               
               
                   
                 Gr2 
                 IV therapies +/− hospitalization. 
               
               
                   
                 Gr3 
                 Hypotension requiring IV fluids or low-dose 
               
               
                   
                   
                 vasoactives or hypoxemia requiring oxygen, 
               
               
                   
                   
                 CPAP, or BIPAP. 
               
               
                   
                 Gr4 
                 Hypotension requiring high-dose vasoactives 
               
               
                   
                   
                 or hypoxemia requiring mechanical ventilation. 
               
               
                   
                 Gr 5 
                 Death 
               
               
                   
                   
               
            
           
         
       
     
     EXAMPLES 
     The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein. 
     Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following working examples specifically point out various aspects of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure. 
     Example 1: Dosage Regimen for Chimeric Antigen Receptor (CAR) T Cell Therapy for Adult Patients with Relapsed or Refractory (r/r) Acute Lymphoblastic Leukemia (ALL) 
     Genetically modified T cells expressing an anti-CD19 CAR result in response rates of 90% in adults with r/r CD19+ ALL. Cytokine release syndrome (CRS) is the most significant treatment-related toxicity and usually responds to anti-cytokine therapy. This example reports outcomes from 30 adults with r/r ALL. 
     Inclusion criteria for the study included that the patients had CD19+ relapsed or refractory ALL (e.g., Primary Refractory, wherein patients failed≥2 lines of upfront treatment, or Relapsed ALL, wherein patients had a 1st or greater relapse); and &gt;5% BM Blasts. Patient characteristics are described below in Table 34: 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Patient Characteristics 
                 N = 30 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Median Age (range) 
                 44 
                 (21, 72) 
               
               
                   
                 Post Allogenic Transplant 
                 10 
                 (33%) 
               
               
                   
                 Post Blinatumomab 
                 10 
                 (33%) 
               
               
                   
                 Ph+ 
                 3 
                 (10%) 
               
               
                   
                 Baseline ALL burden 
               
            
           
           
               
               
               
            
               
                   
                 &gt;5% Blasts 
                 90% 
               
            
           
           
               
               
               
               
            
               
                   
                 0.01-5% Blasts 
                 3 
                 (10%) 
               
            
           
           
               
               
               
            
               
                   
                 &lt;0.01% Blasts 
                 0 
               
               
                   
                   
               
            
           
         
       
     
     Autologous T cells were transduced with a lentiviral vector encoding a murine anti-CD19 scFv/4-1BB/CD3ζ (CTL019) CAR. Adults with r/r CD19+ ALL received CTL019 on one of 2 trials (NCT02030847; NCT01029366). All patients received lymphodepletion followed by CTL019 as a 1-time infusion or fractionated infusions over 3 days (10%:D1, 30%:D2 and 60%:D3). Total planned CTL019 dose varied (5×10 7 -5×10 8 ) with protocol modifications for CRS toxicity. Bone marrow baseline assessment was performed on Day −1 before CTL019 treatment, with a response assessment at day 28, with follow-up assessments at 3, 6, 9, and 12 months. 
     30 patients (median age 44 (range 21-72)); received CTL019 via 4 dosing cohorts (Table 35). 10 patients had prior blinatumomab and 10 had prior allogeneic SCT. 9 patients were treated with 5×10 7  CTL019 cells with either a 1-time dose (n=3) or fractionated dosing (n=6). 6/9 patients had Grade 3-4 CRS managed with tocilizumab and 3 patients achieved a CR (33%). 6 patients were treated with a 1-time CTL019 dose of 5×10 8 . 3/6 patients died with CRS refractory to tocilizumab and corticosteroids. These 3 patients also had concurrent culture positive sepsis. The other 3 patients achieved CR. 15 patients were treated with a planned CTL019 dose of 5×10 8  administered via fractionated dosing. If early CRS was noted, subsequent infusions of CTL019 were held allowing for intra-patient dose modification. Anti-cytokine treatment was initiated at Grade 3 CRS. A subset of the patients had manageable Grade 3-4 CRS with an ORR rate of 83%, including at least 9 complete responses. 
     
       
         
           
               
               
               
               
               
               
               
             
               
                 TABLE 35 
               
               
                   
               
               
                   
                 CTL019 
                   
                   
                 CRS ≥ 
                 CRS 
                 Response 
               
               
                 Cohort 
                 Dose 
                 Schedule 
                 N 
                 Gr3 
                 Gr5 
                 (Evaluable) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
            
               
                 Outcome (by Cohort) 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 High Dose 
                 5 × 10 8   
                 Split 
                 15 
                 66% 
                 0 
                 86% 
                 (0 TRM) 
               
               
                 Split 
               
               
                 High Dose 
                 5 × 10 8   
                 Single 
                 6 
                 100%  
                 3 
                 100% 
                 (3 TRM) 
               
               
                 Single 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Low Dose 
                 5 × 10 7   
                 Single(3) 
                 9 
                 66% 
                 0 
                 33% 
               
               
                   
                   
                 Split(6) 
                   
                   
                   
               
            
           
           
               
            
               
                 Outcome (Total) 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Total (1-4) 
                 5 × 10 7 - 
                 Single(9) 
                 30 
                 75% 
                 3 
                 72% 
                 (3TRM) 
               
               
                   
                 5 × 10 8   
                 Split(21) 
               
               
                   
               
            
           
         
       
     
     Neurologic toxicity was also examined, and no clear dose to neuro-toxicity relationship was observed. All events (encephaly/delirium and seizure) were self-limited with return to baseline by Day 28. 
     Higher doses of CTL019 may be more effective and split dosing may improve safety allowing for intra-patient dose modification without compromising efficacy in adult patients with r/r ALL. There is a high risk of fatal outcome with concurrent sepsis and CRS, and measures to prevent infection and intervene early for CRS are warranted. This study also supports the use of inverse dosing based on disease burden. Furthermore, the study supports the use of cytokine therapy, e.g., as prophylactic or pre-emptive therapy. 
     According to the non-limiting theory herein, higher disease burden can increase the risk of severe CRS. Higher doses of CART cells can improve efficacy, but can also increase the risk of severe CRS. Administering CART cells in a fractionated manner as described herein can reduce the risk of severe CRS, while maintaining efficacy. 
     Example 2: Efficacy and Safety of CTL019 in the First US Phase II Multicenter Trial in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia: Results of an Interim Analysis 
     Background: CTL019 is an investigational therapy derived from autologous T-cells expressing a CD19-specific chimeric antigen receptor (CAR). A single center, phase I/IIa trial of CTL019 showed complete and durable remissions in pediatric/young adult patients (pts) with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) (Maude et al NEJM 2014); these results have yet to be reproduced in a multicenter setting. This study reports results from a 6-month interim analysis of the first multicenter phase II trial of an engineered cell therapy in leukemia.
 
Methods: 9 US sites participated in this single-arm phase II study in pediatric/young adult pts with R/R B-ALL. Leukapheresis products were shipped for centralized manufacturing. T cells were transduced with a lentiviral vector encoding a CAR composed of anti-CD19 scFv, CD3(and 4-1BB domains. Following lymphodepletion with fludarabine and cyclophosphamide, a single dose of CTL019 cells was administered (target dose 2.0-5.0×10 6  cells/kg for ≤50 kg and 1.0-2.5×10 8  cells for &gt;50 kg). The primary endpoint was overall remission rate (ORR=CR+CRi [CRi, complete remission with incomplete blood count recovery] maintained at 2 evaluations ≥28 days apart) as determined by an Independent Review Committee. Secondary objectives included minimal residual disease (MRD), relapse-free survival (RFS), overall survival (OS) and safety. All analyses were performed on infused patient set.
 
Results: 29/35 pts enrolled (82.9%) were infused with CTL019; 6 withdrew prior to infusion (2 manufacturing failures [1 lack of growth, 1 contamination]; 4 deaths [median, 48 days from enrollment; 2 progressive disease, 1 multi-organ failure, 1 pneumonia]). Mean bone marrow involvement at enrollment was 68.2% (SD, 27.3%; Table 36). 2 pts did not receive lymphodepleting chemotherapy due to leukopenia. Collection, manufacturing and infusion were feasible in a multicenter setting with a median time from enrollment to infusion of 37 days. Target cell dose was met in 24/33 (72.7%) manufactured products. ORR in all infused pts was 69.0% (20/29 pts; 98.95% CI 43.6, 88.1). Of the 5 pts who received CTL019 below the target dose, 2 achieved CR/CRi. Of note, deep remission with no evidence of MRD (&lt;0.01%) was achieved in 18/29 pts (62.1%; 95% CI 42.3, 79.3) within 6 months. Median RFS and median survival have not yet been reached. Median duration of follow-up was 6.4 months (range 0.4-14.0). CR/CRi was not achieved in 9 pts: 2 pts died before Day 28 (1 ALL; 1 embolic stroke not attributed to CTL019 at Day 25 after infusion), 6 did not respond and 1 pt achieved CRi at Day 28 but relapsed 17 days later. Of the 20 pts who achieved a CR/CRi, 8 pts relapsed 1.7-7.6 months after onset of remission; 2 were CD19 negative. RFS and OS at 6 months ( FIGS. 1A and 1B ) were 66.4% and 75.7%, respectively. Serious adverse events occurred in 79.3% of pts within 8 weeks of infusion. Overall 10 deaths occurred at 0.4-8.8 months (9 ALL; 1 embolic stroke); no deaths attributable to CTL019. The most common adverse event was cytokine release syndrome (CRS), which was graded on the Penn scale and managed according to a standardized algorithm. All 26 (89.7%) cases of CRS were reversible; 11 pts (37.9%) had grade 3 or 4 CRS, of which 7 (26.9%) required systemic anti-cytokine therapy, 9 (34.6%) required high dose vasopressors for hypotension, 6 (23.1%) required mechanical ventilation, 4 (15.4%) underwent dialysis. Reversible neuropsychiatric events occurred in 9 (31%) pts (1 grade 3; no grade 4), including seizures in 2 pts but no cases of cerebral edema.
 
Conclusions: In this first multicenter trial of CAR-modified T cell therapy, CTL019 therapy was feasible and efficacious, showing a high ORR with durable remissions in pediatric/young adult pts with R/R B-ALL. Despite the high rate of toxicity with CTL019 in the R/R setting, the rate of grade 3 or 4 CRS was comparable to the single center study, and standardized management of CRS was successful in a multicenter trial with no deaths attributable to CRS. In this highly refractory population, a vast majority of eligible pts can be successfully infused in a timely fashion and outcomes appear reproducible in a multicenter setting despite a more heterogeneous population than the single center study.
 
     
       
         
           
               
             
               
                 TABLE 36 
               
             
            
               
                   
               
               
                 Demographics and baseline characterstics. 
               
            
           
           
               
               
            
               
                 Patient Characteristics 
                 All patients (N = 29) 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Age (years); median (range) 
                 12 
                 (3-25) 
               
               
                 Age at initial diagnosis (years); median (range) 
                 7 
                 (1-19) 
               
               
                 Age &lt;10 years at initial diagnosis; n (%) 
                 17 
                 (58.6) 
               
               
                 Prior Hematopoietic Stem Cell Transplant; n (%) 
               
               
                 0 
                 12 
                 (41.4) 
               
               
                 1 
                 15 
                 (51.7) 
               
               
                 2 
                 2 
                 (6.9) 
               
               
                 Disease status; n (%) 
               
               
                 Primary refractory 
                 2 
                 (6.9) 
               
               
                 Chemo-refractory 
                 2 
                 (6.9) 
               
               
                 Relapsed disease 
                 25 
                 (86.2) 
               
               
                 Number of previous therapies; median (range) 
                 3 
                 (1-9) 
               
               
                 Time since initial diagnosis to first relapse (months); median 
                 26 
                 (9-108) 
               
               
                 (range) 
               
               
                 Bone marrow blast count at enrollment (%); mean (SD) 
                 68.2 
                 (27.3) 
               
               
                 CNS status classification at enrollment; n (%) 
               
               
                 CNS 1 
                 26 
                 (89.7) 
               
               
                 CNS 2 
                 3 
                 (10.3) 
               
               
                   
               
               
                 Abbreviations: 
               
               
                 CNS, central nervous system, 
               
               
                 n, number of patients; 
               
               
                 SD, standard deviation 
               
            
           
         
       
     
     Example 3: Posterior Reversible Encephalopathy Syndrome (PRES) after Infusion of Anti-BCMA CAR T Cells (CART-BCMA) for Multiple Myeloma: Successful Treatment with Cyclophosphamide 
     Neurologic toxicity has been observed in patients treated with anti-CD19 chimeric antigen receptor (CAR) T cells and the anti-CD19/anti-CD3 bispecific T-cell engager blinatumomab. Reported neurotoxicities include both focal deficits (e.g., cranial nerve palsy or hemiparesis) and global abnormalities (e.g., generalized seizures, confusion), often associated with systemic cytokine release syndrome (CRS) but also observed after recovery from or in absence of CRS. CART-BCMA involves ex-vivo-expanded autologous T cells transduced via lentiviral vector to express a 4-1BB/CD3-zeta-based CAR specific for B Cell Maturation Antigen. This Example reports clinical characteristics and management of a severe neurotoxicity observed during a phase 1 study of CART-BCMA in multiple myeloma (MM) (NCT02546167). 
     The subject is a 55-year-old female with high-risk IgA lambda MM progressing after 4 prior lines of therapy. Pre-treatment disease manifestations included cytopenias and extramedullary plasmacytomas of the pleura and paravertebral musculature. Bone marrow (BM) was &gt;95% occupied by BCMA+ plasma cells. Pre-treatment brain MRI showed pachymeningeal thickening and enhancement over the left cerebral convexity, possibly due to direct extension of calvarial MM lesions. Pre-treatment examination by a neurologist and CSF cytology showed no evidence of CNS MM. 
     The subject received 2×10 8  CART-BCMA cells, 40% of the planned dose, over two consecutive days, without preceding lymphodepleting chemotherapy; a third planned infusion was held due to fevers. Over the next 4 days, fevers persisted, and hypoxia, pancytopenia and delirium developed. Brain MRI and lumbar puncture on day 4 showed no new abnormalities. Evaluation for infection was negative. These symptoms corresponded with rise in serum IL-6 and other CRS-associated biomarkers. On day 6 after CART-BCMA infusion, two tocilizumab doses were administered for CRS, which led to decline in serum IL-6 and resolution of fevers and hypoxia ( FIG. 2 , circles and triangles). 
     On day 8, the subject became obtunded, prompting intubation and initiation of corticosteroids (methylprednisolone 1000 mg xl, then hydrocortisone 100 mg every 8 hours). Her mental status improved over the subsequent two days, and by day 11 she was extubated, alert, and off steroids. On day 12 she developed a generalized seizure and was again intubated for airway protection and treated with antiepileptic drugs (AED). She again improved and was extubated but, on day 15, developed status epilepticus that required five AEDs to control. Repeat brain MRI showed new diffuse sulcal, cortical, and subcortical T2/FLAIR signal abnormality involving the bilateral frontal, parietal, occipital, posterior temporal, and cerebellar hemispheres, with sulcal effacement concerning for cerebral edema. This deterioration was not associated with recurrence of fevers, other systemic CRS signs/symptoms, or hypertension, but it coincided with striking rise in frequency of circulating, activated (HLA-DR+) CART-BCMA cells ( FIG. 2 , inverted triangles). Serum levels of CRS-related cytokines continued to decrease, but CSF obtained on day 16 showed marked elevation in IL-6, IL-8, and other CRS-associated cytokines compared to both day-16 serum and day-4 CSF ( FIG. 2 , squares). CART-BCMA cells were detected in CSF. High-dose methylprednisolone was restarted on day 15 without clinical improvement. On day 17, cyclophosphamide 1.5 g/m 2  was administered to reduce CART-BCMA cells. Beginning on day 18, alertness and responsiveness improved substantially, and she was extubated on day 20. Corticosteroids were gradually tapered. MRI on day 23 showed near-resolution of cerebral and cerebellar signal abnormalities, which were completely gone on repeat MRI 4 weeks later. Cognitive functioning recovered without long-term neurologic sequelae other than fatigue and mild concentration difficulty attributed to effects of AEDs. The last neurologic symptom to recover was mild difficulty processing visual information. Despite administration of cyclphosphamide and a prolonged corticosteroid course, CART-BCMA cells remained detectable in both blood and marrow at last evaluation, 164 days after infusion, and patient achieved a VGPR lasting 5 months. 
     Given the rapid reversibility and MRI appearance, this neurologic syndrome was felt to be most consistent with posterior reversible leukoencephalopathy syndrome (PRES), possibly due to high levels of CRS-related cytokines in CSF, as opposed to encephalitis from direct CART-BCMA cytotoxicity against neuronal tissue. PRES developed amidst improvement in systemic CRS, suggesting a CNS-localized CRS, which may have been due to occult CNS MM encountered by rising CART-BCMA frequency and/or failure of tocilizumab to block IL-6 receptor in the CNS. While steroids achieved only transient clinical improvement, the syndrome resolved rapidly after cytoreduction with cyclophosphamide, without completely eradicating infused CART-BCMA cells, suggesting that this strategy could be considered for cases of life-threatening CAR T cell neurotoxicity. 
     Example 4: Treatment with Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) Results in Durable Remissions in Patients with Relapsed or Refractory Diffuse Large B Cell Lymphomas of Germinal Center and Non-Germinal Center Origin, “Double Hit” Diffuse Large B Cell Lymphomas, and Transformed Follicular to Diffuse Large B Cell Lymphomas 
     BACKGROUND: The cell of origin (COO) of diffuse large B cell lymphoma (DLBCL), germinal center (GC) or non-germinal center (NGC), may have prognostic significance for treatment outcome in first-line and relapsed settings (Lenz et al NEJM 2008; Thieblemont et al JCO 2011). “Double hit” DLBCL (DHL), defined by chromosomal breakpoints affecting the MYC/8q24 locus and a second oncogene locus and arising either from transformation of follicular lymphoma (FL) or de novo, has no effective therapy in the relapsed setting. Since new therapies are needed for poor prognostic groups of relapsed DLBCL patients (pts), we examined the efficacy of treatment with autologous T cells genetically modified to express a chimeric antigen receptor consisting of an external anti-CD19 single chain murine antibody domain with CD3(and 4-1BB signaling domains (CTL019 cells) in pts with relapsed or refractory GC- and NGC-DLBCL, DHL, and transformed FL as part of an ongoing phase IIa clinical trial (NCT02030834).
 
METHODS: Eligible pts had CD19+ DLBCL with measurable residual disease after primary and salvage therapies, were not eligible for autologous stem cell transplant (ASCT) or had relapsed/residual disease after ASCT, had a limited prognosis (&lt;2 years anticipated survival), and had responsive or stable disease with most recent therapy. COO of DLBCL was determined by immunohistochemistry using Hans&#39; algorithm (Hans et al Blood 2004). Fluorescence in-situ hybridization was performed on diagnostic tissue using Vysis MYC (8q24), BCL2 (18q21) and BCL6 (3q27) break apart probes to determine DHL. DHL was defined by a MYC locus chromosomal translocation with a second translocation involving either BCL2 or BCL6. After steady state apheresis to collect peripheral blood leukocytes, pts received lymphodepleting chemotherapy based on clinical features and past therapies. One to 4 days after chemotherapy, pts received a single intravenous dose of CTL019 cells. Following CTL019 cells, pts received no further therapy. Initial tumor response assessment was performed 3 months after T cell infusion using International Working Group response criteria. Enrollment started in February 2014; data are reported through Jul. 24, 2016.
 
RESULTS: 13 pts with DLBCL are enrolled and evaluable for response (7 pts GC, 5 pts NGC, 1 undetermined). The median age is 59 years (range: 25-77), male:female ratio 10:3, median number of prior therapies 5 (range: 2-8), and number of pts with prior transplant 7 (54%). At enrollment, Ann Arbor stages were: Stage IV 8 pts (61%), Stage III 1 pt (8%), and Stage II 3 pts (23%) Stage IE 1 pt (8%); 3 pts (23%) had bone marrow involvement. LDH was increased in 8 pts (62%). ECOG PS was 0 in 4 pts (31%) and 1 in 9 pts (69%). Lymphodepleting chemotherapy regimens were bendamustine (90 mg/m2×2; 1 pt), cyclophosphamide (1 gm/m 2 ; 2 pts), radiation-cyclophosphamide (4,000 cGy-750 mg/m 2 ; 1 pt), modified-EPOCH (3 pts), and hyper-fractionated cyclophosphamide (300 mg/m2 q12 hours×6; 6 pts). 12 pts received 5.00E+08 (5.10-6.75E+06 cells/kg) CTL019 cells; 1 pt received 1.93E+08 (3.10E+06 cells/kg). Median peak CTL019 cell expansion in blood occurred 7 days after infusion (range: 2-28 days); there is no difference in peak expansion between responders and non-responders or pts with GC- or NGC-DLBCL. Cytokine release syndrome occurred in 9 pts (8 grade 2; 1 grade 3) and did not predict response. Transient neurotoxicity included delirium in 2/13 pts (1 grade 2; 1 grade 3) and cognitive disturbance in 1/13 pts (1 grade 1). At 3 months post CTL019 infusion, overall response rate (ORR) is 52% (7/13 pts); ORR for GC 71% (5/7 pts) and NGC 40% (2/5 pts). Complete response rate (CR) at 3 months is 38% (5/13 pts); CR for GC 43% (3/7 pts) and NGC 40% (2/5 pts). Best response for all pts is CR in 6 of 13 pts (46%); CR for GC 57% (4/7 pts) and NGC 40% (2/5 pts). 3 of 7 pts with GC-DLBCL had transformed FL and all 3 achieved CR; 2 of 7 pts with GC-DLBCL had DHL and both achieved CR. To date, no pt achieving CR has relapsed. 2 of 5 pts with NGC-DLBCL had T-cell rich DLBCL; neither patient responded to CTL019. Median progression-free survival (PFS) is 5.8 months (mo) for all pts, 3.0 mo for NGC pts, and not reached for GC pts (PFS 57.1% [95% C: 17.2%-83.7%] at median follow up 21.9 mo).
 
CONCLUSIONS: These results indicate that a single treatment with CTL019 cells is safe and efficacious in relapsed or refractory GC- and NGC-DLBCL, DHL, and transformed FL.
 
     Example 5: Soluble BCMA in Peripheral Blood Serum is a Useful Minimal Residual Disease Biomarker for Monitoring Patients with Multiple Myeloma, Chronic Lymphocytic Leukemia and Other B Cell Malignancies Following Treatment with CAR-BCMA or CAR-19 
     B cell maturation antigen (BCMA) (BCMA) is expressed on the surface of plasma cells, the final differentiation stage of B cells, and usually on multiple myeloma cells. Soluble BCMA (sBCMA) is readily detectable by immunoassay methods in serum or plasma from normal subjects and in patients with certain B cell malignancies. In multiple myeloma (MM), a plasma cell malignancy localized selectively to the bone marrow, serum sBCMA levels can be greatly elevated compared to the normal range in healthy subjects before treatment. Chimeric antigen receptor cell therapy targeting BCMA have been developed for treating MM patients. This Example uses ELISA to examine serum samples from MM patients before and after CAR-BCMA therapy on clinical trial UPCC14415 and shown that serum sBCMA is greatly reduced in patients experiencing CAR-BCMA expansion and persistence after infusion, and returns if the patients subsequently lose CAR-BCMA cells and undergo clinical relapse. Thus sBCMA is an excellent and convenient minimal residual disease (MRD) biomarker for CAR-BCMA efficacy in MM. 
     In addition, these experiments test sera from MM patients who received chimeric antigen receptor cell therapy targeting CD19 (CAR19) therapy on trial UPCC02413. It was found that CAR19 expansion post infusion was also associated with sBCMA reduction, and that loss of CAR19 and clinical relapse was accompanied by a rise in sBCMA levels. This is a logical correlation given that precursors to plasma cells express CD19, even though plasma cells themselves do not express CD19. sBCMA levels were then examined in serum samples from patients with other B cell malignancies including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL) and non-Hodgkins lymphoma (NHL) and who were treated with CAR19 therapy. Preliminary data suggests that sBCMA levels are elevated in some CLL patients and decrease following effective CAR19 therapy, suggesting that sBCMA may be a useful MRD biomarker for evaluating efficacy of CD19 therapy in other B cell malignancies. 
     Introduction 
     B-cell maturation antigen (BCMA), also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17), is a protein that in humans is encoded by the TNFRSF17 gene. This receptor is preferentially expressed in mature B lymphocytes, and may be important for B cell development and autoimmune response. BCMA has been shown to specifically bind to the tumor necrosis factor (ligand) superfamily, member 13b (TNFSF13B/TALL-1/BAFF), and to lead to NF-kappaB and MAPK8/JNK activation. This receptor also binds to various TRAF family members, and thus may transduce signals for cell survival and proliferation. BCMA is expressed on some activated B cells and Ig-secreting cells; it binds both BAFF and APRIL. BCMA is essential for the maintenance of long-lived plasma cells, an effect mediated by its ligands, APRIL or BAFF. These plasma cells produce IgG that protect not only against pathogens but are also critically involved in autoimmune diseases. Further, BCMA engagement on activated B cells induces MHC class II, enhancing their ability to present antigen. Differentiation of B cells from stem cells in the bone marrow proceeds through immature B cells to mature B cells in the periphery to plasma cells in the bone marrow. While CD19 as a B cell marker is present on all of these except for plasma cells, BCMA is mostly present at high levels on plasma cells, but is also present on some memory B cells and plasmablast cells that express CD19. Note that since plasma cells are not present in the periphery monitoring of these cells by flow cytometry requires a bone marrow sample which, unlike peripheral blood serum, can only be obtained infrequently due to patient care restrictions. Gamma-secretase directly cleaves BCMA, releasing soluble BCMA (sBCMA) which acts as a decoy, neutralizing APRIL. In multiple sclerosis, sBCMA levels in spinal fluid are elevated and associated with intracerebral IgG production, and in systemic lupus erythematosus, sBCMA levels in serum are elevated and correlate with disease activity. In this example, soluble BCMA levels in peripheral blood serum were studied as a surrogate for the level of BCMA-expressing plasma cells in bone marrow. Longitudinal sera were collected from multiple myeloma patients enrolled on a trial of CAR-BCMA. The levels of sBCMA, BAFF and APRIL were measured. Given the strong correlations seen between CAR-BCMA and sBCMA, levels of sBCMA were then examined in multiple myeloma patients treated with CAR-19. Since these results in turn showed that sBCMA levels correlate with successful CAR19 therapy, this analysis was then extended to samples from patients with other B-cell malignancies treated with CAR19. These results support the use of sBCMA as a biomarker for minimal residual disease in several B cell malignancies. 
     Materials and Methods 
     Patient Serum was processed and stored at −80° C. until use in ELISA assays. 
     Note that although multiplexed ELISA was used to measure sBCMA, BAFF and APRIL in serum samples, this was largely due to the objective of measuring all three of these analytes. It would have been possible to utilize a variety of other immunological or physical methods to measure sBCMA, APRIL and BAFF, such as the traditional single analyte ELISA plate assay, single analyte Luminex assay, ProteinSimple, Simoa, SomaLogic, Singulex, Olink. 
     DuoSet ELISA kits for human BCMA (DY193), APRIL (DY884B) and BAFF (DT124-05) were purchased from R&amp;D Systems (Minneapolis, Minn.). PBS pH7.2, 10× (70013-032), Tween 20 (003005), Amplex UltraRed reagent (A36006) were all from Thermo Fisher Scientific (Waltham, Mass.). BSA (BSA-50) was from Rockland (Limerick, Pa.). EASYBind 8-well strips (ES58400) was from Azer Scientific (Morgantown, Pa.). DMSO (D8418-50ML), H 2 O 2  (H1009-100ML) were from Sigma-Aldrich (St. Louis, Mo.). 
     Method to carry out the multiplex ELISA using 8-well strips is as follows. For each analyte, 12 of the strips are enough to test 48 samples in duplicates. Capture antibody (cap AB) diluted in 11 ml of PBS at the working concentration is used to coat every 12 strips in one column of the 4-column reservoir. Gently mix the cap AB with the strips. Seal the 4-column reservoir containing the strips in a Ziploc bag and incubate at room temperature (RT) overnight (ON). On the next day, wash the strips in PBS/0.05% Tween 20 (PBST) 2× and block the strips in 1% BSA/PBS (RD) for 1 hour at RT. Block an assay plate by adding 300 ul/well of RD at the same time. Meanwhile, serum samples cryopreserved at −80° C. with requested time points were thawed. Serum samples diluted at 1:2 in RD were used to test APRIL and BAFF, while serum samples diluted at 1:50, 1:200 or 1:1000 in RD were used to test BCMA. Standard (STD) curves for each analyte was made by diluting STD 1 (5000 pg/ml) at 1:2.5 dilution in RD and continue to STD7. Blank is RD only. At the end of blocking, remove RD from the assay plate and transfer the strips to the corresponding column of an assay plate according to an assay map. Transfer 200 ul of the STDs, blank and samples into each well according to the above assay set-up map. Gently mix the samples with the strips. Seal the assay plate containing the strips in a Ziploc bag and incubate at 4° C. ON. On the next day, block a 4-column reservoir with 20 ml RD/column for 5 minutes. Remove the blocking buffer, and prepare 11 ml of the detection AB/column at working concentration for each analyte using RD. Wash the strips in PBST 2×. Each 12 strips for the same analyte were incubated in one column of the 4-column reservoir containing the corresponding detection AB for 2 hours at RT. Afterwards, wash the strips in PBST 2× and incubate with 11 ml of the corresponding HRP conjugate for 1 hour at RT. Meanwhile, prepare substrate. For every 12 strips, 11 ml of PBS is mixed with 55 ul of the 10 mM Amplex UltraRed and 2.5 ul of 30% H 2 O 2 . Transfer 100 ul/well of the substrate to a round bottom clear 96-well substrate plate. At the end of HRP incubation, wash the strips in PBST 4×. Transfer each strip to one column of the substrate plate according to a substrate map. Let the color develop for 10 to 30 minutes. Stop the color reaction by removing the strips. Read and analyze the plate using FLUO STAR OMEGA (BMG LABTECH, Ortenberg, Germany) following their protocol. 
     Data quality was examined based on the following criteria. The STD curve for each analyte has a R2 value &gt;0.95 at 4-parameter fit based on FLUO STAR analysis software. The results for the in house control should be within the 95% of CI (confidence interval) derived from historical in house control data for the tested analytes. No further tests were done on samples with results out of range low (&lt;OOR) derived from samples at 1:2 dilution. Samples with results that were &lt;OOR derived from higher than 1:2 dilution were re-tested at lower dilutions. Samples with results that were out of range high (&gt;OOR) were re-tested at higher dilutions. Results that passed the above quality controls or retests were used in translational correlative studies. 
     Results 
     1. sBCMA, BAFF and APRIL Serum Levels in Multiple Myeloma Patients Treated with CAR-BCMA 
     This Example used a multiplex ELISA to measure sBCMA, BAFF and APRIL in longitudinal cryopreserved serum samples from six adult multiple myeloma patients treated with CAR-BCMA on the clinical trial UPCC14415 ‘Pilot Study of Redirected Autologous T Cells Engineered to Contain an Anti-BCMA scFv Coupled to TCRζ and 4-1BB Signaling Domains in Patients With Relapsed and/or Refractory Multiple Myeloma’. The expansion and persistence of CAR-BCMA in the patient peripheral blood was monitored by flow cytometry using a streptavidin tagged human BCMA-Fc fusion protein as a detection reagent, and by qPCR on peripheral blood DNA using primers specific for the 4-1BB costimulatory domain. 
     The levels (ng/ml) of serum sBCMA, BAFF and APRIL over time for the first six evaluable UPCC14415 patients on this study were measured ( FIG. 3 ). The Y axis is on a logarithmic scale. Of these six patients only patients 01 and 03 are clinical responders. Patients 02, 09, 10 and 11 are non-responders, in whom the sBCMA levels do not significantly change from baseline which is in the 100s of ng/ml for patients 02, 09 and 11 and in the 1000s for patient 10. In the two patients who do respond to CAR-BCMA therapy and in whom CAR-BCMA proliferate and expand ( FIG. 4 ), the sBCMA levels decline from the baseline level of high 1000s ng/ml by three logs (patient 01), and by about 2.5 logs (patient 03). Notably in both patients this decline is followed after 150 days (patient 01) and 120 days (Patient 03) by a recovery of sBCMA that is more obvious in patient 03. 
       FIG. 4  is a plot of CAR-BCMA levels (circles) as measured by qPCR and expressed as copies of the CAR-BCMA construct per microgram of blood DNA vs. serum sBCMA in ng/ml (quares). Only the responding patients 01 and 03 have expansion of CAR-BCMA to &gt;100,000 copies/microgram DNA. In these two patients the sBCMA levels are inversely correlated with CAR-BCMA levels. Patient 1 remains in clinical remission as of day 270. Patient 03 however, relapsed at around day 150, and is the most dramatic example of inverse correlation of sBCMA and CAR-BCMA, as the square and circle lines cross twice, first at 10 days when the sBCMA declines and the CAR-BCMA expand, and again 160 days later as the CAR-BCMA levels drop below 100 copies/microgram and the sBCMA levels rise back above 100 ng/ml. Both these patients experienced cytokine release syndrome (CRS) during their CAR-BCMA expansion period. 
       FIG. 3  also shows the BAFF and APRIL levels in serum over time. Briefly, these two analytes are present at lower levels (range 1-20 ng/ml for BAFF and 0-10 ng/ml for APRIL), show less dramatic kinetics than BCMA, and are not as clearly correlated with clinical outcome. There is a 1 to 1.5 log increase in both these two analytes in serum from the two responding patients (01 and 03) during the first 20 days after CAR-BCMA infusion which corresponds to the period of cytokine release syndrome that these two patients experienced. After this period the BAFF and APRIL kinetics are mostly flat. 
     2. sBCMA, BAFF and APRIL Serum Levels in Multiple Myeloma Patients Treated with CAR19 
     In this Example, it was hypothesized that sBCMA levels in serum of multiple myeloma patients might be affected by CAR-19 therapy, since flow cytometry data (data not shown) indicated that some of these patients achieved CD19 aplasia (absence of CD19 cells in their peripheral blood and/or bone marrow mononuclear cells as detected by flow cytometry). Thus sBCMA, BAFF and APRIL levels were tested in serum from eleven multiple myeloma patients, ten enrolled on UPCC02413, and one on UPCC19413, a compassionate use, single patient protocol.  FIGS. 5A, 5B and 5C  show plots of levels of CAR-19 (circles) as measured by qPCR and expressed as copies of the CAR-19 construct per microgram of blood DNA vs. serum sBCMA in ng/ml (squares). The horizontal dotted line is the average serum sBCMA level of 38.75 ng/ml that was empirically determined by measuring a panel of 14 normal donor sera with the same assay (data not shown). As is clear from  FIGS. 5A-5C , there is an inverse correlation between CAR19 levels and serum sBCMA levels in all eleven patients. The most common pattern is expansion of CAR19, peaking at around Day 10, with an immediate decline in sBCMA below the level seen in normal subjects. Typically CAR19 then contract in numbers and drop below the level of detection, although in some patients (02, 07, 12) there is some level of longer-term CAR19 persistence. There is a rebound in serum BCMA that happens at some point. The length of time during which the patient is in sub-normal sBCMA varies greatly, one extreme being UPCC02413-01 who experienced sBCMA rebound at around 500 days after CAR19 infusion. At the other extreme, patient UPCC02413-06 had recovery of sBCMA at about 60 days after CAR-19. In summary, there is very strong evidence that CAR19 therapy in multiple myeloma patients reduces serum sBCMA, and that sBCMA rebounds following loss of CAR19. 
     3. sBCMA, BAFF and APRIL Serum Levels in Patients with B Cell Malignancies (CLL, ALL, NHL) Treated with CAR19 
     Given the results above in multiple myeloma patients treated with CAR19, these studies were expanded to other patients with other B cell malignancies who had been treated with CAR19. Table 37 summarizes the clinical trials, indication, CAR-T therapies and observed sBCMA responses to therapy. The myeloma results have been described above in Sections 1 and 2. 
     
       
         
           
               
             
               
                 TABLE 37 
               
             
            
               
                   
               
               
                 Summary of clinical trials, indication, CAR-T therapies and sBCMA responses to therapy 
               
            
           
           
               
               
               
               
            
               
                 Study 
                 Disease (# patients tested) 
                 Therapy 
                 Serum sBCMA levels 
               
               
                   
               
               
                 UPCC14415 
                 Multiple Myeloma (6) 
                 CAR-BCMA 
                 Most much higher than ND, lower 
               
               
                   
                   
                   
                 after treatment, rebound during relapse 
               
               
                 UPCC19413 
                 Multiple Myeloma (1) 
                 mCAR19 
                 1 patient, much higher than ND, lower 
               
               
                   
                   
                   
                 after treatment, rebound during relapse 
               
               
                 UPCC02413 
                 Adult Multiple Myeloma (11) 
                 mCAR19 except for 
                 Most much higher than ND, lower 
               
               
                   
                   
                 huCAR19 -10, -12, -03R 
                 after treatment, rebound during relapse 
               
               
                 UPCC03712 
                 Adult CLL (2) 
                 mCART19 
                 Higher than ND, lower after treatment, 
               
               
                   
                   
                   
                 rebound during relapse 
               
               
                 UPCC13413 
                 NHL (2) 
                 mCAR19 except for 
                 Lower than ND 
               
               
                   
                   
                 huCAR19 13413-09, -36 
               
               
                 UPCC19214 
                 Adult Pancreatic Cancer (3) 
                 huCAR19 + mCART- 
                 ~ND level, lower after treatment 
               
               
                   
                   
                 meso 
               
               
                 UPCC21413 
                 Adult ALL (4) 
                 mCAR19 
                 Much lower than ND, lower after 
               
               
                   
                   
                   
                 treatment 
               
               
                 CHP959 
                 Pediatric ALL (3) 
                 mCAR19 
                 Much lower than ND, lower after 
               
               
                   
                   
                   
                 treatment 
               
               
                 UPCC31415 
                 ALL (3) 
                 CAR-22 
                 Around ND, no obvious treatment 
               
               
                   
                   
                   
                 effect 
               
               
                   
               
            
           
         
       
     
     The results suggest that serum sBCMA levels in ALL and NHL and pancreatic cancer are similar or lower than normal subjects. However, one of the two CLL patients (UPCC03712-1000-00040) is a clinical non-responder with a small expansion of CAR19 around Days 15-20 post infusion, CD19 aplasia at day 21, and then rebound of malignancy by Month 2. The baseline (pre-CAR19 therapy) sBCMA level is much higher than normal range, decreases on CAR19 infusions to normal or lower, and then increases again at month 2 and 3 when the patient relapsed (data not shown). The other patient, (UPCC03712_1000_00045) was a clinical responder with good CAR19 expansion peaking at day 14 post infusion who had a baseline sBCMA level of about 2×normal range, and this decreased with CAR19 therapy to sub-normal range and stayed there out to 1 year (the last timepoint tested) after CAR19 (data not shown). The patient went into CD19 aplasia by Day 14, and stayed in aplasia until Month 5 when the beginning of normal B cell reconstitution was observed. 
     Conclusion 
     Serum BCMA is a potentially useful biomarker for minimal residual disease in several B cell malignancies. Serum sBCMA is an excellent and convenient minimal residual disease (MRD) biomarker for CAR-BCMA efficacy in multiple myeloma. Serum sBCMA seems to be a very good biomarker for CAR19 efficacy in multiple myeloma. These Experiments suggest serum sBCMA is a marker in CLL, where treatment with CAR19 can reduce serum sBCMA and CD19 relapse is accompanied by elevated sBCMA. 
     Example 6: Pilot Study of Anti-CD19 Chimeric Antigen Receptor T Cells (CTL019) in Conjunction with Salvage Autologous Stem Cell Transplantation for Advanced Multiple Myeloma 
     Sox2 is a transcription factor that promotes pluripotency and self-renewal, and is implicated in cancer stem cell phenotypes. Anti-Sox2 antibodies are associated with reduced risk of progression in MGUS patients, are generally absent in untreated multiple myeloma and post-ASCT, and emerge in some multiple myeloma patients after allogeneic stem cell transplant. This Example tests the hypothesis that CTL019 would target myeloma stem cells, triggering an immune response encompassing other stem-cell antigens. According to they hypothesis, subjects with most prolonged time-to-progression after ASCT+CTL019 would exhibit anti-Sox2 immune responses. 
     It was observed that antibodies against the Sox2 emerged specifically in 2 subjects with most prolonged PFS compared to prior ASCT. More particularly,  FIG. 6  shows that subjects 1 and 5 developed anti-Sox2 antibodies after CTL-019 therapy. This was not likely an artifact of general immune reconstitution or low disease burden in these subjects. 
     Example 7: Biomarkers of Response to Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy in Patients with Chronic Lymphocytic Leukemia 
     This Example reports the pharmacokinetics of CTL019 cells in CLL patients. Dramatically different proliferation potential of T cells in responders vs. nonresponders to CTL019 were observed. More particularly, peak expansion and persistence of CTL019 cells was significantly lower in non-responders than every category of responders (CR, PR TD , and PR) ( FIG. 7 ). There were also significant differences in in vitro proliferation, e.g., between non-responders and CR or PR TD  (partial response, transfusion dependent) subjects ( FIG. 7 ). 
     It was also determined that CD19-directed T cells manufactured from CR and PR TD  subjects elaborated higher levels of STAT3 signaling mediators and targets, compared to PRs and NRs, which was consistent with STAT3 pathway upregulation in CAR stimulated CR and PR TD  patient CTL019 cells. In particular, IL-6, IL-17, IL-22, IL-31, CCL20, and a STAT3 gene set showed significant differences between different patient populations, e.g., CR, PR TD , PR, and NR ( FIG. 8 ). 
     It was also determined that the frequency of CD8+ T SCM  cells in pre-manufactured cells predicts response (data not shown). The percent of cells that are CD8+ T SCM  was significantly higher in CR or PR TD  compared to PR or NR subjects. 
     It was also observed that statistically significant lower frequencies of ex vivo CD27+CD45RO− CD8+ patient T cells expressing Ki-67 and elevated levels of granzyme B compared to their CD27+CD45RO+ counterpart (data not shown; p&lt;0.0001). 
     Combination of biomarkers were assessed for predicting response to CTL019. Responders versus non-responders could be predicted by the presence of CAR+CD8+ CD27+PD1-cells (AUC=0.92 in a plot of sensitivity versus specificity), CAR+CD8+ CD27+(AUC=0.70), and CAR+CD8+ PD1− (AUC=0.73). Complete responders versus non-responders could be predicted by the presence of CAR+CD8+ CD27+ PD1− cells (AUC=0.94), CAR+CD8+ CD27+ (AUC=0.75), and CAR+CD8+ PD1− (AUC=0.82). There was a highly significant association between the likelihood of having a response to CTL019 therapy and the infusion of CTL019 products containing a high dose of CD8+ PD1-CD27+ CAR T cells. 
     Example 8: Cellular Kinetics of CD19-Specific Chimeric Antigen Receptor T Cells (CTL019) in Patients with Chemotherapy Resistant or Refractory CD19+ Leukemias 
     CTL019 persistence was measured in patients having ALL (pediatric ALL or adult ALL) or CLL. Patient response was divided into three categories, CR/CRi, PR/PRi, and NR/PD. CTL019 persisted beyond 400 days in all three indications with higher levels in CR/CRi patients. The median T ½ in CR/CRi was −20 days, being only 2 days in NR. Persistence has been observed to 780 days. 
     Persistence was also calculated by AUC28. In ALL, a number of CR patients displayed an AUC of above about 5×10 5  or 1×10 6  CTL019 genomic DNA×time. In CLL, a number of CR or PR patients displayed an AUC of above about 5×10 5  or 1×10 6  CTL019 genomic DNA×time, and a number of NR/PD patients displayed an AUC of below about 1×10 5  or 5×10 4 . A strong concordance was observed between AUC0-28d, AUC0-84d, and Cmax determined qPCR and flow cytometry. 
     In addition, CTL019 trafficking in bone marrow observed beyond 350 days in patients achieving CR/Cri. 
     Example 9: Predictors of Manufacturing (MFG) Feasibility for Chimeric Antigen Receptor (CAR) T Cells in Non-Hodgkin Lymphoma (NHL) 
     As raw material for CAR T cell manufacture, patient apheresis products show variation due to treatment and disease-related factors. Patient peripheral blood laboratory values were used to identify patients at “high risk” of manufacturing fail prior to collection. This Example also explores various methods to mitigate these risks and increase manufacturing success rate. 
     Manufacturing data was analyzed for 45 patients enrolled in a Phase IIa CD19 CAR study, NCT02030834, for relapsed/refractory NHL. Complete blood counts with differential for each patient prior to apheresis was correlated with manufacturing feasibility. Apheresis products were characterized by complete blood count, flow cytometry phenotyping, cell size, and processing pathway. Five manufacturing fails were re-manufactured large scale to produce an infusible dose, and small scale cultures were set up with four products with insufficient T cell growth to test strategies to repair the proliferative capacity. 
     Approximately 62% of the patients met the recommended ALC (absolute lymphocyte count) of &gt;500/ul (28/45) at apheresis, and the manufacturing success rate to produce a CAR T product was 93% (2/28 manufacturing fails by cell number and transduction). The manufacturing success rate decreased to 65% for patients with peripheral ALC &lt;500/ul, as 6/17 were manufacturing fails (5/6 due to poor growth). Of patients with ALC &lt;300/ul, 6/10 were manufacturing fails, further reducing the manufacturing success rate to 40%. Overall, infusible CAR T cell product was produced for 37/45 patients (22/28 DLBCL, 13/15 FL, and 2/2 MCL, respectively), for an 82% manufacturing success rate.). Additional NHL apheresis product predictors of manufacturing failure include: AMC &lt;500/uL (27%), &lt;10% lymphocytes (&lt;27%), &gt;60% neutrophils (23%), &lt;25% CD3+CD45+by FACS (38%), &gt;60% monocytes (33%) and &lt;40% lymphocytes (33%). CD4/CD8 ratio did not predict manufacturing failure. PD1 expression on CD4 or CD8 or bulk T cells did not correlate with proliferative capacity. A second manufacturing collection and/or modified enrichment resulted in a success rate upon second manufacture of 100% (5/5). In each case, the second product underwent cryopreservation/thaw prior to culture compared to positive selection on fresh products for the corresponding failures. This was confirmed in side by side small scale cultures. 
     These signatures in NHL patient peripheral blood and apheresis products associated with a high risk of manufacturing fail can be used to select processing steps more likely to result in effective T cell enrichment for transduction and expansion. 
     Example 10. Efficacy of CTL019 in Inducing CNS Remissions in Relapsed Refractory ALL Pediatric Patients with CNS Involvement 
     Sixty pediatric Acute Lymphocytic Leukemia (ALL) patients were enrolled in a Phase 1/2a clinical trial (CH 959) of CTL019. All patients presented with relapsed/refractory CD19+ ALL, and of those seventeen had central nervous system (CNS) involvement. The patients underwent standard chemotherapy and lymphodepletion regimens prior to administration of CTL019. On Day −1, patients were assessed for the status of their disease in the bone marrow (BM), and for CNS involvement via lumbar puncture (LP). CTL019 was then administered to all patients, and a follow-up assessment to evaluate response to therapy was performed on Day 28. As on Day −1, procedures were performed to assess BM and CNS status on Day 28. Follow-ups were also performed at months 3, 6, 9 and 12 to continue monitoring patient&#39;s response to therapy (BM and CNS status) and/or disease progression. The outcomes of patients with CNS relapse were evaluated within 12 months of infusion. CNS relapse was defined as: CNS3 status (≥5 WBC/uL with blasts from an lumbar puncture (LP)). Brain/ocular involvement was evaluated by imaging. 
     Seventeen of 60 CTL019 treated patients were identified as having a disease with CNS involvement. All 17 patients had a CNS3 status (&gt;5 WBC/uL with blasts from an LP) a median of 4 months prior to infusion, and 3 of those patients had active CNS3 status at time of infusion. Patients ranged from 1st to 7th CNS relapse(s) prior to treatment with CTL019. Ten had isolated CNS relapse and seven had combined BM/CNS relapse. Six patients had ocular involvement and the 3 with active CNS3 had parenchymal changes on brain/spine MRI. Sixteen patients had prior CNS directed radiation and thirteen had undergone prior BMT. CNS relapse was defined as CNS3 by lumbar puncture or brain/ocular involvement by imaging within 12 months of infusion. Table 38 provides a summary of CNS status in all patients. 
     As shown in  FIG. 9 , a complete response (CR) of 93% was observed at Day 28 in this group of patients. CR was subdivided into CR with minimal residual disease (CR, MRD−) or CR without minimal residual disease (CR, MRD+), wherein MRD was defined as &lt;0.01% blasts by flow cytometry. Importantly, all patients had CNS remission, i.e., a 100% CNS remission rate was observed ( FIG. 9 ). Patient response is presented by % ALL blasts in  FIG. 9 , with 100% CR in groups with &lt;0.01% blasts. Patients who had more than 50% or between 5-50% blasts, had 83% and 88% CR respectively. A small number of patients did not respond to therapy (NR, no response). Cytokine release syndrome (CRS) was observed in 88% of patients, of which 27% had severe CRS. 
     
       
         
           
               
             
               
                 TABLE 38 
               
             
            
               
                   
               
               
                 CNS status of ALL patients with CNS involvement. 
               
            
           
           
               
               
               
            
               
                   
                 CNS patient cohort 
                 N = 17 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Active CNS3 at time of infusion 
                 3 
               
               
                   
                 Isolated CNS relapse 
                 10 
               
               
                   
                 Combined BM + CNS relapse 
                 7 
               
               
                   
                 No. of prior CNS relapses 
                 1 to 7 
               
               
                   
                 Ocular involvement 
                 6 
               
               
                   
                 Parenchymal changes on neuroimaging 
                 3 
               
               
                   
                 Prior CNS directed radiation 
                 16 
               
               
                   
                 Prior BMT 
                 13 
               
               
                   
                   
               
            
           
         
       
     
     Importantly, neurotoxicity was not enhanced in the CNS cohort (Table 39). Encephalopathy grade 2-3 was observed in 3/17(18%) CNS vs. 12/43(28%) non-CNS. Seizures grade 2-4 were observed in 1/17(6%) CNS vs. 3/43(7%) non-CNS patients. Vision disturbance, speech disturbance, trigerminal neuralgia and ataxia were only observed in the CNS cohort in 6-12% of patients. Confusion was observed in both groups at low levels, and agitation was only observed in the non-CNS cohort in 5% of patients. Sixteen of 17 patients were CNS1 (no detectable leukemic cells in the cerebrospinal fluid, CSF) on Day 28 post infusion. One patient was not evaluable (N/E) due to rapid progression of disease in the BM. In 2 out of the 3 patients with active CNS3 disease at infusion, 1 was in CR by Day 28, 1 had initial pseudo-progression with CR by 3 months, and the third patient was not evaluable. Twelve of 17 (71%) CNS patients remain in CR 2 to 31 months post-infusion (median 11 months). Five had recurrent BM disease but were CNS negative at relapse. One patient had no response in the BM but this patient&#39;s CNS status was not evaluable. 
     Of the seventeen patients with CNS involvement in this study, three were Philadelphia chromosome (Ph+) positive. These patients initially presented with 3 to 7 CNS relapses, and remain in a CR state at 8 to 31 months (median 23 months) post CTL019 infusion. None of the 60 patients enrolled in this trial have presented with CNS relapse post-infusion, irrespective of their initial CNS status (i.e., irrespective of whether the patients presented with CNS involvement prior to CTL019 infusion). 
     These data suggest that CTL019 as a single agent immunotherapy can induce durable responses in pediatric patients with relapsed/refractory ALL with CNS involvement. Neurotoxicity does not appear to be enhanced in relapsed/refractory ALL patients with CNS involvement compared to relapsed/refractory ALL patients without CNS involvement. 
     
       
         
           
               
             
               
                 TABLE 39 
               
             
            
               
                   
               
               
                 Summary of toxicities observed in all 
               
               
                 ALL patients infused with CTL019 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 No. of 
                   
                   
               
               
                   
                   
                 Patient- 
                 CNS cohort 
                 Non CNS 
               
               
                 Toxicity 
                 Grade 
                 Events 
                 N = 17 
                 N = 43 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Seizures 
                 2 
                 2 
                 1 
                 (6%) 
                 1 
                 (2%) 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 3 
                 1 
                 0 
                 1 
                 (2%) 
               
               
                   
                 4 
                 1 
                 0 
                 1 
                 (2%) 
               
               
                 Encephalopathy 
                 2 
                 2 
                 0 
                 2 
                 (4%) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 3 
                 14 
                 3 
                 (18%) 
                 12 
                 (28%) 
               
            
           
           
               
               
               
               
               
               
            
               
                 Vision disturbance 
                 3 
                 1 
                 1 
                 (6%) 
                 0 
               
               
                 Speech Disturbance 
                 3 
                 2 
                 2 
                 (12%) 
                 0 
               
               
                 Trigeminal 
                 3 
                 1 
                 1 
                 (6%) 
                 0 
               
               
                 Neuralgia 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Confusion 
                 2 
                 3 
                 2 
                 (12%) 
                 1 
                 (2%) 
               
            
           
           
               
               
               
               
               
               
            
               
                 Dizziness 
                 2 
                 0 
                 0 
                 1 
                 (2%) 
               
            
           
           
               
               
               
               
               
               
            
               
                 Ataxia 
                 2 
                 1 
                 1 
                 (6%) 
                 0 
               
            
           
           
               
               
               
               
               
               
            
               
                 Agitation 
                 2 
                 2 
                 0 
                 2 
                 (5%) 
               
               
                   
               
            
           
         
       
     
     Example 11: Predictors of Manufacturing (MFG) Success for Chimeric Antigen Receptor (CAR) T Cells in Non-Hodgkin Lymphoma (NHL) 
     As raw material for CAR T cell manufacture, patient apheresis products show treatment and disease-related variation. Patient peripheral blood laboratory values were used to identify patients at higher risk of manufacturing fail prior to collection. This Example describes various methods to mitigate risk and increase manufacturing success rate of the CAR product. 
     Manufacturing data were analyzed for 45 patients enrolled in a Phase IIa CD19 CAR study (NCT02030834) for relapsed/refractory NHL. Apheresis products were characterized by absolute lymphocyte count (ALC), flow cytometry phenotyping and cell size via a multisizer. 
     Approximately 62% of patients met the recommended ALC of &gt;500/ul (28/45) at apheresis. The CAR T manufacturing success rate in this group was 93% (2 out of 28 were manufacturing fails) ( FIG. 10 ). The manufacturing success rate decreased to 65% for patients with peripheral ALC &lt;500/ul, as 6 out of 17 were manufacturing fails, of which 5 out of 6 were fails due to poor growth. For patients with ALC &lt;300/ul, 6 out of 10 were manufacturing fails, further reducing the manufacturing success rate to 40%. Overall, infusible CAR T cell product was produced for 37 out of 45 patients, for an 82% manufacturing success rate.  FIG. 10  shows the peripheral blood profiles of samples grouped by manufacturing success vs. failure.  FIG. 10A  shows the ALC in these samples and  FIG. 10B  shows the % lymphocytes (LY) in the samples. Samples with high manufacturing success rates demonstrate higher starting ALC and more lymphocytes in the periphery.  FIGS. 11A-11C  further demonstrate the makeup of various immune cell populations in apheresis products grouped by manufacturing success vs. failure.  FIG. 11A  shows a higher percentage of CD3+CD45+ cells in samples with high manufacturing rates. The samples with high manufacturing rates also had higher % lymphocytes ( FIG. 11B ) and lower % monocytes ( FIG. 11C ) in the periphery. In summary, the data showed that apheresis products with &gt;75% monocytes, &lt;23% lymphocytes and &lt;13% CD3+45+ were more likely to fail manufacturing in this study. 
     Small scale test expansion was used to model CAR T clinical manufacturing proliferative capacity, and to avoid failure to meet cell number, phenotype, and transduction criteria. The first 10 patients where test expansions were performed passed these tests, and 9 out of 10 samples were successfully manufactured large scale (the 1 manufacturing fail was due to equipment malfunction). Of the initial 10 subjects screened for enrollment in the test expansion study, 4 had ALC &lt;500/ul, but passed the test expansion, and were successfully manufactured. CD4/CD8 ratio did not correlate with manufacturing failure. The level of PD1expression on CD4, CD8, or bulk T cells did not correlate with proliferative capacity. 
     A second apheresis collection and/or modified enrichment for manufacture resulted in a success rate of 100% (5 out of 5 samples tested). For each of the samples, the second product underwent a cryopreservation and thaw cycle prior to culture compared to positive selection on fresh products for the corresponding failures. This was confirmed in side by side small scale cultures with the first product ( FIGS. 12A-D  and Table 40).  FIGS. 13A-B  shows T cell enrichment post-thaw due to loss of CD45 dim or CD45 negative cells from two patient samples. As further demonstrated in  FIGS. 14A-14B , myeloid derived suppressor cells are sensitive to a freeze-thaw cycle (cryopreservation followed by thawing), as indicated by the decrease in CD15+ and CXCR2+ cells post-thaw for two samples. Taken together, the data suggests that cryopreservation enriched T cells and reduced potential suppressive non-lymphoid cell subsets (e.g., myeloid derived suppressor cells (MDSC)) thus improving manufacturing success rates of samples whose fresh cells had previously failed manufacturing. 
     Signatures in NHL patient peripheral blood and apheresis products associated with high risk of manufacturing fail can be used to select processing steps more likely to result in effective T cell enrichment, transduction, and expansion. For patients with ALC &lt;500/ul, a small scale test expansion incorporated with select processing steps may predict clinical manufacturing success. This strategy to increase the likelihood of engineered T cell manufacturing success may also be applicable for patients with other hematologic malignancies and cancers. 
     
       
         
           
               
             
               
                 TABLE 40 
               
             
            
               
                   
               
               
                 Summary of manufacturing results from 5 samples which failed 
               
               
                 at the first manufacturing attempt. (MFG = manufacturing) 
               
            
           
           
               
               
               
               
               
               
            
               
                 Sample 
                 10 
                 28 
                 41 
                 13 
                 19 
               
               
                   
               
               
                 Input cell source 
                 Fresh APH 
                 Fresh APH 
                 Fresh APH 
                 Fresh APH 
                 Fresh APH 
               
               
                 for 1 st  MFG run 
               
               
                 Outcome of 1 st   
                 FAIL 
                 FAIL 
                 FAIL 
                 FAIL 
                 FAIL 
               
               
                 MFG run 
               
               
                 Collection for 2 nd   
                 2 nd  Collection 
                 2 nd  Collection 
                 2 nd  Collection 
                 1 st  Collection 
                 1 st  Collection 
               
               
                 MFG 
               
               
                 Input cell source 
                 Cryopreserved/ 
                 Cryopreserved/ 
                 Cryopreserved/ 
                 Cryopreserved/ 
                 Cryopreserved/ 
               
               
                 for 2 nd  MFG run 
                 Thawed 
                 Thawed 
                 Thawed 
                 Thawed 
                 Thawed 
               
               
                 Outcome of 2 nd   
                 SUCCESS 
                 SUCCESS 
                 SUCCESS 
                 SUCCESS 
                 SUCCESS 
               
               
                 MFG run 
               
               
                   
               
            
           
         
       
     
     Example 12: CTL019 for the Treatment of Pediatric and Young Adult Patients with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia 
     Clinical Development Program 
     The efficacy and safety of CTL019 has been established in 3 trials involving over 150 pediatric and young adult patients with r/r B-cell ALL (Table 42). 
     Study B2101J was the first clinical study conducted in pediatric and young adult patients with r/r CD19+ hematologic malignancies using CTL019 (N=71). The primary objective of this trial was to determine the safety, tolerability, and engraftment potential (duration of in vivo survival measured by qPCR) of tisagenlecleucel in patients with r/r and incurable CD19+B-cell malignancies (CD19+ leukemia or lymphoma). Entry criteria were designed to include pediatric and young adult patients aged 1 to 24 years with CD19+B-cell malignancies with no available curative treatment options (such as autologous or allogeneic SCT) who had a limited prognosis (several months to &lt;2-year survival) with currently available therapies. Up to three infusions and a wide dose range were allowed. 
     Study B2205J is a multicenter study conducted in the US and similar both in design and study objectives to the pivotal registration trial (Study B2202). Due to its earlier start date, there is a longer duration of follow-up available for this trial compared to Study B2202. Other differences from Study B2202 included a smaller number of patients enrolled (35 vs. 88 patients, respectively), and the geographical location of the clinical and manufacturing sites. In addition, patients with lymphoblastic lymphoma were allowed to participate in this trial but not in Study B2202. 
     Study B2202 is the pivotal registration trial and is a global, multicenter, single-arm, open-label phase II study designed to determine the efficacy and safety of CTL0191 in pediatric and young adult patients with r/r B-cell ALL (N=88). Patients were aged between 3 years at the time of screening and 21 years at the time of initial diagnosis. The single-arm study design was supported by the absence of effective therapies in this setting, and the high unmet medical need of the target patient population. 
     
       
         
           
               
             
               
                 TABLE 42 
               
             
            
               
                   
               
               
                 Pediatric and young adult r/r B-cell ALL clinical development program 
               
            
           
           
               
               
               
               
               
            
               
                 Study 
                 Population, study 
                 No. of 
                 Tisagenlecleucel 
                   
               
               
                 No. 
                 design, and objectives 
                 patients 
                 allowable dose range 
                 Efficacy endpoints 
               
               
                   
               
            
           
           
               
            
               
                 Supportive trials 
               
            
           
           
               
               
               
               
               
            
               
                 B2101J 
                 Single-arm, open-label, 
                 Enrolled: N = 71 
                 Multiple infusions 
                 Primary: Safety, feasibility 
               
               
                   
                 US, single-center, 
                 Infused: N = 55 
                 Up to a total target dose of 
                 of manufacture, and 
               
               
                   
                 phase-I/IIa trial 
                   
                 1.5 × 10 7  to 5 × 10 9  total T 
                 persistence 
               
               
                   
                 Safety, tolerability, and 
                   
                 cells (0.3 × 10 6  to 
                 Secondary: IRC-assessed 
               
               
                   
                 engraftment potential 
                   
                 1.0 × 10 8 /kg) 
                 ORR 
               
               
                 B2205J 
                 Single-arm, open-label, 
                 Enrolled: N = 35 
                 Single infusion 
                 Primary: IRC-assessed 
               
               
                   
                 US, multicenter, phase- 
                 Infused: N = 29 
                 ≤50 kg: 0.2 to 5.0 × 10 6   
                 ORR 
               
               
                   
                 II trial 
                   
                 transduced viable T cells/kg 
                 Secondary: DoR, BOR, 
               
               
                   
                 Efficacy and safety 
                   
                 &gt;50 kg: 0.1 to 2.5 × 10 8   
                 EFS, OS, Safety 
               
               
                   
                   
                   
                 transduced viable T cells 
               
            
           
           
               
            
               
                 Pivotal registration trial 
               
            
           
           
               
               
               
               
               
            
               
                 B2202 
                 Single-arm, open-label, 
                 Enrolled: N = 88 
                 Single infusion 
                 Primary: IRC-assessed 
               
               
                   
                 international, 
                 Infused: N = 68 
                 ≤50 kg: 0.2 to 5.0 × 10 6   
                 ORR 
               
               
                   
                 multicenter, phase-II 
                   
                 transduced viable T cells/kg 
                 Secondary: DoR, BOR, 
               
               
                   
                 trial 
                   
                 &gt;50 kg: 0.1 to 2.5 × 10 8   
                 EFS, OS, Safety 
               
               
                   
                 Efficacy and safety 
                   
                 transduced viable T cells 
               
               
                   
               
               
                 ALL Acute lymphoblastic leukemia; 
               
               
                 BOR Best overall response; 
               
               
                 DoR Duration of remission; 
               
               
                 EFS Event-free survival; 
               
               
                 IRC Independent Review Committee; 
               
               
                 ORR Overall remission rate; 
               
               
                 OS Overall survival; 
               
               
                 r/r Relapsed/refractory 
               
            
           
         
       
     
     Patient Populations 
     Patients recruited to Studies B2101J and B2205J were representative of the clinical population of pediatric and young adult patients with r/r B-cell ALL. 
     The focus of the Study B2101J analysis was on 55 patients with non-CNS3 ALL who received treatment with CTL019. Median age was 11 years (range: 1 to 24). All patients had a Karnofsky/Lansky performance status score of &gt;50%. Patients were heavily pretreated (89.1% had received &gt;3 and 16.4% had received &gt;6 prior regimens), and 63.6% had undergone prior SCT. Available mutation data were limited. 
     Study B2205J enrolled 35 pediatric and young adult patients with r/r B-cell ALL, with a median age of 12 years (range: 3 to 25) (Table 5-2). Twenty-nine patients were infused with CTL019; all had a Karnofsky/Lansky performance status score &gt;50%, and included individuals with high-risk mutations. Patients had received a median of 3 prior therapies (range: 1 to 9) and 58.6% had failed prior allo-SCT. 
     In Study B2202, demographic and baseline disease characteristics reflected the target pediatric and young adult patient population with r/r B-cell ALL for whom the drug is intended. The study enrolled patients with r/r B-cell ALL across 25 centers in the US, Canada, the EU, Australia, and Japan. Patients were aged 3 to 23 years (median: 12) with a Karnofsky/Lansky performance status score of &gt;50%. The population consisted of patients with high-risk mutations following a median of 3 prior therapies (range: 1 to 8), with 58.8% of patients having failed prior allo-SCT. 
     Dose-Selection Rationale 
     Clinical Target Dose 
     The initial dose selection for the first clinical study (Study B2102J) with CTL019 was based on in vivo models of ALL in which human pre-B ALL cells were engrafted into immunodeficient mice. These mice received doses of 1, 5, and 20×10 6  cells. Anti-leukemic treatment effects were observed, supporting further investigation of doses of 5 and 20×10 6  cells in mouse models. 
     Formal dose-escalation studies were not conducted. The target CTL019 doses for Studies B2202 and B2205J were:
         2.0 to 5.0×10 6  transduced viable T-cells per kg body weight for patients ≤50 kg   1.0 to 2.5×10 8  transduced viable T cells for patients &gt;50 kg       

     Importantly, once infused, the transduced cells are expected to expand in vivo and there appears to be no clear relationship between CTL019 dose and expansion across the wide dose range tested. 
     Allowable Infused Dose Ranges 
     In the early clinical studies the target dose was not always achieved due to characteristics of the collected cells, and yet responses were observed; as a result, an allowable dose range was established for Studies B2202 and B2205J:
         0.2 to 5.0×10 6  transduced viable T cells per kg for patients ≤50 kg   0.1 to 2.5×10 8  transduced viable T cells for patients &gt;50 kg.       

     Dose-Response Analysis for CTL019 
       FIGS. 15A and 15B  show dose-response curves for patients ≤50 kg ( FIG. 15A ) or for patients &gt;50 kg ( FIG. 15B ) administered with a range of doses of CTL019. Patients ≤50 kg showed an increasing trend in the probability of response for doses up to 2.0×10 6  transduced viable T cells/kg with a plateau for higher doses (e.g., doses &gt;2.4×10 6  transduced viable T cells/kg)( FIG. 15A ). Responses were also observed at the lowest dose tested, i.e., 0.2×10 6  transduced viable T cells/kg. 
     For patients &gt;50 kg,  FIG. 15B  demonstrates a similar trend in the probability of response for doses up to 1.0×10 8 , with a plateau for higher doses. In this patient group, responses were also observed at the lowest dose tested, i.e., 0.2×10 8 . For both patient cohorts, clinical benefit was evident at lower doses. 
     Example 13: Clinical Pharmacology and Biopharmaceutics in Pediatric Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia 
     Data from two phase 2 studies (ELIANA; NCT02435849 and ENSIGN; NCT02228096) in pediatric and young adult R/R B-cell ALL were pooled to evaluate the cellular kinetics of CTL019, humoral immunogenicity, AUC 0-28d (exposure)-response analysis, and impact of intrinsic, extrinsic and manufacturing factors on CTL019 expansion. 
     Methods 
     Cellular kinetic parameters of CTL019 post infusion were derived using traditional pharmacokinetic principles and reported by response category (complete response [CR]/CR with incomplete blood count recovery [CRi] vs no response [NR]) using 2 assays of peripheral blood cells: qPCR and flow cytometry. AUC 0-28d-response relationships were evaluated by logistic regression. Relationships between manufacturing specifications, therapies for cytokine release syndrome (CRS) management, and anti-CAR19 antibodies on cellular kinetics were explored using summary statistics and graphical- and model-based analyses. 
     Results 
     Data from 79 pts (ELIANA, n=50; ENSIGN, n=29) were pooled for analysis. Using qPCR, pts with CR/CRi (n=62) had about a 2-fold higher CTL019 expansion than patients with NR (n=7) (Cmax, 73.5% higher geometric [geo] mean; AUC0-28d, 104% higher geo mean; Table 41). Patients with NR had delayed Tmax compared with patients with CR/CRi (20 vs 10 days). Intrinsic patient factors including baseline cytogenetics, disease characteristics, and disease status did not appear to affect Cmax or AUC0-28d with the exception that patients with a higher tumor burden at enrollment generally had higher expansion, based on box plots and summary statistics. Extrinsic factors (e.g., prior lines of therapy or stem cell transplant) and parameters related to the manufactured product (e.g., % T cells, transduction efficiency, cell viability, or total cell count), did not appear to impact cellular kinetics, based on graphical analysis. AUC0-28d increased with presence and severity of CRS. Patients who received anti-cytokine agents for grade 3/4 CRS also had higher expansion. CR/CRi patients treated with tocilizumab and steroids (n=17) had 89% higher AUC0-28d than CR patients who did not receive tocilizumab and steroids (n=45). Moderate correlation was observed between transgene levels and CAR surface expression in peripheral blood (r2=0.592) by qPCR and flow cytometry, respectively, when matched by time points from the cellular kinetic profile. Slower B-cell recovery was observed in patients with AUC0-28d above the median. Post-dose anti-CAR19 antibody responses were determined from the fold change of anti-CAR19 antibodies above the baseline pre-dose value. Patients with treatment-induced or boosted anti-CAR19 antibody responses generally had lower expansion, based on box plots, compared with patients with treatment-unaffected anti-CAR19 antibody responses, although AUC0-28d was variable. The boosted levels of anti-CAR19 did not impact clinical response or relapse. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 41 
               
               
                   
               
               
                 Parameter 
                 Statistics 
                 CR/CRi (n = 62) 
                 NR (n = 7) 
               
               
                   
               
             
            
               
                 AUC0-28 d 
                 n 
                 61 
                 6 
               
            
           
           
               
               
               
            
               
                 (copies/μg DNA × days) 
                 CR/CRi fold change over NR 
                 2.0 
               
            
           
           
               
               
               
               
            
               
                 Cmax (copies/μg) 
                 n 
                 61 
                 7 
               
            
           
           
               
               
               
            
               
                   
                 CR/CRi fold change over NR 
                 1.7 
               
            
           
           
               
               
               
               
            
               
                 Tmax (days) 
                 n 
                 61 
                 7 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Median (range) 
                 9.91 
                 (0.00784-27.0) 
                 20.0 
                 (0.0276-62.7) 
               
            
           
           
               
               
               
               
            
               
                 T½ (days) 
                 n 
                 54 
                 3 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Median (range) 
                 14.8 
                 (2.03-208) 
                 1.46 
                 (1.12-9.65) 
               
               
                   
                   
               
               
                   
                 * Unknown response, n = 10 
               
            
           
         
       
     
     Conclusion 
     There was increased expansion of CTL019 in patients with higher tumor burden at enrollment, which correlated with higher CRS grade. A relationship between dose and expansion was not observed, thereby supporting the wide dose range used. Expansion was not attenuated, e.g., by tocilizumab or steroids, indicating therapies for CRS, e.g., do not abrogate CTL019 proliferation. Cellular kinetics are important to understand the determinants of tumor response with CAR T-cell therapy. 
     EQUIVALENTS 
     The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific aspects, it is apparent that other aspects and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such aspects and equivalent variations.