Patent Publication Number: US-2020281973-A1

Title: Cells expressing multiple chimeric antigen receptor (car) molecules and uses therefore

Description:
RELATED APPLICATIONS 
     This application claims priority to U.S. Provisional patent application No. 62/303,466, filed Mar. 4, 2016. The entire contents of this application are incorporated herein by reference. 
    
    
     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 Mar. 31, 2017, is named PAT057255-WO-PCT_SL.txt and is 1,001,738 bytes in size. 
     FIELD OF THE INVENTION 
     The present disclosure relates generally to the use of immune effector cells (e.g., T cells, NK cells) engineered to express a Chimeric Antigen Receptor (CAR) that targets B cells and engineered to express a CAR that targets cells expressing a tumor antigen other than a B-Cell antigen, e.g., cells expressing a solid tumor antigen, myeloid tumor antigen, or cells expressing an antigen of a hematological tumor not of B-Cell origin, to treat a disease associated with expression of the tumor antigen. 
     BACKGROUND OF THE INVENTION 
     Immunotherapy is a promising approach for the treatment of tumors. Immunotherapy with cells expressing chimeric antigen receptors (CARs) that target antigens expressed by the tumor has the advantage of targeted therapies that can invoke a rapid and sustained immune response against a tumor. CAR therapy has shown promising results in the clinic in treating some hematological cancers, such as B cell malignancies (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)). However, studies exploring CAR therapy for treating other cancers have demonstrated variable efficacy, in part due to the limited persistence and proliferation of the CAR-expressing cells in vivo. 
     Thus, there exists a need for CAR cell therapies with enhanced efficacy, e.g., enhanced proliferation or prolonged persistence in a patient. 
     SUMMARY OF THE INVENTION 
     The present disclosure features, at least in part, methods and compositions for treating a disease associated with expression of a tumor antigen, e.g., a cancer, in a subject using an immune effector cell (e.g., T cell) engineered to expresss a first chimeric antigen receptor (CAR) and a second CAR, wherein the antigen binding domain of said first CAR binds to a B-Cell antigen and the antigen binding domain of said second CAR binds to a tumor antigen other than a B-Cell antigen, e.g., to enhance the efficacy (e.g., the persistence and/or proliferation of the tumor antigen-targeting CAR-expressing immune effector cell in a patient) of the CAR-expressing immune effector cell therapy. Without wishing to be bound by theory, treatment with an immune effector cell expressing a CAR targeting a B-Cell antigen and a CAR targeting a tumor antigen enhances the anti tumor efficacy of the tumor antigen-targeting CAR-expressing immune effector cell in a subject, e.g., by one or more of: increasing the proliferation of said CAR-expressing immune effector cells and/or increasing the in vivo persistence of said CAR expressing immune effector cells, e.g., as compared to administering an immune effector cell expressing only the tumor-targeting CAR (e.g., not expressing the CAR targeting a B-Cell antigen). In aspects, the B-Cell antigen and the tumor antigen other than a B-Cell antigen are not expressed on the same cell (e.g., the B-Cell antigen is not expressed on the cell, e.g., tumor cell, which expresses the tumor antigen). 
     In an aspect, the invention provides, a cell that includes a first chimeric antigen receptor (CAR) and a second CAR, each of which includes an antigen binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the antigen binding domain of said first CAR binds to a B-Cell antigen and the antigen binding domain of said second CAR binds to a tumor antigen other than a B-Cell antigen. In aspects of the invention, the B-Cell antigen targeted by the first CAR and the tumor antigen other than a B-Cell antigen targeted by the second CAR are not expressed on the same cell. 
     In embodiments, the second CAR binds: (a) a solid tumor antigen; (b) a myeloid tumor antigen; or (c) an antigen of a hematological tumor not of B-cell lineage. 
     In embodiments, the B-Cell antigen is selected from the group consisting of CD5, CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD27, CD30, CD34, CD37, CD38, CD40, CD53, CD69, CD72, CD73, CD74, CD75, CD77, CD79a, CD79b, CD80, CD81, CD82, CD83, CD84, CD85, CD86, CD123, CD135, CD138, CD179, CD269, Flt3, ROR1, BCMA, FcRn5, FcRn2, CS-1, CXCR4, 5, 7, IL-7/3R, IL7/4/3R, and IL4R. 
     In embodiments, the B-Cell antigen is selected from the group consisting of CD19, CD20, CD22, FcRn5, FcRn2, BCMA, CS-1, and CD138 
     In one aspect, the cell includes a first chimeric antigen receptor that includes an antigen binding domain that binds a B-Cell antigen that is BCMA. In embodiments, the antigen binding domain of said first CAR includes 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 heavy chain binding domain amino acid sequence listed in Table 12 or 13. In embodiments, the antigen binding domain of said first CAR further includes a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3) of any light chain binding domain amino acid sequence listed in Table 12 or 13. In embodiments, the antigen binding domain of said first CAR includes: (i) the amino acid sequence of any light chain variable region listed in Table 12 or 13; (ii) an amino acid sequence having at least one, two or three modifications but not more than 20 or 10 modifications of the amino acid sequence of any of the light chain variable regions provided in Table 12 or 13; or (iii) an amino acid sequence with 95-99% identity to the amino acid sequence of any of the light chain variable regions provided in Table 12 or 13. In embodiments, the antigen binding domain of said first CAR includes: (i) the amino acid sequence of any heavy chain variable region listed in Table 12 or 13; (ii) an amino acid sequence having at least one, two or three modifications but not more than 20 or 10 modifications of the amino acid sequence of any of the heavy chain variable regions provided in Table 12 or 13; or (iii) an amino acid sequence with 95-99% identity to the amino acid sequence of any of the heavy chain variable regions provided in Table 12 or 13. In embodiments, the antigen binding domain of said first CAR includes a polypeptide having the amino acid sequence of any light chain variable region listed in Table 12 or 13, and the amino acid sequence of any heavy chain variable region listed in Table 12 or 13. In embodiments, the antigen binding domain of said first CAR includes a polypeptide having a sequence of SEQ ID NO: 349; SEQ ID NO: 339, SEQ ID NO: 340; SEQ ID NO: 341; SEQ ID NO: 342; SEQ ID NO: 343; SEQ ID NO: 344, SEQ ID NO: 345, SEQ ID NO: 346, SEQ ID NO: 347, SEQ ID NO: 348, SEQ ID NO: 350, SEQ ID NO: 351, SEQ ID NO: 352, SEQ ID NO: 353, SEQ ID NO: 429, SEQ ID NO: 430, SEQ ID NO: 431, SEQ ID NO: 432, SEQ ID NO: 433, SEQ ID NO: 434, SEQ ID NO: 435, SEQ ID NO: 436, SEQ ID NO: 437, SEQ ID NO: 438, SEQ ID NO: 439, SEQ ID NO: 440, SEQ ID NO: 441, SEQ ID NO: 442, SEQ ID NO: 443, SEQ ID NO: 444, SEQ ID NO: 445, SEQ ID NO: 446, SEQ ID NO: 447, SEQ ID NO: 448, SEQ ID NO: 449, SEQ ID NO: 563, SEQ ID NO: 564, SEQ ID NO: 565 or SEQ ID NO: 566. 
     In another aspect, the cell includes a first chimeric antigen receptor that includes an antigen binding domain that binds a B-Cell antigen that is CD19. In embodiments, the antigen binding domain of said first CAR includes 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 heavy chain binding domain amino acid sequence listed in Table 6, Table 7 or Table 9. In embodiments, the antigen binding domain of said first CAR further includes a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3) of any light chain binding domain amino acid sequence listed in Table 6, Table 8 or Table 9. In embodiments, the antigen binding domain of said first CAR includes: (i) the amino acid sequence of any light chain variable region listed in Table 6 or Table 9; (ii) an amino acid sequence having at least one, two or three modifications but not more than 20 or 10 modifications of the amino acid sequence of any of the light chain variable regions provided in Table 6 or Table 9; or (iii) an amino acid sequence with 95-99% identity to the amino acid sequence of any of the light chain variable regions provided in Table 6 or Table 9. In embodiments, the antigen binding domain of said first CAR includes: (i) the amino acid sequence of any heavy chain variable region listed in Table 6 or Table 9; (ii) an amino acid sequence having at least one, two or three modifications but not more than 20 or 10 modifications of the amino acid sequence of any of the heavy chain variable regions provided in Table 6 or Table 9; or (iii) an amino acid sequence with 95-99?/o identity to the amino acid sequence of any of the heavy chain variable regions provided in Table 6 or Table 9. In embodiments, the antigen binding domain of said first CAR includes a polypeptide having the amino acid sequence of any light chain variable region listed in Table 6 or Table 9, and the amino acid sequence of any heavy chain variable region listed in Table 6 or Table 9. In embodiments, the antigen binding domain of said first CAR includes a polypeptide having a sequence of SEQ ID NO: 83; SEQ ID NO: 84, SEQ ID NO: 85; SEQ ID NO: 86; SEQ ID NO: 87; SEQ ID NO: 88; SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, or SEQ ID NO: 112. 
     In another aspect (including in any of the aforementioned aspects and embodiments), the cell includes a second CAR that includes an antigen binding domain that binds a myeloid tumor antigen, and wherein said myeloid tumor antigen is selected from the group consisting of CD123, CD33 and CLL-1. 
     In another aspect (including in any of the aforementioned aspects and embodiments), the cell includes a second CAR that includes an antigen binding domain that binds a T cell lymphoma antigen. 
     In another aspect (including in any of the aforementioned aspects and embodiments), the cell includes a second CAR that includes an antigen binding domain that binds a solid tumor antigen, e.g., wherein said solid tumor antigen is selected from the group consisting of EGFRvIII, mesothelin, GD2, Tn antigen, sTn antigen, Tn-O-Glycopeptides, sTn-O-Glycopeptides, PSMA, CD97, TAG72, CD44v6, CEA, EPCAM, KIT, IL-13Ra2, leguman, GD3, CD171, IL-11Ra, PSCA, MAD-CT-1, MAD-CT-2, VEGFR2, LewisY, CD24, PDGFR-beta, SSEA-4, folate receptor alpha, ERBBs (e.g., ERBB2), Her2/neu, MUC1, EGFR, NCAM, Ephrin B2, CAIX, LMP2, sLe, HMWMAA, o-acetyl-GD2, folate receptor beta, TEM1/CD248, TEM7R, FAP, Legumain, HPV E6 or E7, ML-IAP, CLDN6, TSHR, GPRC5D, ALK, Polysialic acid, Fos-related antigen, neutrophil elastase, TRP-2, CYP1B1, sperm protein 17, beta human chorionic gonadotropin, AFP, thyroglobulin, PLAC1, globoH, RAGE1, MN-CA IX, human telomerase reverse transcriptase, intestinal carboxyl esterase, mut hsp 70-2, NA-17, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, NY-ESO-1, GPR20, Ly6k, OR51E2, TARP, GFRα4, and a peptide of any of these antigens presented on MHC. In embodiments, the solid tumor antigen is selected from the group consisting of CLDN6, mesothelin and EGFRvIII. 
     In one aspect, the cell includes a second chimeric antigen receptor that includes an antigen binding domain that binds EGFRvII. In embodiments, the antigen binding domain of said second CAR includes 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-EGFRvIII heavy chain binding domain amino acid sequence listed in Table 5. In embodiments, the antigen binding domain of said second CAR further includes a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3) of any anti-EGFRvIII light chain binding domain amino acid sequence listed in Table 5. In embodiments, the antigen binding domain of said second CAR includes: (i) the amino acid sequence of any anti-EGFRvII light chain variable region listed in Table 5; (ii) an amino acid sequence having at least one, two or three modifications but not more than 20 or 10 modifications of the amino acid sequence of any of the anti-EGFRvII light chain variable regions provided in Table 5; or (iii) an amino acid sequence with 95-99% identity to the amino acid sequence of any of the anti-EGFRvIII light chain variable regions provided in Table 5. In embodiments, the antigen binding domain of said second CAR includes: (i) the amino acid sequence of any anti-EGFRvIII heavy chain variable region listed in Table 5; (ii) an amino acid sequence having at least one, two or three modifications but not more than 20 or 10 modifications of the amino acid sequence of any of the anti-EGFRvIII heavy chain variable regions provided in Table 5; or (iii) an amino acid sequence with 95-99%/o identity to the amino acid sequence of any of the anti-EGFRvIII heavy chain variable regions provided in Table 5. In embodiments, the antigen binding domain of said second CAR includes a polypeptide having the amino acid sequence of any anti-EGFRvIII light chain variable region listed in Table 5, and the amino acid sequence of any anti-EGFRvIII heavy chain variable region listed in Table 5. In embodiments, the antigen binding domain of said second CAR includes a polypeptide having a sequence of any of SEQ ID NOS: 71-79. 
     In one aspect, the cell includes a second chimeric antigen receptor that includes an antigen binding domain that binds mesothelin. In embodiments, the antigen binding domain of said second CAR includes 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 heavy chain binding domain amino acid sequence listed in Table 2 or 3. In embodiments, the antigen binding domain of said second CAR further includes a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3) of any light chain binding domain amino acid sequence listed in Table 2 or 4. In embodiments, the antigen binding domain of said second CAR includes: (i) the amino acid sequence of any light chain variable region listed in Table 2; (ii) an amino acid sequence having at least one, two or three modifications but not more than 20 or 10 modifications of the amino acid sequence of any of the light chain variable regions provided in Table 2; or (iii) an amino acid sequence with 95-99% identity to the amino acid sequence of any of the light chain variable regions provided in Table 2. In embodiments, the antigen binding domain of said second CAR includes: (i) the amino acid sequence of any heavy chain variable region listed in Table 2; (ii) an amino acid sequence having at least one, two or three modifications but not more than 20 or 10 modifications of the amino acid sequence of any of the heavy chain variable regions provided in Table 2; or (iii) an amino acid sequence with 95-99% identity to the amino acid sequence of any of the heavy chain variable regions provided in Table 2. In embodiments, the antigen binding domain of said second CAR includes a polypeptide having the amino acid sequence of any light chain variable region listed in Table 2, and the amino acid sequence of any heavy chain variable region listed in Table 2. In embodiments, the antigen binding domain of said second CAR includes a polypeptide having a sequence of any one of SEQ ID NOS: 46-70. 
     In embodiments, including in any of the aforementioned aspects and embodiments, the antigen binding domain of said first CAR is in the format of an scFv. 
     In embodiments, including in any of the aforementioned aspects and embodiments, the antigen binding domain of said second CAR is in the format of an scFv. 
     In embodiments, including in any of the aforementioned aspects and embodiments, the intracellular signaling domain of said first or said second CAR includes one or more primary signaling domains, e.g., as described herein. 
     In embodiments, including in any of the aforementioned aspects and embodiments, the intracellular signaling domains of said first CAR and said second CAR include a primary signaling domain, e.g., as described herein. 
     In embodiments, including in any of the aforementioned aspects and embodiments, the intracellular signaling domain of said first or said second CAR includes one or more costimulatory signaling domains, e.g., as described herein. 
     In embodiments, including in any of the aforementioned aspects and embodiments, the intracellular signaling domains of said first CAR and said second CAR include one or more costimulatory signaling domains, e.g., as described herein. 
     In embodiments, including in any of the aforementioned aspects and embodiments, the primary signaling domains include a CD3-zeta stimulatory domain, e.g., as described herein. In embodiments, including in any of the aforementioned aspects and embodiments, the costimulatory signaling domain is an intracellular domain of a costimulatory protein selected from the group consisting of CD27, CD28, 4-1BB (CD137), OX40, GITR, CD30, CD40, ICOS, BAFFR, HVEM, ICAM-1, lymphocyte function-associated antigen-1 (LFA-1), CD2, CDS, CD7, CD287, LIGHT, NKG2C, NKG2D, SLAMF7, NKp80, NKp30, NKp44, NKp46, CD160, B7-H3, and a ligand that specifically binds with CD83. 
     In one embodiment of any of the methods and compositions described herein, the transmembrane domain of the first CAR molecule, the second CAR molecule, or both the first CAR molecule and second CAR molecule comprises a transmembrane domain from 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 some embodiments, the transmembrane domain of the first CAR, the second CAR, or both the first CAR and second CAR comprises the amino acid sequence of SEQ ID NO: 12, an amino acid sequence comprises at least one, two or three modifications but not more than 20, 10 or 5 modifications of the amino acid sequence of SEQ ID NO: 12, or a sequence with 95-99% identity to the amino acid sequence of SEQ ID NO: 12. 
     In embodiments, the transmembrane domains of the first CAR molecule and second CAR molecule are the same. In other embodiments, the transmembrane domains of the first CAR molecule and second CAR molecule are different. 
     In one embodiment of any of the methods and compositions described herein, the antigen binding domain of the first CAR molecule, the antigen binding domain of the second CAR molecule, or the antigen binding domain of both the first CAR molecule and the second CAR molecule is connected to a transmembrane domain by a hinge region. In some embodiments, the hinge region comprises SEQ ID NO:4, or a sequence with 95-99% identity thereof. 
     In one embodiment of any of the methods and compositions described herein, the intracellular signaling domain of the first CAR molecule, the second CAR molecule or both the first CAR molecule and second CAR molecule comprises a costimulatory signaling domain comprising a functional signaling domain obtained from a protein selected from the group consisting of a MHC class I molecule, a TNF receptor protein, an Immunoglobulin-like protein, a cytokine receptor, an integrin, a signaling lymphocytic activation molecule (SLAM protein), an activating NK cell receptor, 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 some embodiments, the costimulatory domain comprises the amino acid sequence of SEQ ID NO: 14, or an amino acid sequence having at least one, two or three modifications but not more than 20, 10 or 5 modifications of the amino acid sequence of SEQ ID NO: 14, or an amino acid sequence with 95-99% identity to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the intracellular signaling domain comprises a functional signaling domain of 4-1BB and/or a functional signaling domain of CD3 zeta. In some embodiments, the intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 14 and/or the amino acid sequence of SEQ ID NO: 18 or SEQ ID NO:20; or an amino acid sequence having at least one, two or three modifications but not more than 20, 10 or 5 modifications of the amino acid sequence of SEQ ID NO:14 and/or the amino acid sequence of SEQ ID NO:18 or SEQ ID NO:20; or an amino acid sequence with 95-99% identity to the amino acid sequence of SEQ ID NO: 14 and/or the amino acid sequence of SEQ ID NO: 18 or SEQ ID NO:20. In some embodiments, the intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 14 and the amino acid sequence of SEQ ID NO: 18 or SEQ ID NO:20, wherein the amino acid sequences comprising the intracellular signaling domain are expressed in the same frame and as a single polypeptide chain. 
     In some embodiments, the first CAR molecule (e.g., the B-Cell antigen-targeting CAR molecule) comprises an intracellular signaling domain that comprises a costimulatory signaling domain, e.g., as described herein, but does not comprise a primary signaling domain. In other embodiments, the first CAR molecule (e.g., the B-Cell antigen-targeting CAR molecule) comprises an intracellular signaling domain that comprises a costimulatory signaling domain, e.g., as described herein, and a primary signaling domain, e.g., as described herein. 
     In some embodiments, the second CAR molecule (e.g., the tumor antigen-targeting CAR molecule) comprises an intracellular signaling domain that comprises a costimulatory signaling domain, e.g., as described herein, but does not comprise a primary signaling domain. In some embodiments, the second CAR molecule (e.g., the tumor antigen-targeting CAR molecule) comprises an intracellular signaling domain that comprises a primary signaling domain, e.g., as described herein, but does not comprise a costimulatory signaling domain. In other embodiments, the second CAR molecule (e.g., the tumor antigen-targeting CAR molecule) comprises an intracellular signaling domain that comprises a costimulatory signaling domain, e.g., as described herein, and a primary signaling domain, e.g., as described herein. 
     In a preferred embodiment, the first CAR molecule (e.g., the B-Cell antigen-targeting CAR molecule) comprises an intracellular signaling domain that comprises a costimulatory signaling domain, e.g., as described herein, but does not comprise a primary signaling domain, and the second CAR molecule (e.g., the tumor antigen-targeting CAR molecule), comprises an intracellular signaling domain that comprises a costimulatory signaling domain, e.g., as described herein, and a primary signaling domain, e.g., as described herein. 
     In another preferred embodiment, the first CAR molecule (e.g., the B-Cell antigen-targeting CAR molecule) comprises an intracellular signaling domain that comprises a costimulatory signaling domain, e.g., as described herein, and a primary signaling domain, e.g., as described herein, and the second CAR molecule (e.g., the tumor antigen-targeting CAR molecule), comprises an intracellular signaling domain that comprises a costimulatory signaling domain, e.g., as described herein, and a primary signaling domain, e.g., as described herein. 
     In one embodiment of any of the methods and compositions described herein, the first CAR molecule, the second CAR molecule, or both the first CAR molecule and the second CAR molecule further comprises a leader sequence comprising the amino acid sequence of SEQ ID NO:2. 
     In embodiments, including in any of the aforementioned aspects and embodiments, the costimulatory domain of both said first and said second CAR include an intracellular domain of 4-1BB, e.g., as described herein. 
     In embodiments, including in any of the aforementioned aspects and embodiments, the one or more of said costimulatory domains includes an intracellular domain of CD28, e.g., as described herein. 
     In embodiments, including in any of the aforementioned aspects and embodiments, the first or second CAR includes two costimulatory domains: (1) a 4-1BB costimulatory domain, e.g., as described herein; and (2) a CD28 costimulatory domain, e.g., as described herein. 
     In an aspect (including in any of the aforementioned aspects and embodiments that include a BCMA CAR) the antigen binding domain of said first CAR binds BCMA and the first CAR includes a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 949, SEQ ID NO: 950, SEQ ID NO: 951, SEQ ID NO: 952, SEQ ID NO: 953, SEQ ID NO: 954, SEQ ID NO: 955, SEQ ID NO: 956, SEQ ID NO: 957, SEQ ID NO: 958, SEQ ID NO: 959, SEQ ID NO: 960, SEQ ID NO: 961, SEQ ID NO: 962, SEQ ID NO: 963, SEQ ID NO: 979, SEQ ID NO: 980, SEQ ID NO: 981, SEQ ID NO: 982, SEQ ID NO: 983, SEQ ID NO: 984, SEQ ID NO: 985, SEQ ID NO: 986, SEQ ID NO: 987, SEQ ID NO: 988, SEQ ID NO: 989, SEQ ID NO: 990, SEQ ID NO: 991, SEQ ID NO: 992, SEQ ID NO: 993, SEQ ID NO: 994, SEQ ID NO: 995, SEQ ID NO: 996, SEQ ID NO: 997, SEQ ID NO: 998, and SEQ ID NO: 999. 
     In an aspect (including in any of the aforementioned aspects and embodiments that include a CD19 CAR) the antigen binding domain of said first CAR binds CD19 and the first CAR includes a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 269, SEQ ID NO: 270, SEQ ID NO: 271, SEQ ID NO: 272, SEQ ID NO: 273, SEQ ID NO: 274, SEQ ID NO: 275, SEQ ID NO: 276, SEQ ID NO: 277, SEQ ID NO: 278, SEQ ID NO: 279, SEQ ID NO: 280, and SEQ ID NO: 281. 
     In an aspect (including in any of the aforementioned aspects and embodiments that include a EGFRvIII CAR) the antigen binding domain of said second CAR binds EGFRvIII and the second CAR includes a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1043, SEQ ID NO: 1049, SEQ ID NO: 1055, SEQ ID NO: 1061, SEQ ID NO: 1067, SEQ ID NO: 1073, SEQ ID NO: 1079, SEQ ID NO: 1085, SEQ ID NO: 1090, and SEQ ID NO: 1096. 
     In an aspect (including in any of the aforementioned aspects and embodiments that include a mesothelin CAR) the antigen binding domain of said second CAR binds mesothelin and the second CAR includes a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 282, SEQ ID NO: 283, SEQ ID NO: 284, SEQ ID NO: 285, SEQ ID NO: 286, SEQ ID NO: 287, SEQ ID NO: 288, SEQ ID NO: 289, SEQ ID NO: 290, SEQ ID NO: 291, SEQ ID NO: 292, SEQ ID NO: 293, SEQ ID NO: 294, SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, SEQ ID NO: 299, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 305, and SEQ ID NO: 306. 
     In another aspect, the invention provides a cell which includes a CAR, e.g., a bispecific CAR (e.g., as described herein), which includes a first antigen binding domain that binds a B-Cell antigen, e.g., as described herein, a second antigen binding domain that binds a tumor antigen, e.g., as described herein, a transmembrane domain, e.g., as described herein, and an intracellular signaling domain, e.g., as described herein. In embodiments, the first antigen binding domain binds CD19, e.g., includes a CD19 binding domain described herein. In embodiments, the first antigen binding domain binds BCMA, e.g., includes a BCMA binding domain described herein. In embodiments, the second antigen biding domain binds a solid tumor antigen, a myeloid tumor antigen, or an antigen of a hematological tumor not of B-Cell lineage. In embodiments, the second antigen binding domain binds a solid tumor antigen, e.g., as described herein. In embodiments, the second antigen binding domain binds EGFRvIII (e.g., includes a EGFRvIII binding domain described herein). In other embodiments, the second antigen binding domain binds mesothelin (e.g., includes a mesothelin binding domain described herein). In embodiments, the CAR includes a first antigen binding domain to CD19, e.g., as described herein, and a second antigen binding domain to EGFRvIII, e.g., as described herein. In embodiments, the CAR includes a first antigen binding domain to BCMA, e.g., as described herein, and a second antigen binding domain to EGFRvIII, e.g., as described herein. In embodiments, the CAR includes a first antigen binding domain to CD19, e.g., as described herein, and a second antigen binding domain to mesothelin, e.g., as described herein. In embodiments, the CAR includes a first antigen binding domain to BCMA, e.g., as described herein, and a second antigen binding domain to mesothelin, e.g., as described herein. In embodiments, the CAR includes an intracellular signaling domain that includes a CD3z primary signaling domain, e.g., as described herein, and a 4-1BB costimulatory signaling domain, e.g., as described herein. In embodiments, the CAR includes an intracellular signaling domain that includes a CD3z primary signaling domain, e.g., as described herein, and a CD28 costimulatory signaling domain, e.g., as described herein. 
     In an aspect (including in any of the aforementioned aspects and embodiments), the cell is derived from a patient diagnosed with a myeloid tumor, or a hematological tumor not of B-Cell lineage. 
     In an aspect (including in any of the aforementioned aspects and embodiments), the patient is diagnosed with a myeloid tumor expressing an antigen selected from the group consisting of CD123, CD33 and CLL-1. 
     In an aspect (including in any of the aforementioned aspects and embodiments), the cell is derived from a patient diagnosed with a solid tumor. In embodiments, the patient is diagnosed with a solid tumor expressing an antigen selected from the group consisting of: EGFRvIII, mesothelin, GD2, Tn Ag, PSMA, TAG72, CD44v6, CEA, EPCAM, KIT, IL-13Ra2, GD3, CD171, IL-11Ra, PSCA, VEGFR2, LewisY, CD24, PDGFR-beta, SSEA-4, folate receptor alpha, ERBB2, Her2/neu, MUC1, EGFR, NCAM, Ephrin B2, CAIX, LMP2, sLe, HMWMAA, o-acetyl-GD2, folate receptor beta, TEM1/CD248, TEM7R, FAP, Legumain, HPV E6 or E7, CLDN6, TSHR, GPRC5D, ALK, Plysialic acid, PLAC1, globoH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, Ly6k, OR51E2, TARP, and GFRα4. 
     In an aspect (including in any of the aforementioned aspects and embodiments), the cell is a human cell and is not derived from a patient diagnosed with a tumor. 
     In an aspect (including in any of the aforementioned aspects and embodiments), the cell is a T cell, a natural killer (NK) cell, a cytotoxic T lymphocyte (CTL), a tumor infiltrating lymphocyte (TIL), or a regulatory T cell. 
     In another aspect, the invention provides a method for stimulating a T cell-mediated immune response to a myeloid tumor cell in a mammal, the method including administering to a mammal an effective amount of a cell as described herein, e.g., a cell of any of the aforementioned aspects and embodiments. 
     In another aspect, the invention provides a method of providing an anti-myeloid tumor, immunity in a mammal, including administering to the mammal an effective amount of a cell as described herein, e.g., in any of the aforementioned aspects and embodiments. 
     In another aspect, the invention provides a method of treating a mammal having a disease associated with expression of a myeloid tumor antigen, said method including administering an effective amount of a cell as described herein, e.g., in any of the aforementioned aspects and embodiments. 
     In embodiments of the aspects involving a method for stimulating a T cell-mediated immune response to a myeloid tumor cell in a mammal, a method of providing an anti-myeloid tumor, immunity in a mammal and/or a method of treating a mammal having a disease associated with expression of a myeloid tumor antigen, the myeloid tumor expresses an antigen selected from the group consisting of CD123, CD33 and CLL-1. In embodiments, the mammal has a tumor characterized as acute myeloid leukemia (AML), acute lymphoblastic B-cell leukemia (B-cell acute lymphoid leukemia, BALL), acute lymphoblastic T-cell leukemia (T cell acute lymphoid leukemia (TALL)), B-cell prolymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia (CML), myelodysplastic syndrome, plasma cell myeloma, or a combination thereof. 
     In another aspect, the invention provides a method for stimulating a T cell-mediated immune response to a hematological tumor not of B-cell lineage, e.g., a T cell lymphoma tumor cell in a mammal, the method including administering to a mammal an effective amount of a cell as described herein, e.g., a cell of any of the aforementioned aspects and embodiments. In another aspect, the invention provides a method of providing immunity to an anti-hematological tumor not of B-cell lineage, e.g., an anti-T cell lymphoma tumor immunity, in a mammal, including administering to the mammal an effective amount of a cell as described herein, e.g., in any of the aforementioned aspects and embodiments. 
     In another aspect, the invention provides a method of treating a mammal having a disease associated with expression of an antigen of a hematological tumor not of B-cell lineage, e.g., a T cell lymphoma tumor antigen, said method including administering an effective amount of a cell as described herein, e.g., in any of the aforementioned aspects and embodiments. 
     In another aspect, the invention provides a method for stimulating a T cell-mediated immune response to a solid tumor cell in a mammal, the method including administering to a mammal an effective amount of a cell as described herein, e.g., a cell of any of the aforementioned aspects and embodiments. 
     In another aspect, the invention provides a method of providing an anti-solid tumor, immunity in a mammal, including administering to the mammal an effective amount of a cell as described herein, e.g., in any of the aforementioned aspects and embodiments. 
     In another aspect, the invention provides a method of treating a mammal having a disease associated with expression of a solid tumor antigen, said method including administering an effective amount of a cell as described herein, e.g., in any of the aforementioned aspects and embodiments. 
     In embodiments of the aspects involving a method for stimulating a T cell-mediated immune response to a solid tumor cell in a mammal, a method of providing an anti-solid tumor, immunity in a mammal and/or a method of treating a mammal having a disease associated with expression of a solid tumor antigen, the solid tumor cell expresses an antigen selected from the group consisting of: EGFRvIII, mesothelin, CS-1, GD2, Tn Ag, PSMA, TAG72, CD44v6, CEA, EPCAM, KIT, IL-13Ra2, GD3, CD171, IL-11Ra, PSCA, VEGFR2, LewisY, CD24, PDGFR-beta, SSEA-4, folate receptor alpha, ERBB2, Her2/neu, MUC1, EGFR, NCAM, Ephrin B2, CAIX, LMP2, sLe, HMWMAA, o-acetyl-GD2, folate receptor beta, TEM1/CD248, TEM7R, FAP, Legumain, HPV E6 or E7, CLDN6, TSHR, GPRC5D, ALK, Plysialic acid, PLAC1, globoH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, Ly6k, OR51E2, TARP, and GFRα4, e.g., EGFRvIII or mesothelin. In embodiments, the mammal has a tumor characterized as glioblastoma, ovarian cancer, lung cancer, prostate cancer, colorectal cancer, pancreatic cancer, breast carcinoma, adenocarcinoma or mesothelioma. 
     In some embodiments, the solid tumor antigen is present in/on a mesothelioma (e.g., a malignant pleural mesothelioma), a lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, squamous cell lung cancer, or large cell lung cancer), a pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), an esophageal adenocarcinoma, an ovarian cancer, a breast cancer, a colorectal cancer, a bladder cancer or any combination thereof, or a metastasis of any of the aforementioned cancers. In one embodiment of any of the methods and compositions described herein, the disease associated with expression of the tumor antigen is a pancreatic cancer, e.g., a metastatic pancreatic ductal adenocarcinoma (PDA). In one embodiment, the pancreatic cancer is in a subject who has progressed on at least one prior standard therapy. In one embodiment, the disease is mesothelioma (e.g., malignant pleural mesothelioma), e.g., in a subject who has progressed on at least one prior standard therapy. In one embodiment, the disease is ovarian cancer, e.g., serous epithelial ovarian cancer, e.g., in a subject who has progressed after at least one prior regimen of standard therapy. In one embodiment, the disease is mesothelioma, malignant pleural mesothelioma, non-small cell lung cancer, small cell lung cancer, squamous cell lung cancer, or large cell lung cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, pancreatic metastatic, esophageal adenocarcinoma, breast cancer, ovarian cancer, colorectal cancer and bladder cancer, or any combination thereof. 
     In embodiments, the cells are autologous to the treated mammal. 
     In embodiments, the cells are allogeneic to the treated mammal. 
     In embodiments, the mammal is a human. 
     In another aspect, the invention provides a method, including any of the aforementioned methods, wherein the administering of the cells of the invention, e.g., as described herein, results in partial or complete elimination of said tumor cells and, thereafter, continue to persist in said subject at a level greater than, or for a length of time longer than, otherwise identical cells that lack the first CAR. 
     In embodiments of the methods described herein, the mammal is administered a lymphodepleting therapy prior to, concurrently with, or after administration of said cells. 
     In embodiments of the methods described herein, mammal is not administered a lymphodepleting therapy prior to or concurrently with administration of said cells. 
     In embodiments of any of the methods and compositions described herein, the method can further comprise administering a lymphodepleting agent. In one embodiment, the lymphodepleting agent reduces the level of T cells, e.g., regulatory T cells, and/or regulatory B cells, as compared to the level prior to administration of the lymphodepleting agent. In one embodiment, the lymphodepleting agent comprises fludarabine, cyclophosphamide, corticosteroids, alemtuzumab, or total body irradiation (TBI), or a combination thereof. 
     Any of the methods and compositions described herein can further comprise administering an additional therapeutic agent that treats the disease associated with a tumor antigen. In one embodiment, the additional therapeutic agent is an anti-cancer therapeutic agent. 
     In another aspect, the invention provides a nucleic acid encoding the first CAR and the second CAR of any one of the aforementioned aspects and embodiments, e.g., as described herein. In embodiments, the sequence of said first CAR and said second CAR are separated by an independent ribosomal entry site, a promoter element, or a sequence encoding a T2A, P2A, E2A, or F2A element. 
     In another aspect, the invention provides a vector including the nucleic acid of the aforementioned aspect and embodiments, e.g., as described herein. In embodiments, the vector is a lentiviral vector. 
     In another aspect, the invention provides a composition including a first nucleic acid encoding the first CAR (e.g., a CAR comprising a binding domain to a B-Cell antigen, e.g., as described herein) of any one of the preceding aspects and embodiments, and a second nucleic acid encoding the second CAR (e.g., a CAR comprising a biding domain to a tumor antigen, e.g., as described herein) of any one of the preceding aspects and embodiments. In embodiments, the first and the second nucleic acids are included within separate vectors. In embodiments, the vectors are lentiviral vectors. 
     In another aspect, the invention provides a method of generating the cell of any one of the aforementioned aspects and embodiments, e.g., a cell as described herein, including introducing into said cell the nucleic acid of any one of the preceding nucleic acid aspects and embodiments, e.g., as described herein, the vector of any one of the preceding vector aspects and embodiments, e.g., as described herein, or the composition of any one of the preceding composition aspects and embodiments, e.g., as described herein. 
     In another aspect, the invention provides a method of generating the cell of any one of the preceding aspects and embodiments, including introducing into said cell a first vector including nucleic acid encoding the first CAR of any one of the aforementioned aspects and embodiments, e.g., as described herein, and introducing into said cells a second vector including nucleic acid encoding the second CAR of any one of the aforementioned aspects and embodiments, e.g., as described herein. In embodiments, the introduction of said first vector and said second vector is simultaneous. In embodiments, the introduction of said first vector and said second vector is sequential. 
     In another aspect, the invention provides a cell including nucleic acid encoding the first CAR of any one of the aforementioned aspects and embodiments, e.g., as described herein, and the second CAR of any one of the aforementioned aspects and embodiments, e.g., as described herein. 
     In another aspect, the invention provides a cell described herein, e.g., a cell expressing a CAR which binds a B-Cell antigen, e.g., described herein, and expressing a CAR which binds a tumor antigen other than a B-Cell antigen, e.g., described herein, for use as a medicament. In another aspect, the invention provides a cell described herein, e.g., a cell expressing a CAR which binds a B-Cell antigen, e.g., described herein, and expressing a CAR which binds a tumor antigen other than a B-Cell antigen, e.g., described herein, for use as a medicament for the treatment of a disease associated with the expression of the tumor antigen other than a B-Cell antigen. In another aspect, the invention provides a cell described herein, e.g., a cell expressing a CAR which binds a B-Cell antigen, e.g., described herein, and expressing a CAR which binds a tumor antigen other than a B-Cell antigen, e.g., described herein, for use as a medicament for the treatment of cancer, e.g., a cancer expressing the tumor antigen other than a B-Cell antigen. In another aspect, the invention provides a cell described herein, e.g., a cell expressing a CAR which binds a B-Cell antigen, e.g., described herein, and expressing a CAR which binds a tumor antigen other than a B-Cell antigen, e.g., described herein; a nucleic acid described herein; or a composition described herein; for use in the manufacture of a medicament. 
     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 disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. 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 
         FIG. 1  shows a diagram of a nucleic acid construct for bicistronic expression of a B-cell antigen CAR and a solid tumor antigen CAR. The top construct encodes a CD19 CAR (B-cell antigen CAR) and an EGFRvII CAR (solid tumor CAR), separated by a P2A protease cleavage site. The bottom construct encodes a CD19 CAR (B-cell antigen CAR) and a Mesothelin CAR (solid tumor CAR), separated by a P2A protease cleavage site. 
         FIG. 2 , shows a diagram of a set of nucleic acid constructs for expression of a B-cell antigen CAR and a solid tumor antigen CAR A first construct encodes a CD19 CAR (B-cell antigen CAR) and a second construct encodes a EGFRvIII CAR (solid tumor CAR). The constructs may be provided in separate vectors, e.g., separate lentiviral vectors. Cells are transfected with the set of constructs to express both the B-cell antigen CAR and the solid tumor antigen CAR 
     
    
    
     DETAILED DESCRIPTION 
     Methods and compositions for treating a disease associated with expression of a tumor antigen, e.g., a cancer, in a subject using an immune effector cell (e.g., T cell) engineered to expresss a first chimeric antigen receptor (CAR) and a second CAR, wherein the antigen binding domain of said first CAR binds to a B-Cell antigen and the antigen binding domain of said second CAR binds to a tumor antigen other than a B-Cell antigen, e.g., to enhance the efficacy (e.g., the persistence and/or proliferation of the CAR-expressing immune effector cell in a patient) of the CAR-expressing immune effector cell therapy. Without wishing to be bound by theory, treatment with an immune effector cell expressing a CAR targeting a B-Cell antigen and a CAR targeting a tumor antigen enhances the anti tumor efficacy of the CAR-expressing immune effector cell in a subject, e.g., by one or more of: increasing the proliferation of said CAR-expressing immune effector cells and/or increasing the in vivo persistence of said CAR expressing immune effector cells, e.g., as compared to administering an immune effector cell expressing only the tumor-targeting CAR (e.g., not expressing the CAR targeting a B-Cell antigen). 
     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 “Chimeric Antigen Receptor” or alternatively a “CAR” refers to a recombinant polypeptide construct comprising 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 as defined below. In some embodiments, the domains in the CAR polypeptide construct are in the same polypeptide chain, e.g., comprise a chimeric fusion protein. In some embodiments, the domains in the CAR polypeptide construct are not contiguous with each other, e.g., are in different polypeptide chains, e.g., as provided in an RCAR as described herein. 
     In one aspect, the stimulatory molecule is the zeta chain associated with the T cell receptor complex. 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 4-1BB (i.e., CD137), CD27, ICOS, 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 co-stimulatory 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 co-stimulatory 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 co-stimulatory 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 recognition domain (e.g., a scFv) during cellular processing and localization of the CAR to the cellular membrane. 
     A CAR that comprises an antigen binding domain (e.g., a scFv, or TCR) that targets, e.g., binds to, a specific antigen X, such as those described herein, is also referred to as XCAR, X-CAR or X-targeting CAR. For example, a CAR that comprises an antigen binding domain that targets CD19 is referred to as CD19CAR. A CAR that comprises an antigen binding domain (e.g., a scFv or TCR) that targets a specific tumor antigen (TA), such as those described herein, is also referred to as TA CAR. A CAR that comprises an antigen binding domain (e.g., a scFv or TCR) that targets a specific B cell antigen (BCA), such as those described herein (e.g. in connection with the first CAR molecule of the compositions of the invention), is also referred to as BCA CAR 
     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. In some aspects, the signaling domain of the CAR described herein is derived from a stimulatory molecule or co-stimulatory molecule described herein, or is a synthesized or engineered signaling domain. 
     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 intact antibody, or recombinant variants thereof, and refers to the antigen binding domain, e.g., an antigenic determining variable region of an intact antibody, that is sufficient to confer recognition and specific binding of the antibody fragment to a target, such as an antigen. Examples of antibody fragments include, but are not limited to, Fab, Fab′, F(ab′) 2 , and Fv fragments, scFv antibody fragments, linear antibodies, single domain antibodies such as sdAb (either VL or VH), camelid VHH domains, and multi-specific antibodies formed from antibody fragments such as a bivalent fragment comprising two Fab fragments linked by a disulfide brudge 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 I (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 via 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. 
     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, scFv antibody fragments, linear antibodies, single domain antibodies such as sdAb (either VL or VH), camelid VHH domains, a humanized antibody, a bispecific antibody, an antibody conjugate (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 of the invention comprises an antibody fragment. In a further aspect, the CAR comprises an antibody fragment that comprises a scFv. 
     As used herein, the term “binding domain” or “antibody molecule” (also referred to herein as “anti-target (e.g., CD19) binding domain”) 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 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 (κ) and lambda (λ) 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 disclosure 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 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 term “anti-tumor effect” or “anti-tumor activity” 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 the number of metastases, an increase in life expectancy, decrease in tumor cell proliferation, decrease in tumor cell survival, or amelioration of various physiological symptoms associated with the cancerous condition. An “anti-tumor effect” can also be manifested by the ability of the peptides, polynucleotides, cells and antibodies of the invention in prevention of the occurrence of tumor in the first place. 
     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 “apheresis” as used herein refers to an 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, in the context of “an apheresis sample” refers to a sample obtained using apheresis. 
     The term “cancer” refers to a disease characterized by the uncontrolled growth of aberrant cells. Cancer includes all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues or organs irrespective of the histopathologic type or stage of invasiveness. 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. 
     “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 connotate 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 connotate 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 phrase “disease associated with expression of a tumor antigen” includes, but is not limited to, a disease associated with expression of a tumor antigen as described herein or condition associated with cells which express a tumor antigen as described herein 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 a tumor antigen as described herein. In one aspect, a cancer associated with expression of a tumor antigen as described herein is a hematological cancer. In one aspect, a cancer associated with expression of a tumor antigen as described herein is a solid cancer. Further diseases associated with expression of a tumor antigen described herein include, but not limited to, e.g., atypical and/or non-classical cancers, malignancies, precancerous conditions or proliferative diseases associated with expression of a tumor antigen as described herein. Non-cancer related indications associated with expression of a tumor antigen as described herein include, but are not limited to, e.g., autoimmune disease, (e.g., lupus), inflammatory disorders (allergy and asthma) and transplantation. 
     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, such as downregulation of TGF-β, and/or reorganization of cytoskeletal structures, and the like. 
     The term “stimulatory molecule,” refers to a molecule expressed by an immune effector cell (e.g., a T cell, NK cell, B cell) that provides the cytoplasmic signaling sequence(s) that regulate activation of the immune effector cell in a stimulatory way for at least some aspect of the immune effector cell signaling pathway, e.g., the T 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 primary 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, CD5, CD22, CD79a, CD79b, CD278 (also known as “ICOS”), FcεRI, DAP10, DAP12, and CD66d. 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: 18, 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:20, 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. 
     An “intracellular signaling domain,” as the term is used herein, refers to an intracellular portion of a molecule. The intracellular signaling domain generates a signal that promotes an immune effector function of the CAR-expressing cell, e.g., a CART cell or CAR-expressing NK cell. Examples of immune effector function, e.g., in a CART cell or CAR-expressing NK cell, include cytolytic activity and helper activity, including the secretion of cytokines. 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. In an embodiment, the intracellular signaling domain is synthesized or engineered. For example, in the case of a CAR-expressing immune effector cell, e.g., CART cell or CAR-expressing NK cell, a primary intracellular signaling domain can comprise a cytoplasmic sequence of a T cell receptor, 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, common FcR gamma (FCER1G), Fc gamma RIIa, FcR beta, CD3 gamma, CD3 delta, CD3 epsilon, CD5, CD22, CD79a, CD79b, CD278 (“ICOS”), FcεRI CD66d, DAP10 and DAP12. 
     The term “zeta” or alternatively “zeta chain”, “CD3-zeta” or “TCR-zeta” is defined as the protein provided as GenBan Ace. 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 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: 18. In one aspect, the “zeta stimulatory domain” or a “CD3-zeta stimulatory domain” is the sequence provided as SEQ ID NO:20. Also encompassed herein are CD3 zeta domains comprising one or more mutations to the amino acid sequences described herein, e.g., SEQ ID NO: 20. 
     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 are required for an efficient immune response. Costimulatory molecules include, but are not limited to an MHC class I molecule, a TNF receptor protein, an Immunoglobulin-like protein, a cytokine receptor, an integrin, a signaling lymphocytic activation molecule (SLAM protein), an activating NK cell receptor, 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 or costimulatory signaling domain can be 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 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: 14 or the equivalent residues from a non-human species, e.g., mouse, rodent, monkey, ape and the like. 
     “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 (NKT) 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. 
     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 antibody 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 disclosure, 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. Unless specifically limited, the term encompasses nucleic acids containing known analogues 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. 
     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 terms “B cell antigen” or “B-Cell antigen” are used interchangeably, and refer to a molecule (typically a protein, carbohydrate or lipid) that is preferentially and specifically expressed on the surface of a B cell which can be targeted with an agent which binds thereto. The B cell antigen of particular interest is preferentially expressed on B cells compared to other non-B cell tissues of a mammal. The B cell antigen may be expressed on one particular B cell population, e.g., B cell precursors or mature B cells, or on more than one particular B cell population, e.g., both precursor B cells and mature B cells. Exemplary B cell surface markers include: CD5, CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD27, CD30, CD34, CD37, CD38, CD40, CD53, CD69, CD72, CD73, CD74, CD75, CD77, CD79a, CD79b, CD80, CD81, CD82, CD83, CD84, CD85, CD86, CD123, CD135, CD138, CD179, CD269, Flt3, ROR1, BCMA, FcRn5, FcRn2, CS-1, CXCR4, 5, 7, IL-7/3R, IL7/4/3R, and IL4R Particularly preferred B-Cell antigens include: CD19, CD20, CD22, FcRn5, FcRn2, BCMA, CS-1 and CD138. In embodiments, the B-Cell antigen is CD19. In embodiments, the B-Cell antigen is CD20. In embodiments, the B-Cell antigen is CD22. In embodiments, the B-Cell antigen is BCMA. In embodiments, the B-Cell antigen is FcRn5. In embodiments, the B-Cell antigen is FcRn2. In embodiments, the B-Cell antigen is CS-1. In embodiments, the B-Cell antigen is CD138. 
     The terms “cancer associated antigen” or “tumor antigen” interchangeably refers to a molecule (typically a protein, carbohydrate or lipid) that is expressed on the surface of a cancer cell, either entirely or as a fragment (e.g., MHC/peptide), 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 some embodiments, a tumor 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 tumor 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 tumor 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 disclosure 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. 2011 85(5):1935-1942; Sergeeva et al., Blood, 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. Accordingly, the present disclosure provides CARs that comprise an antigen binding domain that binds to a MHC presented peptide of a molecule selected from the group of WT1, NY-ESO-1, LAGE-1a, MAGE-A1 and RAGE-1. 
     The terms “solid tumor antigen” or “solid tumor cell antigen” refer to a molecule (typically a protein, carbohydrate or lipid) that is preferentially and specifically expressed on the surface of a solid tumor cell which can be targeted with an agent which binds thereto. The solid tumor antigen of particular interest is preferentially expressed on a solid tumor cell compared to other non-tumor tissues of a mammal. The solid tumor antigen may be expressed on one particular solid tumor cell population, e.g., on mesothelioma tumor cells, or on more than one particular solid tumor cell population, e.g., both mesothelioma tumor cells and ovarian cancer cells. Exemplary solid tumor antigens include: EGFRvIII, mesothelin, GD2, Tn Ag, PSMA, TAG72, CD44v6, CEA, EPCAM, KIT, IL-13Ra2, leguman, GD3, CD171, IL-11Ra, PSCA, MAD-CT-1, MAD-CT-2, VEGFR2, LewisY, CD24, PDGFR-beta, SSEA-4, folate receptor alpha, ERBBs (e.g., ERBB2), Her2/neu, MUC1, EGFR, NCAM, Ephrin B2, CAIX, LMP2, sLe, HMWMAA, o-acetyl-GD2, folate receptor beta, TEM1/CD248, TEM7R, FAP, Legumain, HPV E6 or E7, ML-IAP, CLDN6, TSHR, GPRC5D, ALK, Polysialic acid, Fos-related antigen, neutrophil elastase, TRP-2, CYP1B, sperm protein 17, beta human chorionic gonadotropin, AFP, thyroglobulin, PLAC1, globoH, RAGE1, MN-CA IX, human telomerase reverse transcriptase, intestinal carboxyl esterase, mut hsp 70-2, NA-17, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, Ly6k, OR51E2, TARP, GFRα4, and a peptide of any of these antigens presented on MHC. Particularly preferred solid tumor antigens include: CLDN6, mesothelin and EGFRvIII. 
     The terms “myeloid tumor antigen” or “myeloid tumor cell antigen” refer to a molecule (typically a protein, carbohydrate or lipid) that is preferentially and specifically expressed on the surface of a myeloid tumor cell which can be targeted with an agent which binds thereto. The myeloid tumor antigen of particular interest is preferentially expressed on a myeloid tumor cell compared to other non-tumor tissues of a mammal. The myeloid tumor antigen may be expressed on one particular myeloid tumor cell population, e.g., on acute myeloid leukemia (AML) tumor cells, or on more than one particular myeloid tumor cell population. Exemplary myeloid tumor antigens include: CD123, CD33 and CLL-1. 
     The term “antigen of a hematological tumor not of B-Cell lineage” refers to a molecule (typically a protein, carbohydrate or lipid) that is preferentially and specifically expressed on the surface of a tumor or cancer of hematopoietic or lymphoid tissue origin, other than of B-Cell origin. These include tumors of myeloid lineage origin, e.g., tumors derived from granulocyte, erythrocyte, thrombocyte, macrophage and/or mast cell origin, or any of their precursor cell populations, and tumors of lymphoid origin other than B-Cell origin, e.g., T cell, NK cell and/or plasma cell origin, or any of their precursor cell populations. 
     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 and n=6, n=7, n=8, n=9 and n=10 (SEQ ID NO:28). In one embodiment, the flexible polypeptide linkers include, but are not limited to, (Gly4 Ser) 4  (SEQ ID NO:29) or (Gly4 Ser) 3  (SEQ ID NO:30). In another embodiment, the linkers include multiple repeats of (Gly2Ser), (GlySer) or (Gly3Ser) (SEQ ID NO:31). 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 critical 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, preferably 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 the preferred embodiment of a construct for transient expression, the polyA is between 50 and 5000 (SEQ ID NO: 34), preferably greater than 64, more preferably greater than 100, most preferably greater 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. 
     As used herein, the terms “treat”, “treatment” and “treating” refer to the reduction or amelioration of the progression, severity and/or duration of a proliferative disorder, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a proliferative disorder resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a CAR of the invention). In specific embodiments, the terms “treat,” “treatment” and “treating” refer to the amelioration of at least one measurable physical parameter of a proliferative disorder, such as growth of a tumor, not necessarily discernible by the patient. In other embodiments the terms “treat”, “treatment” and “treating”-refer to the inhibition of the progression of a proliferative disorder, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In other embodiments the terms “treat”, “treatment” and “treating” refer to the reduction or stabilization of tumor size or cancerous cell count. 
     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 “tolerance” or “immune tolerance” as used herein refers to a state in which a subject has a reduced or absent immune response to a specific antigen or group of antigens to which the subject is normally responsive to. Tolerance is achieved under conditions that suppress the immune reaction and is not just the absence of an immune response. In an embodiment, tolerance in a subject can be characterized by one or more of the following: a decreased level of a specific immunological response (e.g., mediated by antigen-specific effector T lymphocytes, B lymphocytes, or antibody); a delay in the onset or progression of a specific immunological response; or a reduced risk of the onset or progression of a specific immunological response, as compared to untreated subjects. 
     The term “prophylaxis” as used herein means the prevention of or protective treatment for a disease or disease state. 
     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. 
     The term “specifically binds,” refers to an antibody, or a ligand, which recognizes and binds with a cognate binding partner (e.g., a stimulatory and/or costimulatory molecule present on a T cell) protein present in a sample, but which antibody or ligand, does not substantially recognize or bind other molecules in the sample. 
     “Regulatable chimeric antigen receptor (RCAR),” as used herein, 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 regulatable intracellular signal generation. In some embodiments, an RCAR comprises at least an extracellular antigen binding domain, a transmembrane 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 herein in the context of a CAR molecule. In some embodiments, the set of polypeptides in the RCAR are not contiguous with each other, e.g., are in different polypeptide chains. In some embodiments, the RCAR includes 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 some embodiments, the RCAR is expressed in a cell (e.g., an immune effector cell) as described herein, e.g., an RCAR-expressing cell (also referred to herein as “RCARX cell”). In an embodiment the RCARX cell is a T cell, and is referred to as a RCART cell. In an embodiment the RCARX cell is an NK cell, and is referred to as a RCARN cell. The RCAR can provide the RCAR-expressing 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 RCAR-expressing cell. In embodiments, an RCAR 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. 
     “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 “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 “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 naive 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. 
     “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. 
     “Relapsed” or “relapse” as used herein refers to the return or reappearance of a disease (e.g., cancer) or the signs and symptoms of a disease such as cancer after a period of improvement or responsiveness, e.g., after prior treatment of a therapy, e.g., cancer therapy. The initial period of responsiveness may involve the level of cancer cells falling below a certain threshold, e.g., below 200, 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. 
     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 
     Provided herein are compositions and methods of use for the treatment of a disease, such as cancer, comprising the use of a cell, e.g., an immune effector cell (e.g., an NK cell or T cell) engineered to express a first CAR molecule that targets a B-Cell antigen (e.g., a BCA CAR) and a second CAR molecule that targets a tumor antigen (e.g., a TA CAR). In an embodiment, the disease is a cancer, such as a solid tumor, myeloid tumor or hematological tumor not of B-Cell lineage. In an embodiment, the tumor is a solid tumor. In an embodiment, the tumor is a myeloid tumor. In an embodiment, the tumor is a hematological tumor not of B-Cell lineage. 
     In embodiments, the compositions and methods described herein result in a tumor-targeting CAR-expressing immune effector cell with enchanted proliferation and/or with increased or prolonged in vivo persistence, relative to the same cell which does not express the BCA CAR. 
     Without wishing to be bound by theory, treatment with a cell, e.g., an immune effector cell expressing a CAR targeting a B-Cell antigen (BCA CAR) on an immune effector cell expressing a CAR targeting a tumor antigen (TA CAR) enhances the anti tumor efficacy of the TA CAR-expressing immune effector cell in a subject, e.g., by one or more of: increasing the proliferation of said CAR-expressing immune effector cells and/or increasing the in vivo persistence of said CAR expressing immune effector cells, e.g., as compared to administering an immune effector cell expressing only the TA CAR (e.g., not expressing the BCA CAR). Without being bound by theory, CAR cell therapies targeting, e.g., solid tumors, may suffer from lack of persistence in vivo as cells expressing the tumor antigen targeted by the CAR become inaccessible, or drop in number due to the effect of the CAR expressing cell. In contrast, CAR-T cell therapy targeting B-Cell antigens such as, for example, CD19, exhibit rapid and significant expansion in vivo, followed by long-term persistence. Without being bound by theory, these beneficial effects observed for CAR-T cell therapy targeting B-Cell antigens may be mediated by the widespread (i.e., circulating) availability of B-Cells which allows cells expressing a B-Cell antigen-targeting CAR to be exposed to, and be stimulated by, this readily available cell population and may further be enhanced by the natural immune-stimulatory effects of B-cell/T-cell interaction. Thus, without being bound by theory, inclusion of a CAR targeting a B-cell antigen is beneficial in that it mediates rapid expansion and persistence of the CART cell expressing said CAR, and that when the CAR cell further expresses a tumor antigen, such cell benefits from those effects relative to a CAR T cell which only expresses the tumor antigen-targeting CAReven when populations of cells expressing the tumor antigen are low, inaccessible or non-existent, thereby allowing the CART cells be primed for mediating improved cytotoxicity against the tumor antigen-expressing cell, e.g., cancer, and to persist through periods of remission and can then become effective in periods of relapse, without having to readminister cells. Thus, administering cells, e.g., immune effector cells, expressing both a BCA CAR and a TA CAR can enhance the efficacy of a TA CAR-expressing cell for treating a disease, e.g., cancer. 
     The cells of the present disclosure are genetically engineered to express a first CAR molecule, wherein the first CAR molecule comprises an antigen binding domain specific for a B-Cell antigen, and genetically engineered to express a second CAR molecule, wherein the second CAR molecule comprises an antigen binding domain specific for a tumor antigen. In embodiments, the B-cell antigen is not expressed on the cell which expresses the tumor antigen. The antigen binding domain binds to a B cell antigen described herein or a tumor antigen described herein. A CAR molecule that binds to a B cell antigen is also referred to herein as “BCA CAR”. A CAR molecule that binds to a tumor antigen other than a B-Cell antigen, e.g., a solid tumor antigen, a myeloid tumor antigen, or an antigen of a hematological tumor not of B-Cell origin, is also referred to herein as “TA CAR”. The CAR may further comprise a transmembrane domain and an intracellular signaling domain comprising a costimulatory domain and/or a primary signaling domain, e.g., as described herein. In an embodiment, the intracellular signaling domain of the BCA CAR and/or TA CAR includes, but is not limited to, one or more of a CD3-zeta chain, 4-1BB, CD27, ICOS, and CD28 signaling modules and combinations thereof. 
     In one aspect, the invention provides an immune effector cell (e.g., T cell, NK cell) engineered to express a TA CAR and engineered to express a BCA CAR, wherein the engineered immune effector cell exhibits an antitumor property, e.g., reduces tumor volume, stimulates tumor regression, decreases tumor burden, or increases overall survival; while at the same time having increased persistence in vivo, or increased proliferation, relative to the same cell which does not express the BCA CAR. 
     Also described herein are methods of using said cells engineered to express a BCA CAR and a TA CAR. 
     Also described herein are methods of making or selecting a cell engineered to express a BCA CAR and a TA CAR, methods for administering the cells for treating a disease associated with a tumor antigen, and additional combination therapies for use with the cells of the invention. 
     Chimeric Antigen Receptor (CAR) 
     The present disclosure encompasses immune effector cells (e.g., T cells or NK cells) comprising one or more recombinant nucleic acid constructs comprising sequences encoding a CAR molecule that binds to a tumor antigen (e.g., a TA CAR) and a CAR molecule that binds to a B cell antigen (e.g., a BCA CAR), wherein the TA CAR comprises an antigen binding domain (e.g., antibody or antibody fragment, TCR or TCR fragment) that binds specifically to a tumor antigen described herein and the BCA CAR comprises an antigen binding domain (e.g., antibody or antibody fragment, TCR or TCR fragment) that binds specifically to a B cell antigen described herein, e.g., wherein the sequence of the antigen binding domain 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 aspect, the CARs of the invention comprise at least one intracellular signaling domain selected from the group of a CD137 (4-1BB) signaling domain, a CD28 signaling domain, a CD27 signaling domain, an ICOS signaling domain, a CD3zeta signal domain, and any combination thereof. In one aspect, the CARs of the invention comprise at least one intracellular signaling domain is from one or more costimulatory molecule(s) selected from CD137 (4-1BB), CD28, CD27, or ICOS. 
     Sequences of non-limiting examples of various components that can be part of a CAR molecule, e.g., a TA CAR or a BCA CAR described herein, are listed in Table 1, where “aa” stands for amino acids, and “na” stands for nucleic acids that encode the corresponding peptide. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Sequences of various components of CAR (aa-amino acids; 
               
               
                 na-nucleic acids that encodes the corresponding protein 
               
            
           
           
               
               
               
            
               
                 SEQ 
                   
                   
               
               
                 ID NO 
                 Description 
                 Sequence 
               
               
                   
               
               
                   1 
                 EF-1 
                 CGTGAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAG 
               
               
                   
                 promoter (na) 
                 TTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTG 
               
               
                   
                   
                 GAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATAT 
               
               
                   
                   
                 AAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGG 
               
               
                   
                   
                 TAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTG 
               
               
                   
                   
                 CCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGG 
               
               
                   
                   
                 AAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAG 
               
               
                   
                   
                 TTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCC 
               
               
                   
                   
                 TGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGAC 
               
               
                   
                   
                 GCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTT 
               
               
                   
                   
                 CGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCG 
               
               
                   
                   
                 AGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCG 
               
               
                   
                   
                 GCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGC 
               
               
                   
                   
                 TGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCA 
               
               
                   
                   
                 GGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACA 
               
               
                   
                   
                 AAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGG 
               
               
                   
                   
                 CGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGG 
               
               
                   
                   
                 GGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAG 
               
               
                   
                   
                 GCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTT 
               
               
                   
                   
                 GGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCG 
               
               
                   
                   
                 TGA 
               
               
                   
               
               
                   2 
                 Leader (aa) 
                 MALPVTALLLPLALLLHAARP 
               
               
                   
               
               
                   3 
                 Leader (na) 
                 ATGGCCCTGCCTGTGACAGCCCTGCTGCTGCCTCTGGCTCTGCTGCTGCATGCCGCTAG 
               
               
                   
                   
                 ACCC 
               
               
                   
               
               
                 307 
                 Leader 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCACGCCGCTCG 
               
               
                   
                 (na-v2) 
                 GCCC 
               
               
                   
               
               
                   4 
                 CD 8 hinge 
                 TTTPAPRPPTPAPTIASQPLSLRPEQACRPAAGGAVHTRGLDFACD 
               
               
                   
                 (aa) 
                   
               
               
                   
               
               
                   5 
                 CD8 hinge 
                 ACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCT 
               
               
                   
                 (na) 
                 GTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGC 
               
               
                   
                   
                 TGGACTTCGCCTGTGAT 
               
               
                   
               
               
                   6 
                 Ig4 hinge 
                 ESKYGPPCPPAPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVSVSQEDPEVQFNW 
               
               
                   
                 (aa) 
                 YVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI 
               
               
                   
                   
                 SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP 
               
               
                   
                   
                 PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKM 
               
               
                   
               
               
                   7 
                 Ig4 hinge 
                 GAGAGCAAGTACGGCCCTCCCTGCCCCCCTTGCCCTGCCCCCGAGTTCCTGGGCGGACC 
               
               
                   
                 (na) 
                 CAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCG 
               
               
                   
                   
                 AGGTGACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGG 
               
               
                   
                   
                 TACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCCGGGAGGAGCAGTTCAA 
               
               
                   
                   
                 TAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCA 
               
               
                   
                   
                 AGGAATACAAGTGTAAGGTGTCCAACAAGGGCCTGCCCAGCAGCATCGAGAAAACCATC 
               
               
                   
                   
                 AGCAAGGCCAAGGGCCAGCCTCGGGAGCCCCAGGTGTACACCCTGCCCCCTAGCCAAGA 
               
               
                   
                   
                 GGAGATGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCG 
               
               
                   
                   
                 ACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCC 
               
               
                   
                   
                 CCTGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCCGGCTGACCGTGGACAAGAG 
               
               
                   
                   
                 CCGGTGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACC 
               
               
                   
                   
                 ACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGCAAGATG 
               
               
                   
               
               
                   8 
                 IgD hinge 
                 RWPESPKAQASSVPTAQPQAEGSLAKATTAPATTRNTGRGGEEKKKEKEKEEQEERETK 
               
               
                   
                 (aa) 
                 TPECPSHTQPLGVYLLTPAVQDLWLRDKATFTCFVVGSDLKDAHLTWEVAGKVPTGGVE 
               
               
                   
                   
                 EGLLERHSNGSQSQHSRLTLPRSLWNAGTSVTCTLNHPSLPPQRLMALREPAAQAPVKL 
               
               
                   
                   
                 SLNLLASSDPPEAASWLLCEVSGFSPPNILLMWLEDQREVNTSGFAPARPPPQPGSTTF 
               
               
                   
                   
                 WAWSVLRVPAPPSPQPATYTCVVSHEDSRTLLNASRSLEVSYVTDH 
               
               
                   
               
               
                   9 
                 IgD hinge 
                 AGGTGGCCCGAAAGTCCCAAGGCCCAGGCATCTAGTGTTCCTACTGCACAGCCCCAGGC 
               
               
                   
                 (na) 
                 AGAAGGCAGCCTAGCCAAAGCTACTACTGCACCTGCCACTACGCGCAATACTGGCCGTG 
               
               
                   
                   
                 GCGGGGAGGAGAAGAAAAAGGAGAAAGAGAAAGAAGAACAGGAAGAGAGGGAGACCAAG 
               
               
                   
                   
                 ACCCCTGAATGTCCATCCCATACCCAGCCGCTGGGCGTCTATCTCTTGACTCCCGCAGT 
               
               
                   
                   
                 ACAGGACTTGTGGCTTAGAGATAAGGCCACCTTTACATGTTTCGTCGTGGGCTCTGACC 
               
               
                   
                   
                 TGAAGGATGCCCATTTGACTTGGGAGGTTGCCGGAAAGGTACCCACAGGGGGGGTTGAG 
               
               
                   
                   
                 GAAGGGTTGCTGGAGCGCCATTCCAATGGCTCTCAGAGCAGCACTCAAGACTCACCCTT 
               
               
                   
                   
                 CCGAGATCCCTGTGGAACGCCGGGACCTCTGTCACATGTACTCTAAATCATCCTAGCCT 
               
               
                   
                   
                 GCCCCCACAGCGTCTGATGGCCCTTAGAGAGCCAGCCGCCCAGGCACCAGTTAAGCTTA 
               
               
                   
                   
                 GCCTGAATCTGCTCGCCAGTAGTGATCCCCCAGAGGCCGCCAGCTGGCTCTTATGCGAA 
               
               
                   
                   
                 GTGTCCGGCTTTAGCCCGCCCAACATCTTGCTCATGTGGCTGGAGGACCAGCGAGAAGT 
               
               
                   
                   
                 GAACACCAGCGGCTTCGCTCCAGCCCGGCCCCCACCCCAGCCGGGTTCTACCACATTCT 
               
               
                   
                   
                 GGGCCTGGAGTGTCTTAAGGGTCCCAGCACCACCTAGCCCCCAGCCAGCCACATACACC 
               
               
                   
                   
                 TGTGTTGTGTCCCATGAAGATAGCAGGACCCTGCTAAATGCTTCTAGGAGTCTGGAGGT 
               
               
                   
                   
                 TTCCTACGTGACTGACCATT 
               
               
                   
               
               
                  10 
                 GS 
                 GGGGSGGGGS 
               
               
                   
                 hinge/linker 
                   
               
               
                   
                 (aa) 
                   
               
               
                   
               
               
                  11 
                 GS 
                 GGTGGCGGAGGTTCTGGAGGTGGAGGTTCC 
               
               
                   
                 hinge/linker 
                   
               
               
                   
                 (na) 
                   
               
               
                   
               
               
                  12 
                 CD8TM 
                 IYIQAPLAGTCGVLLLSLVITLYC 
               
               
                   
                 (aa) 
                   
               
               
                   
               
               
                  13 
                 CD8 TM 
                 ATCTACATCTGGGCGCCCTTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTAT 
               
               
                   
                 (na) 
                 CACCCTTTACTGC 
               
               
                   
               
               
                 308 
                 CD8 TM 
                 ATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGAT 
               
               
                   
                 (na-v2) 
                 CACTCTTTACTGT 
               
               
                   
               
               
                  14 
                 4-1BB 
                 KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL 
               
               
                   
                 intracellular 
                   
               
               
                   
                 domain (aa) 
                   
               
               
                   
               
               
                 15 
                 4-1BB 
                 AAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACA 
               
               
                   
                 intracellular 
                 AACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGAT 
               
               
                   
                 domain (na) 
                 GTGAACTG 
               
               
                   
               
               
                 309 
                 4-1BB 
                 AAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACC 
               
               
                   
                 intracellular 
                   
               
               
                   
                 domain 
                   
               
               
                   
                 (na-v2) 
                   
               
               
                   
               
               
                  16 
                 CD27 
                 QRRKYRSNKGESPVEPAEPCRYSCPREEEGSTIPIQEDYRKPEPACSP 
               
               
                   
                 intracellular 
                   
               
               
                   
                 domain (aa) 
                   
               
               
                   
               
               
                  17 
                 CD27 
                 AGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCC 
               
               
                   
                 intracellular 
                 CGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATC 
               
               
                   
                 domain (na) 
                 GCTCC 
               
               
                   
               
               
                  18 
                 CD3-zeta 
                 RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLY 
               
               
                   
                 (aa) 
                 NELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                  19 
                 CD3-zeta 
                 AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACAAGCAGGGCCAGAACCAGCT 
               
               
                   
                 (na) 
                 CTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTG 
               
               
                   
                   
                 GCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTAC 
               
               
                   
                   
                 AATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGA 
               
               
                   
                   
                 GCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGG 
               
               
                   
                   
                 ACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC 
               
               
                   
               
               
                 310 
                 CD3-zeta 
                 CGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCT 
               
               
                   
                 (na-v2) 
                 CTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAG 
               
               
                   
                   
                 GACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTAC 
               
               
                   
                   
                 AACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGA 
               
               
                   
                   
                 ACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGG 
               
               
                   
                   
                 ACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
               
                  20 
                 CD3-zeta 
                 RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLY 
               
               
                   
                 (aa) 
                 NELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
               
                  21 
                 CD3-zeta 
                 AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCT 
               
               
                   
                 (na) 
                 CTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTG 
               
               
                   
                   
                 GCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTAC 
               
               
                   
                   
                 AATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGA 
               
               
                   
                   
                 GCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGG 
               
               
                   
                   
                 ACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC 
               
               
                   
               
               
                  22 
                 linker 
                 GGGGS 
               
               
                   
               
               
                  23 
                 linker 
                 GGTGGCGGAGGTTCTGGAGGTGGAGGTTCC 
               
               
                   
               
               
                  24 
                 PD-1 
                 Pgwfldspdrpwnpptfspallvvtgegdnatftcsfsntsesfvlnwyrmspsnqtdk 
               
               
                   
                 extracellular 
                 laafpedrsqpgqdcrfrvtqlpngrdfhmsvvrarrndsgtylcgaislapkaqikes 
               
               
                   
                 domain (aa) 
                 lraelrvterraevptahpspsprpagqfqtlv 
               
               
                   
               
               
                  25 
                 PD-1 
                 Cccggatggtttctggactctccggatcgcccgtggaatcccccaaccttctcaccggc 
               
               
                   
                 extracellular 
                 actcttggttgtgactgagggcgataatgcgaccttcacgtgctcgttctccaacacct 
               
               
                   
                 domain (na) 
                 ccgaatcattcgtgctgaactggtaccgcatgagcccgtcaaaccagaccgacaagctc 
               
               
                   
                   
                 gccgcgtttccggaagatcggtcgcaaccgggacaggattgtcggttccgcgtgactca 
               
               
                   
                   
                 actgccgaatggcagagacttccacatgagcgtggtccgcgctaggcgaaacgactccg 
               
               
                   
                   
                 ggacctacctgtgcggagccatctcgctggcgcctaaggcccaaatcaaagagagcttg 
               
               
                   
                   
                 agggccgaactgagagtgaccgagcgcagagctgaggtgccaactgcacatccatcccc 
               
               
                   
                   
                 atcgcctcggcctgcggggcagtttcagaccctggtc 
               
               
                   
               
               
                  26 
                 PD-1 CAR 
                 Malppvtalllplalllhaarppgwfldspdrpwnpptfspallvvtgegdnatftcsf 
               
               
                   
                 (aa) with 
                 sntsesfvlnwyrmspsnqtdklaafpedrsqpgqdcrfrvtqlpngrdfhmsvvrarr 
               
               
                   
                 signal 
                 ndsgtylcgaislapkaqikeslraelrvterraevptahpspsprpagqfqtlvtttp 
               
               
                   
                   
                 aprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllsl 
               
               
                   
                   
                 vitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadap 
               
               
                   
                   
                 aykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaea 
               
               
                   
                   
                 yseigmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
               
                  27 
                 PD-1 CAR 
                 Atggccctccctgtcactgccctgcttctccccctcgcactcctgctccacgccgctag 
               
               
                   
                 (na) 
                 accacccggatggtttctggactctccggatcgcccgtggaatcccccaaccttctcac 
               
               
                   
                   
                 cggcactcttggttgtgactgagggcgataatgcgaccttcacgtgctcgttctccaac 
               
               
                   
                   
                 acctccgaatcattcgtgctgaactggtaccgcatgagcccgtcaaaccagaccgacaa 
               
               
                   
                   
                 gctcgccgcgtttccggaagatcggtcgcaaccgggacaggattgtcggttccgcgtga 
               
               
                   
                   
                 ctcaactgccgaatggcagagacttccacatgagcgtggtccgcgctaggcgaaacgac 
               
               
                   
                   
                 tccgggacctacctgtgcggagccatctcgctggcgcctaaggcccaaatcaaagagag 
               
               
                   
                   
                 cttgagggccgaactgagagtgaccgagcgcagagctgaggtgccaactgcacatccat 
               
               
                   
                   
                 ccccatcgcctcggcctgcggggcagtttcagaccctggtcacgaccactccggcgccg 
               
               
                   
                   
                 cgcccaccgactccggccccaactatcgcgagccagcccctgtcgctgaggccggaagc 
               
               
                   
                   
                 atgccgccctgccgccggaggtgctgtgcatacccggggattggacttcgcatgcgaca 
               
               
                   
                   
                 tctacatttgggctcctctcgccggaacttgtggcgtgctccttctgtccctggtcatc 
               
               
                   
                   
                 accctgtactgcaagcggggtcggaaaaagcttctgtacattttcaagcagcccttcat 
               
               
                   
                   
                 gaggcccgtgcaaaccacccaggaggaggacggttgctcctgccggttccccgaagagg 
               
               
                   
                   
                 aagaaggaggttgcgagctgcgcgtgaagttctcccggagcgccgacgcccccgcctat 
               
               
                   
                   
                 aagcagggccagaaccagctgtacaacgaactgaacctgggacggcgggaagagtacga 
               
               
                   
                   
                 tgtgctggacaagcggcgcggccgggaccccgaaatgggcgggaagcctagaagaaaga 
               
               
                   
                   
                 accctcaggaaggcctgtataacgagctgcagaaggacaagatggccgaggcctactcc 
               
               
                   
                   
                 gaaattgggatgaagggagagcggcggaggggaaaggggcacgacggcctgtaccaagg 
               
               
                   
                   
                 actgtccaccgccaccaaggacacatacgatgccctgcacatgcaggcccttccccctc 
               
               
                   
                   
                 gc 
               
               
                   
               
               
                  28 
                 linker 
                 (Gly-Gly-Gly-Ser) n , where n = 1-10 
               
               
                   
               
               
                  29 
                 linker 
                 (Gly 4  Ser) 4   
               
               
                   
               
               
                  30 
                 linker 
                 (Gly 4  Ser)3 
               
               
                   
               
               
                  31 
                 linker 
                 (Gly 3 Ser) 
               
               
                   
               
               
                  32 
                 poly A 
                 [a] 2000   
               
               
                   
                 (2000 A&#39;s) 
                   
               
               
                   
               
               
                  33 
                 poly A 
                 [a] 150   
               
               
                   
                 (1500 A&#39;s) 
                   
               
               
                   
               
               
                  34 
                 poly A 
                 [a] 5000   
               
               
                   
                 (5900 A&#39;s) 
                   
               
               
                   
               
               
                  35 
                 poly A 
                 [t] 100   
               
               
                   
                 (100 T&#39;s) 
                   
               
               
                   
               
               
                  36 
                 poly A 
                 [t] 500   
               
               
                   
                 (500 T&#39;s) 
                   
               
               
                   
               
               
                  37 
                 poly A 
                 [a] 64   
               
               
                   
                 (64 A&#39;s) 
                   
               
               
                   
               
               
                  38 
                 poly A 
                 [a] 400   
               
               
                   
                 (400 A&#39;s) 
                   
               
               
                   
               
               
                  39 
                 PD1 CAR 
                 
                   Pgwfldspdrpwnpptfspallvvtegdnatftcsfsntsesfvlnwyrmspsnqtdkl 
                 
               
               
                   
                 (aa) 
                 
                   aafpedrsqpgqdcrfrvtqlpngrdfhmsvvrarrndsgtylcgaislapkaqikesl 
                 
               
               
                   
                   
                   raelrvterraevptahpspsprpagqfqtlv tttpaprpptpaptiasqplslrpeac 
               
               
                   
                   
                 rpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmr 
               
               
                   
                   
                 pvqttqeedgcscrfpeeeeggcelrvkfsrsadapaykqgqnqlynelnlgrreeydv 
               
               
                   
                   
                 ldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqgl 
               
               
                   
                   
                 statkdtydalhmqalppr 
               
               
                   
               
               
                  40 
                 ICOS 
                 T K K K Y S S S V H D P N G E Y M F M R A V N T A K K S R L 
               
               
                   
                 intracellular 
                 T D V T L 
               
               
                   
                 domain (aa) 
                   
               
               
                   
               
               
                  41 
                 ICOS 
                 ACAAAAAAGAAGTATTCATCCAGTGTGCACGACCCTAACGGTGAATACATGTTCATGAG 
               
               
                   
                 intracellular 
                 AGCAGTGAACACAGCCAAAAAATCCAGACTCACAGATGTGACCCTA 
               
               
                   
                 domain (na) 
                   
               
               
                   
               
               
                  42 
                 ICOS TM 
                 T T T P A P R P P T P A P T I A S Q P L S L R P E A C R P A 
               
               
                   
                 domain (aa) 
                 A G G A V H T R G L D F A C D F W L P I G C A A F V V V C I 
               
               
                   
                   
                 L G C I L I C W L 
               
               
                   
               
               
                  43 
                 ICOS TM 
                 ACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCT 
               
               
                   
                 domain (na) 
                 GTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGC 
               
               
                   
                   
                 TGGACTTCGCCTGTGATTTCTGGTTACCCATAGGATGTGCAGCCTTTGTTGTAGTCTGC 
               
               
                   
                   
                 ATTTTGGGATGCATACTTATTTGTTGGCTT 
               
               
                   
               
               
                  44 
                 CD28 
                 RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS 
               
               
                   
                 intracellular 
                   
               
               
                   
                 domain (aa) 
                   
               
               
                   
               
               
                  45 
                 CD28 
                 AGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCC 
               
               
                   
                 intracellular 
                 CGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATC 
               
               
                   
                 domain (na) 
                 GCTCC 
               
               
                   
               
            
           
         
       
     
     In specific aspects, a CAR construct of the invention (a CAR that binds to a B cell antigen or a CAR that binds to a tumor antigen) comprises a scFv domain, wherein the scFv may be preceded by an optional leader sequence such as provided in SEQ ID NO: 2, and followed by an optional hinge sequence such as provided in SEQ ID NO:4 or SEQ ID NO:6 or SEQ ID NO:8 or SEQ ID NO: 10, a transmembrane region such as provided in SEQ ID NO: 12, an intracellular signalling domain that includes SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 42, or SEQ ID NO:44 and a CD3 zeta sequence that includes SEQ ID NO: 18 or SEQ ID NO:20, e.g., wherein the domains are contiguous with and in the same reading frame to form a single fusion protein. 
     In one aspect, an exemplary CAR constructs comprise an optional leader sequence (e.g., a leader sequence described herein), an extracellular antigen binding domain (e.g., an antigen binding domain described herein), a hinge (e.g., a hinge region described herein), a transmembrane domain (e.g., a transmembrane domain described herein), and an intracellular stimulatory domain (e.g., an 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 (e.g., an antigen binding domain described herein), a hinge (e.g., a hinge region described herein), a transmembrane domain (e.g., a transmembrane domain described herein), an intracellular costimulatory signaling domain (e.g., a costimulatory signaling domain described herein) and/or an intracellular primary signaling domain (e.g., a primary signaling domain described herein). 
     An exemplary leader sequence is provided as SEQ ID NO: 2. An exemplary hinge/spacer sequence is provided as SEQ ID NO: 4 or SEQ ID NO:6 or SEQ ID NO:8 or SEQ ID NO: 10. An exemplary transmembrane domain sequence is provided as SEQ ID NO: 12. An exemplary sequence of the intracellular signaling domain of the 4-1BB protein is provided as SEQ ID NO: 14. An exemplary sequence of the intracellular signaling domain of CD27 is provided as SEQ ID NO: 16. An exemplary sequence of the intracellular signaling domain of CD28 is provided as SEQ ID NO:42. An exemplary sequence of the intracellular signaling domain of CD28 is provided as SEQ ID NO:44. An exemplary CD3zeta domain sequence is provided as SEQ ID NO: 18 or SEQ ID NO:20. 
     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 nucleic acid molecule, by deriving the nucleic acid molecule 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 disclosure includes retroviral and lentiviral vector constructs expressing a CAR that can be directly transduced into a cell. Methods for viral transduction are described herein, and are well known in the art. 
     The present disclosure 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”) (e.g., a 3′ and/or 5′ UTR described herein), a 5′ cap (e.g., a 5′ cap described herein) and/or Internal Ribosome Entry Site (IRES) (e.g., an IRES described herein), the nucleic acid to be expressed, and a polyA tail, typically 50-2000 bases in length (SEQ ID NO:32). 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 transfected into a cell, e.g., a T cell or a NK cell, by electroporation. 
     Antigen Binding Domain 
     In one aspect, the CAR-expressing cells of the invention comprise 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 or engineered to recognize a ligand that acts as a cell surface marker on target cells associated with a particular disease state, e.g., a tumor antigen associated with a particular cancer (e.g., an antigen binding domain that binds to a tumor antigen). In other embodiments, the antigen binding domain is chosen or engineered to recognize normal B cells, or a subpopulation of B cells, for depleting normal B cells or a target B cell population (e.g., an antigen binding domain that binds to a B cell antigen). 
     The antigen binding domain can be any domain that binds to the antigen including but not limited to a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a bispecific antibody, a conjugated 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, a T cell receptor (TCR), a recombinant TCR with enhanced affinity, or a fragment there of, e.g., single chain TCR, 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. 
     Tumor Antigens 
     The present disclosure provides immune effector cells (e.g., T cells, NK cells) that are engineered to contain one or more CARs that direct the immune effector cells to cancer cell. This is achieved through an antigen binding domain on the CAR that is specific for a tumor antigen. There are two classes of tumor antigens (tumor antigens) that can be targeted by the CARs of the instant invention: (1) a tumor antigen that is expressed on the surface of cancer cells; and (2) a tumor antigen that itself is intracellar, however, a fragment of such antigen (peptide) is presented on the surface of the cancer cells by MHC (major histocompatibility complex). 
     In one embodiment, the tumor antigen is expressed on both normal cells and cancer cells, but is expressed at lower levels on normal cells. In one embodiment, the method further comprises selecting a TA CAR that binds a tumor antigen with an affinity that allows the cell engineered to express the TA CAR to bind and kill the cancer cells expressing a tumor antigen but less than 30%, 25%, 20%, 15%, 10%, 5% or less of the normal cells expressing a tumor antigen are killed, e.g., as determined by an assay described herein. For example, a killing assay such as flow cytometry based on Cr51 CTL can be used. In one embodiment, the selected TA CAR has an antigen binding domain that has a binding affinity K D  of 10 −4  M to 10 −8  M, e.g., 10 −5  M to 10 −7  M, e.g., 10 −6  M or 10 −7  M, for the target antigen. In one embodiment, the selected antigen binding domain has a binding affinity that is at least five-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold or 1,000-fold less than a reference antibody, e.g., an antibody described herein. 
     Accordingly, the cells of the invention are engineered to express, e.g., express, a TA CAR comprising an antigen binding domain that can target, e.g., bind to, any one of the exemplary tumor antigens (tumor antigens): CD123, CD30, CD171, CS-1, CLL-1 (CLECL1), CD33, EGFRvIII, GD2, GD3, Tn Ag, sTn Ag, Tn-O-Glycopeptides, Stn-O-Glycopeptides, PSMA, FLT3, FAP, TAG72, CD44v6, CEA, EPCAM, B7H3, KIT, LL-13Ra2, Mesothelin, IL-11Ra, PSCA, VEGFR2, LewisY, PDGFR-beta, PRSS21, SSEA-4, Folate receptor alpha, ERBB2 (Her2/neu), MUC1, EGFR, NCAM, Prostase, PAP, ELF2M, Ephrin B2, IGF-1 receptor, CAIX, LMP2, gp100, bcr-abl, tyrosinase, EphA2, Fucosyl GM1, sLe, GM3, TGS5, HMWMAA, o-acetyl-GD2, Folate receptor beta, TEM1/CD248, TEM7R, CLDN6, TSHR, GPRC5D, CXORF61, CD97, CD179a, ALK, Plysialic acid, PLAC1, GloboH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6K, OR51E2, TARP, WT1, NY-ESO-1, LAGE-1a, legumain, HPV E6, E7, MAGE-A1, MAGE A1, ETV6-AML, sperm protein 17, XAGE1, Tie 2, MAD-CT-1, MAD-CT-2, Fos-related antigen 1, p53, p53 mutant, prostein, survivin and telomerase, PCTA-1/Galectin 8, MelanA/MARTI, Ras mutant, hTERT, sarcoma translocation breakpoints, ML-IAP, ERG (TMPRSS2 ETS fusion gene), NA17, PAX3, Androgen receptor, Cyclin B1, MYCN, RhoC, TRP-2, CYPIB1, BORIS, SART3, PAX5, OY-TES1, LCK, AKAP-4, SSX2, RAGE-1, human telomerase reverse transcriptase, RU1, RU2, intestinal carboxyl esterase, mut hsp70-2, LAIR1, FCAR, LILRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5, IGLL1, and peptides of these antigens presented on MHC. 
     In embodiments, the antigen binding domain of a TA CAR, e.g., a TA CAR expressed by a cell of the invention, targets a tumor antigen that is associated with a solid tumor, e.g., expressed by a solid tumor cell, referred to herein as a solid tumor associated antigen, e.g., an antigen associated with mesothelioma (e.g., malignant pleural mesothelioma), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, squamous cell lung cancer, or large cell lung cancer), pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), esophageal adenocarcinoma, ovarian cancer, breast cancer, colorectal cancer and bladder cancer or any combination thereof. In one embodiment, the disease is pancreatic cancer, e.g., metastatic pancreatic ductal adenocarcinoma (PDA), e.g., in a subject who has progressed on at least one prior standard therapy. In one embodiment, the disease is mesothelioma (e.g., malignant pleural mesothelioma), e.g., in a subject who has progressed on at least one prior standard therapy. In one embodiment, the disease is ovarian cancer, e.g., serous epithelial ovarian cancer, e.g., in a subject who has progressed after at least one prior regimen of standard therapy. 
     Examples of solid tumor associated antigens (i.e., solid tumor antigens) include, without limitation: EGFRvIII, mesothelin, GD2, Tn antigen, sTn antigen, Tn-O-Glycopeptides, sTn-O-Glycopeptides, PSMA, CD97, TAG72, CD44v6, CEA, EPCAM, KIT, IL-13Ra2, leguman, GD3, CD171, IL-11Ra, PSCA, MAD-CT-1, MAD-CT-2, VEGFR2, LewisY, CD24, PDGFR-beta, SSEA-4, folate receptor alpha, ERBBs (e.g., ERBB2), Her2/neu, MUC1, EGFR, NCAM, Ephrin B2, CAIX, LMP2, sLe, HMWMAA, o-acetyl-GD2, folate receptor beta, TEM1/CD248, TEM7R, FAP, Legumain, HPV E6 or E7, ML-IAP, CLDN6, TSHR, GPRC5D, ALK, Polysialic acid, Fos-related antigen, neutrophil elastase, TRP-2, CYPIB1, sperm protein 17, beta human chorionic gonadotropin, AFP, thyroglobulin, PLAC1, globoH, RAGE1, MN-CA IX, human telomerase reverse transcriptase, intestinal carboxyl esterase, mut hsp 70-2, NA-17, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, NY-ESO-1, GPR20, Ly6k, OR51E2, TARP, GFRα4, and a peptide of any of these antigens presented on MHC. 
     In an embodiment, the antigen binding domain of a TA CAR, e.g., a TA CAR expressed by a cell of the invention, binds to human mesothelin. In an embodiment, the antigen binding domain is a murine scFv domain that binds to human mesothelin, e.g., SS1 or SEQ ID NO: 46. In an embodiment, the antigen binding domain is a humanized antibody or antibody fragment, e.g., scFv domain, derived from the murine SS1 scFv. In an embodiment, the antigen binding domain is a human antibody or antibody fragment that binds to human mesothelin. Exemplary human scFv domains (and their sequences) and the murine SS1 scFv that bind to mesothelin are provided in Table 2. CDR sequences are underlined. The scFv domain sequences provided in Table 2 include a light chain variable region (VL) and a heavy chain variable region (VH). The VL and VH are attached by a linker comprising the sequence GGGGSGGGGSGGGGS (SEQ ID NO: 30) (e.g., as shown in SS1 scFv domains) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 29) (e.g., as shown in M1, M2, M3, M4, M5, M6, M7, M8, M9, M10, M11, M12, M13, M14, M15, M16, M17, M18, M19, M20, M21, M22, M23, or M24 scFv domains). The scFv domains listed in Table 2 are in the following orientation: VL-linker-VH. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Antigen binding domains that bind to mesothelin 
               
            
           
           
               
               
               
               
            
               
                 Tumor 
                   
                   
                 SEQ 
               
               
                 antigen 
                 Name 
                 Amino acid sequence 
                 ID NO: 
               
               
                   
               
               
                 mesothelin 
                 M5 
                 QVQLVQSGAEVEKPGASVKVSCKAS GYTFTDYYMH WVRQAPGQGLEWMG W   
                 51 
               
               
                   
                 (human) 
                   INPNSGGTNYAQKFQG RVTMTRDTSISTAYMELSRLRSDDTAVYYCAS GW   
                   
               
               
                   
                   
                   DFDY WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQSPSSLSASV 
                   
               
               
                   
                   
                 GDRVTITC RASQSIRYYLS WYQQKPGKAPKLLIY TASILQN GVPSRFSGS 
                   
               
               
                   
                   
                 GSGTDFTLTISSLQPEDFATYYC LQTYTTPD FGPGTKVEIK 
                   
               
               
                   
               
               
                 mesothelin 
                 M11 
                 QVQLQQSGAEVKKPGASVKVSCKAS GYTFTGYYMH WVRQAPGQGLEWMG W   
                 57 
               
               
                   
                 (human) 
                   INPNSGGTNYAQNFQG RVTMTRDTSISTAYMELRRLRSDDTAVYYCAS GW   
                   
               
               
                   
                   
                   DFDY WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIRMTQSPSSLSASV 
                   
               
               
                   
                   
                 GDRVTITC RASQSIRYYLS WYQQKPGKAPKLLIY TASILQN GVPSRFSGS 
                   
               
               
                   
                   
                 GSGTDFTLTISSLQPEDFATYYC LQTYTTPD FGPGTKVEIK 
                   
               
               
                   
               
               
                 mesothelin 
                 ss1 
                 Q V Q L Q Q S G P E L E K P G A S V K I S C K A S 
                 46 
               
               
                   
                 (murine) 
                 G Y S F T G Y T M N W V K Q S H G K S L E W I G L 
                   
               
               
                   
                   
                 I T P Y N G A S S Y N Q K F R G K A T L T V D K S 
                   
               
               
                   
                   
                 S S T A Y M D L L S L T S E D S A V Y F C A R G G 
                   
               
               
                   
                   
                 Y D G R G F D Y W G Q G T T V T V S S G G G G S G 
                   
               
               
                   
                   
                 G G G S G G G G S D I E L T Q S P A I M S A S P G 
                   
               
               
                   
                   
                 E K V T M T C S A S S S V S Y M H W Y Q Q K S G T 
                   
               
               
                   
                   
                 S P K R W I Y D T S K L A S G V P G R F S G S G S 
                   
               
               
                   
                   
                 G N S Y S L T I S S V E A E D D A T Y Y C Q Q W S 
                   
               
               
                   
                   
                 G Y P L T F G A G T K L E I 
                   
               
               
                   
               
               
                 mesothelin 
                 M1 
                 QVQLQQSGAEVKKPGASVKVSCKAS GYTFTGYYMH WVRQAPGQGLEWMG R   
                 47 
               
               
                   
                 (human) 
                   INPNSGGTNYAQKFQG RVTMTRDTSISTAYMELSRLRSEDTAVYYCAR GR   
                   
               
               
                   
                   
                   YYGMDV WGQGTMVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPATLSL 
                   
               
               
                   
                   
                 SPGERATISC RASQSVSSNFA WYQQRPGQAPRLLIY DASNRAT GIPPRFS 
                   
               
               
                   
                   
                 GSGSGTDFTLTISSLEPEDFAAYYC HQRSNWLYT FGQGTKVDIK 
                   
               
               
                   
               
               
                 mesothelin 
                 M2 
                 QVLQVQSGAEVKKPGASVKVSCKAS GYTFTGYYMH WVRQAPGQGLEWMG W   
                 48 
               
               
                   
                 (human) 
                   INPNSGGTNYAQKFQG RVTMTRDTSISTAYMELSRLRSDDTAVYYCAR DL   
                   
               
               
                   
                   
                   RRTVVTPRAYYGMDV WGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQL 
                   
               
               
                   
                   
                 TQSPSTLSASVGDRVTITC QASQDISNSLN WYQQKAGKAPKLLIY DASTL   
                   
               
               
                   
                   
                   ET GVPSRFSGSGSGTDFSFTISSLQPEDIATYYC QQHDNLPLT FGQGTKV 
                   
               
               
                   
                   
                 EIK 
                   
               
               
                   
               
               
                 mesothelin 
                 M3 
                 QVQLVQSGAEVKKPGAPVKVSCKAS GYTFTGYYMH WVRQAPGQGLEWMG W   
                 49 
               
               
                   
                 (human) 
                   INPNSGGTNYAQKFQG RVTMTRDTSISTAYMELSRLRSDDTAVYYCAR GE   
                   
               
               
                   
                   
                   WDGSYYYDY WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQTPSS 
                   
               
               
                   
                   
                 LSASVGDRVTITC RASQSINTYLN WYQHKPGKAPKLLIY AASSLQS GVPS 
                   
               
               
                   
                   
                 RFSGSGSGTDFTLTISSLQPEDFATYYC QQSFSPLT FGGGTKLEIK 
                   
               
               
                   
               
               
                 mesothelin 
                 M4 
                 QVQLVESGGGLVQPGGSLRLSCAAS GFTFSSYWMH WVRQVPGKGLVWVS R   
                 50 
               
               
                   
                 (human) 
                   INTDGSTTTYADSVEG RFTISRDNAKNTLYLQMNSLRDDDTAVYYCVG GH   
                   
               
               
                   
                   
                   WAV WGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVG 
                   
               
               
                   
                   
                 DRVTITC RASQSISDRLA WYQQKPGKAPKLLIY KASSLE SGVPSRFSGSG 
                   
               
               
                   
                   
                 SGTEFTLTISSLQPDDFAVYYC QQYGHLPMYT FGQGTKVEIK 
                   
               
               
                   
               
               
                 mesothelin 
                 M6 
                 QVQLVQSGAEVKKPGASVKVSCKAS GYFTFSYYMH WVRQAPGQGLEWMG I   
                 52 
               
               
                   
                 (human) 
                   INPSGGSTSYAQKFQG RVTMTRDTATSTVYMELSSLRSEDTAVYYCAR YR   
                   
               
               
                   
                   
                   LIAVAGDYYYYGMDV WGQGTMVTVSSGGGGSGGGGSGGGGSGGGGSDIQM 
                   
               
               
                   
                   
                 TQSPSSVASVGDRVTITC RASQGVGRWLA WYQQKPGTAPKLLIY AASTLQ   
                   
               
               
                   
                   
                   S GVPSRFSGSGSGTDFTLTINNLQPEDFATYYC QQANSFPLT FGGGTRLE 
                   
               
               
                   
                   
                 IK 
                   
               
               
                   
               
               
                 mesothelin 
                 M7 
                 QVQLVQSGGGVVQPGRSLRLSCAAS GFTFSSYAMH WVRQAPGKGLEWVA V   
                 53 
               
               
                   
                 (human) 
                   ISYDGSNKYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR WK   
                   
               
               
                   
                   
                   VSSSSPAFDY WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPA 
                   
               
               
                   
                   
                 TLSLSPGERAILSC RASQSVYTKYLG WYQQKPGQAPRLLIYDASTRATGI 
                   
               
               
                   
                   
                 PDRFSGSGSGTDFTLTINRLEPEDFAVYYC QHYGGSPLIT FGQGTRLEIK 
                   
               
               
                   
               
               
                 mesothelin 
                 M8 
                 QVQLQQSGAEVKKPGASVKVSCKTS GYPFTGYSLH WVRQAPGQGLEWMG W   
                 54 
               
               
                   
                 (human) 
                   INPNSGGTNYAQKFQG RVTMTRDTSISTAYMELSRLRSDDTAVYYCAR DH   
                   
               
               
                   
                   
                   YGGNSLFY WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSSI 
                   
               
               
                   
                   
                 SASVGDTVSITC RASQDSGTWLA WYQQKPGKAPNLLMY DASTLED GVPSR 
                   
               
               
                   
                   
                 FSGSASGTEFTLTVNRLQPEDSATYYC QQYNSYPLT FGGGTKVDIK 
                   
               
               
                   
               
               
                 mesothelin 
                 M9 
                 QVQLVQSGAEVKKPGASVEVSCKAS GYTFTSYYMH WVRQAPGQGLEWMG I   
                 55 
               
               
                   
                 (human) 
                   INPSGGSTGYAQKFQG RVTMTRDTSTSTVHMELSSLRSEDTAVYYCAR GG   
                   
               
               
                   
                   
                   YSSSSDAFDI WGQGTMVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPP 
                   
               
               
                   
                   
                 SLSASVGDRVTITC RASQDISSALA WYQQKPGTPPKLLIY DASSLES GVP 
                   
               
               
                   
                   
                 SRFSGSGSGTDFTLTISSLQPEDFATYYC QQFSSYPLT FGGGTRLEIK 
                   
               
               
                   
               
               
                 mesothelin 
                 M10 
                 QVQLVQSGAEVKKPGASVKVSCKAS GYTFTSYGIS WVRQAPGQGLEWMG W   
                 56 
               
               
                   
                 (human) 
                   ISAYNGNTNYAQKLQ GRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR VA   
                   
               
               
                   
                   
                   GGIYYYYGMDV WGQGTTITVSSGGGGSGGGGSGGGGSGGGGSDIVMTQTP 
                   
               
               
                   
                   
                 DSLAVSLGERATISC KSSHSVLYNRNNKNYLA WYQQKPGQPPKLLFY WAS   
                   
               
               
                   
                   
                   TRKS GVPDRFSGSGSGTDFTLTISSLQPEDFATYFC QQTQTFPLT FGQGT 
                   
               
               
                   
                   
                 RELIN 
                   
               
               
                   
               
               
                 mesothelin 
                 M12 
                 QVQLVQSGAEVKKPGASVKVSCKAS GYTFTGYYMH WVRQAPGQGLEWMG R   
                 58 
               
               
                   
                 (human) 
                   INPNSGGTNYAQKFQG RVTMTTDTSTATAYMELRSLRSDDTAVYYCAR TT   
                   
               
               
                   
                   
                   TSYAFDI WGQGTMVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSTLS 
                   
               
               
                   
                   
                 ASVGDRVTITC RASQSISTWLA WYQQKPGKAPNLLIY KASTLES GVPSRF 
                   
               
               
                   
                   
                 SGSGSGTEFTLTISSLQPDDFATYYC QQYNTYSPYT FGQGTKLEIK 
                   
               
               
                   
               
               
                 mesothelin 
                 M13 
                 QVQLVQSGGGLVKPGGSLRLSCEAS GFIFSDYYMG WIRQAPGKGLEWVS Y   
                 59 
               
               
                   
                 (human) 
                   IGRSGSSMYYADSVKG RFTFSRDNAKNSLYLQMNSLRAEDTAVYYCAA SP   
                   
               
               
                   
                   
                   VVAATEDFQH WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQTPA 
                   
               
               
                   
                   
                 TLSLSPGERATLSC RASQSVTSNYLA WYQQKPGQAPRLLLF GASTRAT GI 
                   
               
               
                   
                   
                 PDRFSGSGSGTDFTLTINRLEPEDFAMYYC QQYGSAPVT FGQGTKLEIK 
                   
               
               
                   
               
               
                 mesothelin 
                 M14 
                 QVQLVQSGAEVRAPGASVKISCKAS GFTFRGYYIH WVRQAPGQGLEWMG I   
                 60 
               
               
                   
                 (human) 
                   INPSGGSRAYAQKFQG RVTMTRDTSTSTVYMELSSLRSDDTAMYYCAR TA   
                   
               
               
                   
                   
                   SCGGDCYYLDY WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSP 
                   
               
               
                   
                   
                 PTLSASVGDRVTITC RASENVNIWLA WYQQKPGKAPKLLIY KSSSLAS GV 
                   
               
               
                   
                   
                 PSRFSGSGSGAEFTLTISSLQPDDFATYYC QQYQSYPLT FGGGTKVDIK 
                   
               
               
                   
               
               
                 mesothelin 
                 M15 
                 QVQLVQSGGGLVQPGRSLRLSCAAS GFTFDDYAMH WVRQAPGKGLEWVS G   
                 61 
               
               
                   
                 (human) 
                   ISWNSGSIGYADSVK GRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAK DG   
                   
               
               
                   
                   
                   SSSWSWGYFDY WGQGTLVTVSGGGGSGGGGSGGGGSSSELTQPDPAVSVA 
                   
               
               
                   
                   
                 LGQTVRTTC QGDALRSYYAS WYQQKPGQAPMLVIY GKNNRPS GIPDRFSG 
                   
               
               
                   
                   
                 SDSGDTASLTITGAQAEDEADYYC NSRDSSGYPV FGTGTKVTVL 
                   
               
               
                   
               
               
                 mesothelin 
                 M16 
                 EVLQVESGGGLVQPGRSLRLSCAAS GFTFDDYAMH WVRQAPGKGLEWVS G   
                 62 
               
               
                   
                 (human) 
                   ISWNSGSTGYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTALYYCAK DS   
                   
               
               
                   
                   
                   SSWYGGGSAFDI WGQGTMVTVSSGGGGSGGGGSGGGGSSSELTQEPAVSV 
                   
               
               
                   
                   
                 ALGQTVRITC QGDSLRSYYAS WYQQKPGQAPVLVIF GRSRRPS GIPDRFS 
                   
               
               
                   
                   
                 GSSSGNTASLIITGAQAEDEADYYC NSRDNTANHYV FGTGTKLTVL 
                   
               
               
                   
               
               
                 mesothelin 
                 M17 
                 EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYAMH WVRQAPGKGLEWVS G   
                 63 
               
               
                   
                 (human) 
                   ISWNSGSTGYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTALYYCAK DS   
                   
               
               
                   
                   
                   SSWYGGGSAFDI WGQGTMVTVSSGGGGSGGGGSGGGGSSSELTQDPAVSV 
                   
               
               
                   
                   
                 ALGQTVRITC QGDSLRSYYAS WYQQKPGQAPVLVIY GKNNRPS GIPDRFS 
                   
               
               
                   
                   
                 GSSSGNTASLTITGAQAEDEADYYC NSRGSSGNHYV FGTGTKVTVL 
                   
               
               
                   
               
               
                 mesothelin 
                 M18 
                 QVQLVQSGGGLVQPGGSLRLSCAAS GFTFSSYWMH WVRQAPGKGLVWVS R   
                 64 
               
               
                   
                 (human) 
                   INSDGSSTSYADSVKG RFTISRDNAKNTLYLQMNSLRAEDTAVYYCVR TG   
                   
               
               
                   
                   
                   WVGSYYYYMDV WGKGTTVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSP 
                   
               
               
                   
                   
                 GTLSLSPGERATLSC RASQSVSSNYLA WYQQKPGQPPRLLIY DVSTRAT G 
                   
               
               
                   
                   
                 IPARFSGGGSGTDFTLTISSLEPEDFAVYYC QQRSNWPPWT FGQGTKVEI 
                   
               
               
                   
                   
                 K 
                   
               
               
                   
               
               
                 mesothelin 
                 M19 
                 QVQLVQSGGGVVQPGRSLRLSCAAS GFTFSSYGMH WVRQAPGKGLEWVA V   
                 65 
               
               
                   
                 (human) 
                   ISYDGSNKYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK GY   
                   
               
               
                   
                   
                   SRYYYYGMDV WGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPA 
                   
               
               
                   
                   
                 TLSLSPGERAILSC RASQSVYTKYLG WYQQKPGQAPRLLIY DASTRAT GI 
                   
               
               
                   
                   
                 PDRFSGSGSGTDFTLTINRLEPEDFAVYYC QHYGGSPLIT FGQGTKVDIK 
                   
               
               
                   
               
               
                 mesothelin 
                 M20 
                 QVQLVQSGGGLVQPGGSLRLSCAAS GFTFSSYAMS WVRQAPGKGLEWVS A   
                 66 
               
               
                   
                 (human) 
                   ISGSGGSTYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK RE   
                   
               
               
                   
                   
                   AAAGHDWYFDL WGRGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIRVTQSP 
                   
               
               
                   
                   
                 SSLSASVGDRVTITC RASQSISSYLN WYQQKPGKAPKLLIY AASSLQS GV 
                   
               
               
                   
                   
                 PSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSIPLT FGQGTKVEIK 
                   
               
               
                   
               
               
                 mesothelin 
                 M21 
                 QVQLVQSWAEVKKPGASVKVSCKAS GYFTFSYYMH WVRQAPGQGLEWMG I   
                 67 
               
               
                   
                 (human) 
                   INPSGGSTSYAQKFQG RVTMTRDTSTSTVYMELSNLRSEDTAVYYCAR SP   
                   
               
               
                   
                   
                   RVTTGYFDY WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPST 
                   
               
               
                   
                   
                 LSASVGDRVTITC RASQSISSWLA WYQQKPGKAPKLLIY KASSLE SGVPS 
                   
               
               
                   
                   
                 RFSGSGSGTEFTLTISSLQPDDFATYYC QQYSSYPLT FGGGTRLEIK 
                   
               
               
                   
               
               
                 mesothelin 
                 M22 
                 QVQLVQSGAEVRRPGASVKISCRAS GDTSTRHYIH WLRQAPGQGPEWMG V   
                 68 
               
               
                   
                 (human) 
                   INPTTGPATGSPAYAQMLQG RVTMTRDTSTRTVYMELRSLRFEDTAVYYC 
                   
               
               
                   
                   
                 AR SVVGRSAPYYFDY WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQM 
                   
               
               
                   
                   
                 TQSPSSLSASVGDRVTITCRASQGSIDYSAWYQQKPGKAPKLLIY AASTL   
                   
               
               
                   
                   
                   QS GVPSRFSGSGSGTDFTLTISYLQSEDFATYYC QQYYSYPLT FGGGTKV 
                   
               
               
                   
                   
                 DIK 
                   
               
               
                   
               
               
                 mesothelin 
                 M23 
                 QVQLQQSGAEVKKPGASVKVSCKAS GYTFTNYYMH WVRQAPGQGLEWMG I   
                 69 
               
               
                   
                 (human) 
                   INPSGGYTTYAQKFQG RLTMTRDTSTSTVYMELSSLRSEDTAVYYCAR IR   
                   
               
               
                   
                   
                   SCGGDCYYFDN WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSP 
                   
               
               
                   
                   
                 STLSASVGDRVTITC RASENVNIWLA WYQQKPGKAPKLLIY KSSSLAS GV 
                   
               
               
                   
                   
                 PSRFSGSGSGAEFTLTISSLQPDDFATYYC QQYQSYPLT FGGGTKVDIK 
                   
               
               
                   
               
               
                 mesothelin 
                 M24 
                 QITLKESGPALVKPTQTLTLTCTFS GFSLSTAGVHVG WIRQPPGKALEWL 
                 70 
               
               
                   
                 (human) 
                 A LISWADDKRYRPSLRS RLDITRVTSKDQVVLSMTNMQPEDTATYYCAL Q   
                   
               
               
                   
                   
                   GFDGYEAN WGPGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQSPSSL 
                   
               
               
                   
                   
                 SASAGDRVTITC RASRGISSALA WYQQKPGKPPKLLIY DASSLES GVPSR 
                   
               
               
                   
                   
                 FSGSGSGTDFTLTIDSLEPEDFATYYC QQSYSTPWT FGQGTKVDIK 
               
               
                   
               
            
           
         
       
     
     The sequences of the CDR sequences of the scFv domains of the mesothelin antigen binding domains provided in Table 2 are shown in Table 3 for the heavy chain variable domains and in Table 4 for the light chain variable domains. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Amino acid sequences for the heavy chain (HC) CDR1, CDR2, 
               
               
                 and CDR3 regions of human anti-mesothelin scFvs 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 SEQ 
                   
                 SEQ 
                   
                 SEQ 
               
               
                 Descrip. 
                 HC-CDR1 
                 ID NO: 
                 HC-CDR2 
                 ID NO: 
                 HC-CDR3 
                 ID NO: 
               
               
                   
               
               
                 M5 
                 GYTFTDYYMH 
                 115 
                 WINPNSGGTNYAQKFQG 
                 134 
                 GWDFDY 
                 159 
               
               
                   
               
               
                 M11 
                 GYTFTGYYMH 
                 121 
                 WINPNSGGTNYAQNFQG 
                 141 
                 GWDFDY 
                 165 
               
               
                   
               
               
                 Ss1 
                 GYSFTGYTMN 
                 132 
                 LITPYNGASSYNQKFRG 
                 154 
                 GGYDGRGFDY 
                 179 
               
               
                   
               
               
                 M1 
                 GYTFTGYYMH 
                 113 
                 RINPNSGGTNYAQKFQG 
                 133 
                 GRYYGMDV 
                 155 
               
               
                   
               
               
                 M2 
                 GYTFTGYYMH 
                 113 
                 WINPNSGGTNYAQKFQG 
                 134 
                 DLRRTVVTPRAYYGMDV 
                 156 
               
               
                   
               
               
                 M3 
                 GYTFTGYYMN 
                 113 
                 WINPNSGGTNYAQKFQG 
                 134 
                 GEWDGSYYYDY 
                 157 
               
               
                   
               
               
                 M4 
                 GFTFSSYWMH 
                 114 
                 RINTDGSTTTYADSVEG 
                 135 
                 GHWAV 
                 158 
               
               
                   
               
               
                 M6 
                 GYTFTSYYMH 
                 116 
                 IINPSGGSTSYAQKFQ 
                 136 
                 YRLIAVAGDYYYYGMDV 
                 160 
               
               
                   
               
               
                 M7 
                 GFTFSSYAMH 
                 117 
                 VISYDGSNKYYADSVKG 
                 137 
                 WKVSSSSPAFDY 
                 161 
               
               
                   
               
               
                 M8 
                 GYPFTGYSLH 
                 118 
                 WINPNSGGTNYAQKFQG 
                 138 
                 DHYGGSNLFY 
                 162 
               
               
                   
               
               
                 M9 
                 GYTFTSYYMH 
                 119 
                 IINPSGGSTGYAQKFQG 
                 139 
                 GGYSSSSDAFDI 
                 163 
               
               
                   
               
               
                 M10 
                 GYTFTSYGIS 
                 120 
                 WASAYNGNTNYAQKLQ 
                 140 
                 VAGGIYYYYGMDV 
                 164 
               
               
                   
               
               
                 M12 
                 GYTFTGYYMH 
                 121 
                 RINPNSGGTNYAQKFQG 
                 142 
                 TTTSYAFDI 
                 166 
               
               
                   
               
               
                 M13 
                 GFIFSDYYMG 
                 122 
                 YIGRSGSSMYYADSVKG 
                 143 
                 SPVVAATEDFGH 
                 167 
               
               
                   
               
               
                 M14 
                 GFTFRGYYIH 
                 123 
                 IINPSGGSRAYAQKFQG 
                 144 
                 TASCGGDCYYLDY 
                 168 
               
               
                   
               
               
                 M15 
                 GFTFDDYAMH 
                 124 
                 GISWNSGSIGYADSVK 
                 145 
                 DGSSSWSWGYFDY 
                 169 
               
               
                   
               
               
                 M16 
                 GFTFDDYAMH 
                 124 
                 GISWNSGSTGYADSVKG 
                 146 
                 DSSSWYGGGSAFDI 
                 170 
               
               
                   
               
               
                 M17 
                 GFTFDDYAMH 
                 124 
                 GISWNSGSTGYADSVKG 
                 146 
                 DSSSWYGGGSAFDI 
                 171 
               
               
                   
               
               
                 M18 
                 GFTFSSYWMH 
                 125 
                 RINSDGSSTSYADSVKG 
                 147 
                 TGWVGSYYYYMDV 
                 172 
               
               
                   
               
               
                 M19 
                 GFTFSSYGMH 
                 126 
                 VISYDGSNKYYADSVKG 
                 148 
                 GYSRYYYYGMDV 
                 173 
               
               
                   
               
               
                 M20 
                 GFTFSSYAMS 
                 127 
                 AISGSGGSTYYADSVKG 
                 149 
                 REAAAGHDWYFDL 
                 174 
               
               
                   
               
               
                 M21 
                 GYTFTSYYMH 
                 128 
                 IINPSGGSTSYAQKFQG 
                 150 
                 SPRVTTGYFDY 
                 175 
               
               
                   
               
               
                 M22 
                 GDTSTRHYIH 
                 129 
                 VINPTTGPATGSPAYAQMLQG 
                 151 
                 SVVGRSAPYYFDY 
                 176 
               
               
                   
               
               
                 M23 
                 GYTFTNYYMH 
                 130 
                 IINPSGGYTTYAQKFQG 
                 152 
                 IRSCGGDCYYFDN 
                 177 
               
               
                   
               
               
                 M24 
                 GFSLSTAGVHVG 
                 131 
                 LISWADDKRYRPSLRS 
                 153 
                 QGFDGYEAN 
                 178 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Amino acid sequences for the light chain (LC) CDR1, 
               
               
                 CDR2, and CDR3 regions of human anti-mesothelin scFvs 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 SEQ 
                   
                 SEQ 
                   
                 SEQ 
               
               
                 Description 
                 LC-CDR1 
                 ID NO: 
                 LC-CDR2 
                 ID NO: 
                 LC-CDR3 
                 ID NO: 
               
               
                   
               
               
                 M5 
                 RASQSIRYYLS 
                 184 
                 TASILQN 
                 203 
                 LQTYTTPD 
                 234 
               
               
                   
               
               
                 M11 
                 RASQSIRYYLS 
                 190 
                 TASILQN 
                 215 
                 LQTYTTPD 
                 240 
               
               
                   
               
               
                 Ss1 
                 SASSSVSYMH 
                 204 
                 DTSKLAS 
                 229 
                 QQWSGYPLT 
                 254 
               
               
                   
               
               
                 M1 
                 RASQSVSSNFA 
                 180 
                 DASNRAT 
                 205 
                 HQRSNWLYT 
                 230 
               
               
                   
               
               
                 M2 
                 QASQDISNSLN 
                 181 
                 DASTLET 
                 206 
                 QQHDNLPLT 
                 231 
               
               
                   
               
               
                 M3 
                 RASQSINTYLN 
                 182 
                 AASSLQS 
                 207 
                 QQSFSPLT 
                 232 
               
               
                   
               
               
                 M4 
                 RASQSISDRLA 
                 183 
                 KASSLES 
                 208 
                 QQYGHLPMYT 
                 233 
               
               
                   
               
               
                 M6 
                 RASQGVGRWLA 
                 185 
                 AASTLQS 
                 210 
                 QQANSFPLT 
                 235 
               
               
                   
               
               
                 M7 
                 RASQSVYTKYLG 
                 186 
                 DASTRAT 
                 211 
                 QHYGGSPLIT 
                 236 
               
               
                   
               
               
                 M8 
                 RASQDSGTWLA 
                 187 
                 DASTLED 
                 212 
                 QQYNSYPLT 
                 237 
               
               
                   
               
               
                 M9 
                 RASQDISSALA 
                 188 
                 DASSLES 
                 213 
                 QQFSSYPLT 
                 238 
               
               
                   
               
               
                 M10 
                 KSSHSVLYNRNNKNYLA 
                 189 
                 WASTRKS 
                 214 
                 QQTQTFPLT 
                 239 
               
               
                   
               
               
                 M12 
                 RASQSISTWLA 
                 191 
                 KASTLES 
                 216 
                 QQYNTYSPYT 
                 241 
               
               
                   
               
               
                 M13 
                 RASQSVTSNYLA 
                 192 
                 GASTRAT 
                 217 
                 QQYGSAPVT 
                 242 
               
               
                   
               
               
                 M14 
                 RASENVNIWLA 
                 193 
                 KSSSLAS 
                 218 
                 QQYQSYPLT 
                 243 
               
               
                   
               
               
                 M15 
                 QGDALRSYYAS 
                 194 
                 GKNNRPS 
                 219 
                 NSRDSSGYPV 
                 244 
               
               
                   
               
               
                 M16 
                 QGDSLRSYYAS 
                 195 
                 GRSRRPS 
                 220 
                 NSRDNTANHYV 
                 245 
               
               
                   
               
               
                 M17 
                 QGDSLRSYYAS 
                 196 
                 GKNNRPS 
                 221 
                 NSRGSSGNHYV 
                 246 
               
               
                   
               
               
                 M18 
                 RASQSVSSNYLA 
                 197 
                 DVSTRAT 
                 222 
                 QQRSNWPPWT 
                 247 
               
               
                   
               
               
                 M19 
                 RASQSVYTKYLG 
                 198 
                 DASTRAT 
                 223 
                 QHYGGSPLIT 
                 248 
               
               
                   
               
               
                 M20 
                 RASQSISSYLN 
                 199 
                 AASSLQS 
                 224 
                 QQSYSIPLT 
                 249 
               
               
                   
               
               
                 M21 
                 RASQSISSWLA 
                 200 
                 KASSLES 
                 225 
                 QQYSSYPLT 
                 250 
               
               
                   
               
               
                 M22 
                 RASQGISDYS 
                 201 
                 AASTLQS 
                 226 
                 QQYYSYPLT 
                 251 
               
               
                   
               
               
                 M23 
                 RASENVNIWLA 
                 202 
                 KSSSLAS 
                 227 
                 QQYQSYPLT 
                 252 
               
               
                   
               
               
                 M24 
                 RASRGISSALA 
                 203 
                 DASSLES 
                 228 
                 QQSYSTPWT 
                 253 
               
               
                   
               
            
           
         
       
     
     Any known anti-mesothelin binding domain, from, for example, a known antibody, bispecific molecule or CAR, may be suitable for use in the TA CAR of the present invention. For example, the antigen binding domain against mesothelin is or may be derived from an antigen binding, e.g., CDRs or VH and VL, of an antibody, antigen-binding fragment or CAR described in, e.g., PCT publication WO2015/090230. In embodiments, the antigen binding domain against mesothelin is or is derived from an antigen binding portion, e.g., CDRs or VH and VL, of an antibody, antigen-binding fragment, or CAR described in, e.g., PCT publication WO1997/025068, WO1999/028471, WO2005/014652, WO2006/099141, WO2009/045957, WO2009/068204, WO2013/142034, WO2013/040557, or WO2013/063419. 
     In one embodiment, the mesothelin 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 mesothelin binding domain described herein, e.g., provided in Table 2 or 4, 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 mesothelin binding domain described herein, e.g., provided in Table 2 or 3. In one embodiment, the mesothelin binding domain comprises one, two, or all of LC CDR1, LC CDR2, and LC CDR3 of any amino acid sequences as provided in Table 4; and one, two or three of all of HC CDR1, HC CDR2 and HC CDR3, of any amino acid sequences as provided in Table 3. 
     In one embodiment, the mesothelin antigen binding domain comprises:
         (i) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 184, a LC CDR2 amino acid sequence of SEQ ID NO: 209, and a LC CDR3 amino acid sequence of SEQ ID NO: 234; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 115, a HC CDR2 amino acid sequence of SEQ ID NO: 134, and a HC CDR3 amino acid sequence of SEQ ID NO: 159;   (ii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 190, a LC CDR2 amino acid sequence of SEQ ID NO: 215, and a LC CDR3 amino acid sequence of SEQ ID NO: 240; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 121, a HC CDR2 amino acid sequence of SEQ ID NO: 141, and a HC CDR3 amino acid sequence of SEQ ID NO: 165;   (iii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 204, a LC CDR2 amino acid sequence of SEQ ID NO: 229, and a LC CDR3 amino acid sequence of SEQ ID NO: 254; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 132, a HC CDR2 amino acid sequence of SEQ ID NO: 154, and a HC CDR3 amino acid sequence of SEQ ID NO: 179;   (iv) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 180, a LC CDR2 amino acid sequence of SEQ ID NO: 205, and a LC CDR3 amino acid sequence of SEQ ID NO: 230; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 113, a HC CDR2 amino acid sequence of SEQ ID NO: 133, and a HC CDR3 amino acid sequence of SEQ ID NO: 155;   (v) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 181, a LC CDR2 amino acid sequence of SEQ ID NO: 206, and a LC CDR3 amino acid sequence of SEQ ID NO: 231; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 113, a HC CDR2 amino acid sequence of SEQ ID NO: 134, and a HC CDR3 amino acid sequence of SEQ ID NO: 156;   (vi) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 182, a LC CDR2 amino acid sequence of SEQ ID NO: 207, and a LC CDR3 amino acid sequence of SEQ ID NO: 232; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 113, a HC CDR2 amino acid sequence of SEQ ID NO: 134, and a HC CDR3 amino acid sequence of SEQ ID NO: 157;   (vii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 183, a LC CDR2 amino acid sequence of SEQ ID NO: 208, and a LC CDR3 amino acid sequence of SEQ ID NO: 233; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 114, a HC CDR2 amino acid sequence of SEQ ID NO: 135, and a HC CDR3 amino acid sequence of SEQ ID NO: 158;   (viii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 186, a LC CDR2 amino acid sequence of SEQ ID NO: 210, and a LC CDR3 amino acid sequence of SEQ ID NO: 235; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 116, a HC CDR2 amino acid sequence of SEQ ID NO: 136, and a HC CDR3 amino acid sequence of SEQ ID NO: 160;   (ix) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 186, a LC CDR2 amino acid sequence of SEQ ID NO: 211, and a LC CDR3 amino acid sequence of SEQ ID NO: 236; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 117, a HC CDR2 amino acid sequence of SEQ ID NO: 137, and a HC CDR3 amino acid sequence of SEQ ID NO: 161;   (x) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 187, a LC CDR2 amino acid sequence of SEQ ID NO: 212, and a LC CDR3 amino acid sequence of SEQ ID NO: 237; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 118, a HC CDR2 amino acid sequence of SEQ ID NO: 138, and a HC CDR3 amino acid sequence of SEQ ID NO: 162;   (xi) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 188, a LC CDR2 amino acid sequence of SEQ ID NO: 213, and a LC CDR3 amino acid sequence of SEQ ID NO: 238; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 119, a HC CDR2 amino acid sequence of SEQ ID NO: 139, and a HC CDR3 amino acid sequence of SEQ ID NO: 163;   (xii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 189, a LC CDR2 amino acid sequence of SEQ ID NO: 214, and a LC CDR3 amino acid sequence of SEQ ID NO: 239; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 120, a HC CDR2 amino acid sequence of SEQ ID NO: 140, and a HC CDR3 amino acid sequence of SEQ ID NO: 164;   (xiii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 191, a LC CDR2 amino acid sequence of SEQ ID NO: 216, and a LC CDR3 amino acid sequence of SEQ ID NO: 241; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 121, a HC CDR2 amino acid sequence of SEQ ID NO: 142, and a HC CDR3 amino acid sequence of SEQ ID NO: 166;   (xiv) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 192, a LC CDR2 amino acid sequence of SEQ ID NO: 217, and a LC CDR3 amino acid sequence of SEQ ID NO: 242; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 122, a HC CDR2 amino acid sequence of SEQ ID NO: 143, and a HC CDR3 amino acid sequence of SEQ ID NO: 167;   (xv) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 193, a LC CDR2 amino acid sequence of SEQ ID NO: 218, and a LC CDR3 amino acid sequence of SEQ ID NO: 243; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 123, a HC CDR2 amino acid sequence of SEQ ID NO: 144, and a HC CDR3 amino acid sequence of SEQ ID NO: 168;   (xvi) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 194, a LC CDR2 amino acid sequence of SEQ ID NO: 219, and a LC CDR3 amino acid sequence of SEQ ID NO: 244; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 124, a HC CDR2 amino acid sequence of SEQ ID NO: 145, and a HC CDR3 amino acid sequence of SEQ ID NO: 169;   (xvii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 195, a LC CDR2 amino acid sequence of SEQ ID NO: 220, and a LC CDR3 amino acid sequence of SEQ ID NO: 245; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 124, a HC CDR2 amino acid sequence of SEQ ID NO: 146, and a HC CDR3 amino acid sequence of SEQ ID NO: 170;   (xviii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 196, a LC CDR2 amino acid sequence of SEQ ID NO: 221, and a LC CDR3 amino acid sequence of SEQ ID NO: 246; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 124, a HC CDR2 amino acid sequence of SEQ ID NO: 146, and a HC CDR3 amino acid sequence of SEQ ID NO: 171;   (xix) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 197, a LC CDR2 amino acid sequence of SEQ ID NO: 222, and a LC CDR3 amino acid sequence of SEQ ID NO: 247; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 125, a HC CDR2 amino acid sequence of SEQ ID NO: 147, and a HC CDR3 amino acid sequence of SEQ ID NO: 172;   (xx) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 198, a LC CDR2 amino acid sequence of SEQ ID NO: 223, and a LC CDR3 amino acid sequence of SEQ ID NO: 248; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 126, a HC CDR2 amino acid sequence of SEQ ID NO: 148, and a HC CDR3 amino acid sequence of SEQ ID NO: 173;   (xxi) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 199, a LC CDR2 amino acid sequence of SEQ ID NO: 224, and a LC CDR3 amino acid sequence of SEQ ID NO: 249; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 127, a HC CDR2 amino acid sequence of SEQ ID NO: 149, and a HC CDR3 amino acid sequence of SEQ ID NO: 174;   (xxii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 200, a LC CDR2 amino acid sequence of SEQ ID NO: 225, and a LC CDR3 amino acid sequence of SEQ ID NO: 250; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 128, a HC CDR2 amino acid sequence of SEQ ID NO: 150, and a HC CDR3 amino acid sequence of SEQ ID NO: 175;   (xxiii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 201, a LC CDR2 amino acid sequence of SEQ ID NO: 226, and a LC CDR3 amino acid sequence of SEQ ID NO: 251; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 129, a HC CDR2 amino acid sequence of SEQ ID NO: 151, and a HC CDR3 amino acid sequence of SEQ ID NO: 176;   (xxiv) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 202, a LC CDR2 amino acid sequence of SEQ ID NO: 227, and a LC CDR3 amino acid sequence of SEQ ID NO: 252; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 130, a HC CDR2 amino acid sequence of SEQ ID NO: 152, and a HC CDR3 amino acid sequence of SEQ ID NO: 177; or   (xxv) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 203, a LC CDR2 amino acid sequence of SEQ ID NO: 228, and a LC CDR3 amino acid sequence of SEQ ID NO: 253; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 131, a HC CDR2 amino acid sequence of SEQ ID NO: 153, and a HC CDR3 amino acid sequence of SEQ ID NO: 178.       

     In one embodiment, the mesothelin 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 mesothelin binding domain is a scFv comprising a light chain and a heavy chain of an amino acid sequence listed in Table 2. In an embodiment, the mesothelin 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 2, or a sequence with 95-99% identity with an amino acid sequence provided in 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, 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 2, or a sequence with 95-99%/o identity to an amino acid sequence provided in Table 2. 
     In one embodiment, the mesothelin binding domain comprises an amino acid sequence selected from a group consisting of SEQ ID NO: 46; SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 53; SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60; 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: 69; and SEQ ID NO: 70; or 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) to any of the aforesaid sequences; or a sequence with 95-99% identity to any of the aforesaid sequences. In one embodiment, the mesothelin 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 mesothelin binding domain includes a (Gly4-Ser)n linker, wherein n is 1, 2, 3, 4, 5, or 6, preferably 4 (SEQ ID NO: 80). 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 an embodiment, the antigen binding domain of a TA CAR, e.g., a TA CAR expressed by a cell of the invention, binds to human EGFRvIII. In an embodiment, the antigen binding domain is a murine scFv domain that binds to human EGFRvIII such as, e.g., mu310C. In an embodiment, the antigen binding domain is a humanized antibody or antibody fragment, e.g., scFv domain, derived from the murine mu310C scFv. Exemplary humanized scFv domains (and their sequences) and murine SS1 scFv that bind to EGFRvIII are provided in Table 5. In an embodiment, the antigen binding domain of a TA CAR, e.g., a TA CAR expressed by a cell of the invention, binds to human claudin 6 (CLDN6). In an embodiment, the antigen binding domain is a murine scFv domain that binds to human CLDN6. In an embodiment, the antigen binding domain is a humanized antibody or antibody fragment. Exemplary scFv domains (and their sequences) that bind to CLDN6 are provided in Table 5. The scFv domain sequences provided in Table 5 include a light chain variable region (VL) and a heavy chain variable region (VH). The VL and VH are attached by a linker comprising the sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 29), e.g., in the following orientation: VL-linker-VH. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Antigen binding domains that bind to the tumor antigen EGFRvIII 
               
            
           
           
               
               
               
               
            
               
                 Tumor 
                   
                   
                 SEQ 
               
               
                 antigen 
                 Name 
                 Amino acid sequence 
                 ID NO: 
               
               
                   
               
               
                 EGFR 
                 huscFv1 
                 Eiqlvqsgaevkkpgatvkisckgsgfniedyyihwvqqapgkglewmgridpendet 
                  71 
               
               
                 vIII 
                   
                 kygpifqgrvtitadtstntvymelsslrsedtavyycafrggvywgqgttvtvssgg 
                   
               
               
                   
                   
                 ggsggggsggggsggggsdvvmtqspdslavslgeratinckssqslldsdgktylnw 
                   
               
               
                   
                   
                 lqqkpgqppkrlislvskldsgvpdrfsgsgsgtdftltisslqaedvavyycwqgth 
                   
               
               
                   
                   
                 fpgtfgggtkveik 
                   
               
               
                   
               
               
                 EGFR 
                 huscFv2 
                 Dvvmtqspdslavslgeratinckssqslldsdgktylnwlqqkpgqppkrlislvsk 
                  72 
               
               
                 vIII 
                   
                 ldsgvpdrfsgsgsgtdftltisslqaedvavyycwqgthfpgtfgggtkveikgggg 
                   
               
               
                   
                   
                 sggggsggggsggggseiqlvqsgaevkkpgatvkisckgsgfniedyyihwvqqapg 
                   
               
               
                   
                   
                 kglewmgridpendetkygpifqgrvtitadtstntvymelsslrsedtavyycafrg 
                   
               
               
                   
                   
                 gvywgqgttvtvss 
                   
               
               
                   
               
               
                 EGFR 
                 huscFv3 
                 Eiqlvqsgaevkkpgeslrisckgsgfniedyyihwvrqmpgkglewmgridpendet 
                  73 
               
               
                 vIII 
                   
                 kygpifqghvtisadtsintvylqwsslkasdtamyycafrggvywgqgttvtvssgg 
                   
               
               
                   
                   
                 ggsggggsggggsggggsdvvmtqsplslpvtlgqpasisckssqslldsdgktylnw 
                   
               
               
                   
                   
                 lqqrpgqsprrlislvskldsgvpdrfsgsgsgtdftlkisrveaedvgvyycwqgth 
                   
               
               
                   
                   
                 fpgtfgggtkveik 
                   
               
               
                   
               
               
                 EGFR 
                 huscFv4 
                 Dvvmtqsplslpvtlgqpasisckssqslldsdgktylnwlqqrpgqsprrlislvsk 
                  74 
               
               
                 vIII 
                   
                 ldsgvpdrfsgsgsgtdftlkisrveaedvgvyycwqghtfpgtfgggtkveikgggg 
                   
               
               
                   
                   
                 sggggsggggsggggseiqlvqsgaevkkpgeslrisckgsgfniedyyihwvrqmpg 
                   
               
               
                   
                   
                 kglewvmgridpendetkygpifqghvtisadtsintvylqwsslkasdtamyycafr 
                   
               
               
                   
                   
                 ggvywgqgttvtvss 
                   
               
               
                   
               
               
                 EGFR 
                 huscFv5 
                 Eiqlvqsgaevkkpgatvkisckgsgfniedyyihwvqqapgkglewmgridpendet 
                  75 
               
               
                 vIII 
                   
                 kygpifqgrvtitadtstntvymelsslrsedtavyycafrggvywgqgttvtvssgg 
                   
               
               
                   
                   
                 ggsggggsggggsggggsdvvmtqsplslpvtlgqpasisckssqslldsdgktylnw 
                   
               
               
                   
                   
                 lqqrpgqsprrlislvskldsgvpdrfsgsgsgtdftlkisrveaedvgvyycwqgth 
                   
               
               
                   
                   
                 fpgtffftkveik 
                   
               
               
                   
               
               
                 EGFR 
                 huscFv6 
                 Eiqlvqsgaevkkpgeslrisckgsgfniedyyihwvrqmpgkglewmgridpendet 
                  76 
               
               
                 vIII 
                   
                 kygpifqghvtisadtsintvylqwsslkasdtamyycafrggvywgqgttvtvssgg 
                   
               
               
                   
                   
                 ggsggggsggggsggggsdvvmtqspdslavslgeratinckssqslldsdgktylnw 
                   
               
               
                   
                   
                 lqqkpgqppkrlislvskldsgvpdrfsgsgsgtdftltisslqaedvavyycwqgth 
                   
               
               
                   
                   
                 fpgtfgggtkveik 
                   
               
               
                   
               
               
                 EGFR 
                 huscFv7 
                 Dvvmtqspdslavslgeratinckssqslldsdgktylnwlqqkpgqppkrlislvsk 
                  77 
               
               
                 vIII 
                   
                 ldsgvpdrfsgsgsgtdftltisslqaedvavyycwqgthfpgtfgggtkveikgggg 
                   
               
               
                   
                   
                 sggggsggggsggggseiqlvqsgaevkkpgeslrisckgsgfniedyyihwvrqmpg 
                   
               
               
                   
                   
                 kglewmgridpendetkygpifqghvtisadtsintvylqwsslkasdtamyycafrg 
                   
               
               
                   
                   
                 gvywgqgttvtvss 
                   
               
               
                   
               
               
                 EGFR 
                 huscFv8 
                 Dvvmtqsplslpvtlgqpasisckssqslldsdgktylnwlqqrpgpsprrlislvsk 
                  78 
               
               
                 vIII 
                   
                 ldsgvpdrfsgsgsgtdftlkisrveaedvgvyycwqgthfpgtfgggtkveikgggg 
                   
               
               
                   
                   
                 sggggsggggsggggseiqlvqsgaevkkpgatvkisckgsgfniedyyihwvqqapg 
                   
               
               
                   
                   
                 kglewmgridpendetkygpifqgrvtitadtstntvymelsslrsedtavyycafrg 
                   
               
               
                   
                   
                 gvywgqgttvtvss 
                   
               
               
                   
               
               
                 EGFR 
                 Mu310C 
                 eiqlqqsgaelvkpgasvklsctgsgfniedyyihwvkqrteqglewigridpendet 
                  79 
               
               
                 vIII 
                   
                 kygpifqgratitadtssntvylqlssltsedtavyycafrggvywgpgttltvssgg 
                   
               
               
                   
                   
                 ggsggggsggggshmdvvmtqspltlsvaigqsasisckssqslldsdgktylnwllq 
                   
               
               
                   
                   
                 rpgqspkrlislvskldsgvpdrftgsgsgtdftlrisrveaedlgiyycwqghtfpg 
                   
               
               
                   
                   
                 tfgggtkleik 
                   
               
               
                   
               
               
                 Claudin6 
                 muMAB 
                 EVQLQQSGPELVKPGASMKISCKASGYSFTGYTMNWVKQSHGKNLEWIGLINPYNGGT 
                  98 
               
               
                   
                 64A 
                 IYNQKFKGKATLTVDKSSSTAYMELLSLTSEDSAVYYCARDYGFVLDYWGQGTTLTVS 
                   
               
               
                   
                   
                 SGGGGSGGGGSGGGGSGGGGSQIVLTQSPSIMSVSPGEKVTITCSASSSVSYMHWFQQ 
                   
               
               
                   
                   
                 KPGTSPKLCIYSTSNLASGVPARFSGRGSGTSYSLTISRVAAEDAATYYCQQRSNYPP 
                   
               
               
                   
                   
                 WTFGGGTKLEIK 
                   
               
               
                   
               
               
                 Claudin6 
                 mAb206- 
                 EVQLQQSGPELVKPGASMKISCKASGYSFTGYTMNWVKQSHGKNLEWIGLINPYNGGT 
                  99 
               
               
                   
                 LCC 
                 IYNQKFKGKATLTVDKSSSTAYMELLSLTSEDSAVYYCARDYGFVLDYWGQGTTLTVS 
                   
               
               
                   
                   
                 SGGGGSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTITCSASSSVSYLHWFQQ 
                   
               
               
                   
                   
                 KPGTSPKLWVYSTSNLPSGVPARFGGSGSGTSYSLTISRMEAEDAATYYCQQRSIYPP 
                   
               
               
                   
                   
                 WTFGGGTKLEIK 
                   
               
               
                   
               
               
                 Claudin6 
                 mAb206- 
                 EVQLQQSGPELVKPGASMKISCKASGYSFTGYTMNWVKQSHGKNLEWIGLINPYNGGT 
                 100 
               
               
                   
                 SUBG 
                 IYNQKFKGKATLTVDKSSSTAYMELLSLTSEDSAVYYCARDYGFVLDYWGQGTTLVTV 
                   
               
               
                   
                   
                 SSGGGGSGGGGSGGGGSGGGGSQIVLTQSPSIMSVSPGEKVTITCSASSSVSYMHWFQ 
                   
               
               
                   
                   
                 QKPGTSPKLGIYSTSNLASGVPARFSGRGSGTSYSLTISRVAAEDAATYYCQQRSNYP 
                   
               
               
                   
                   
                 PWTFGGGTKLEIK 
               
               
                   
               
            
           
         
       
     
     In one embodiment, the EGFRvIII 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 an EGFRvIII binding domain described herein, e.g., provided in Table 5, 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 an EGFRvIII binding domain described herein, e.g., provided in Table 5. 
     In one embodiment, the EGFRvII binding domain comprises a light chain variable region described herein (e.g., in Table 5) and/or a heavy chain variable region described herein (e.g., in Table 5). In one embodiment, the EGFRvIII binding domain is a scFv comprising a light chain and a heavy chain of an amino acid sequence listed in Table 5. In an embodiment, the EGFRvIII 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 5, or a sequence with 95-99% identity with an amino acid sequence provided in Table 5; 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 5, or a sequence with 95-99% identity to an amino acid sequence provided in Table 5. 
     In one embodiment, the EGFRvIII binding domain comprises an amino acid sequence selected from a group consisting of SEQ ID NO: 71; SEQ ID NO: 72; SEQ ID NO: 73; SEQ ID NO: 74; SEQ ID NO: 75; SEQ ID NO: 76; SEQ ID NO: 77; SEQ ID NO: 78; and SEQ ID NO: 79; or 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) to any of the aforesaid sequences; or a sequence with 95-99% identity to any of the aforesaid sequences. In one embodiment, the EGFRvIII binding domain is a scFv, and a light chain variable region comprising an amino acid sequence described herein, e.g., in Table 5, is attached to a heavy chain variable region comprising an amino acid sequence described herein, e.g., in Table 5, via a linker, e.g., a linker described herein. In one embodiment, the EGFRvIII binding domain includes a (Gly4-Ser)n linker, wherein n is 1, 2, 3, 4, 5, or 6, preferably 4 (SEQ ID NO: 80). 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 claudin-6 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 an EGFRvIII binding domain described herein, e.g., provided in Table 5, 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 an claudin-6 binding domain described herein, e.g., provided in Table 5. 
     In one embodiment, the claudin-6 binding domain comprises a light chain variable region described herein (e.g., in Table 5) and/or a heavy chain variable region described herein (e.g., in Table 5). In one embodiment, the claudin-6 binding domain is a scFv comprising a light chain and a heavy chain of an amino acid sequence listed in Table 5. In an embodiment, the claudin-6 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 5, or a sequence with 95-99% identity with an amino acid sequence provided in Table 5; 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 5, or a sequence with 95-99% identity to an amino acid sequence provided in Table 5. 
     In one embodiment, the claudin-6 binding domain comprises an amino acid sequence selected from a group consisting of SEQ ID NO: 98; SEQ ID NO: 99; and SEQ ID NO: 100; or 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) to any of the aforesaid sequences; or a sequence with 95-99% identity to any of the aforesaid sequences. In one embodiment, the claudin-6 binding domain is a scFv, and a light chain variable region comprising an amino acid sequence described herein, e.g., in Table 5, is attached to a heavy chain variable region comprising an amino acid sequence described herein, e.g., in Table 5, via a linker, e.g., a linker described herein. In one embodiment, the claudin-6 binding domain includes a (Gly4-Ser)n linker, wherein n is 1, 2, 3, 4, 5, or 6, preferably 4 (SEQ ID NO: 80). 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, an antigen binding domain against GD2 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Mujoo et al., Cancer Res. 47(4):1098-1104 (1987); Cheung et al., Cancer Res 45(6):2642-2649 (1985), Cheung et al., J Clin Oncol 5(9):1430-1440 (1987), Cheung et al., J Clin Oncol 16(9):3053-3060 (1998), Handgretinger et al., Cancer Immunol Immunother 35(3):199-204 (1992). In some embodiments, an antigen binding domain against GD2 is an antigen binding portion of an antibody selected from mAb 14.18, 14G2a, ch14.18, hu14.18, 3F8, hu3F8, 3G6, 8B6, 60C3, 10B8, ME36.1, and 8H9, see e.g., WO2012033885, WO2013040371, WO2013192294, WO2013061273, WO2013123061, WO2013074916, and WO201385552. In some embodiments, an antigen binding domain against GD2 is an antigen binding portion of an antibody described in US Publication No.: 20100150910 or PCT Publication No.: WO 2011160119. 
     In one embodiment, an antigen binding domain against the Tn antigen, the sTn antigen, a Tn-O-glycopeptide antigen, or a sTn-O-glycopeptide antigen is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., US 2014/0178365, WO2015/120180, U.S. Pat. No. 8,440,798, EP 2083868 A2, Brooks et al., PNAS 107(22): 10056-10061 (2010), and Stone et al., Oncolmmunology 1(6):863-873(2012). 
     In one embodiment, an antigen binding domain against PSMA is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Parker et al., Protein Expr Purif 89(2): 136-145 (2013), US 20110268656 (J591 ScFv); Frigerio et al, European J Cancer 49(9):2223-2232 (2013) (scFvD2B); WO 2006125481 (mAbs 3/A12, 3/E7 and 3/F11) and single chain antibody fragments (scFv A5 and D7). 
     In one embodiment, an antigen binding domain against CD97 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., U.S. Pat. No. 6,846,911; de Groot et al., J Immunol 183(6):4127-4134 (2009); or an antibody from R&amp;D:MAB3734. 
     In one embodiment, an antigen binding domain against TAG72 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Hombach et al., Gastroenterology 113(4):1163-1170 (1997); and Abcam ab691. 
     In one embodiment, an antigen binding domain against CD44v6 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Casucci et al., Blood 122(20):3461-3472 (2013). 
     In one embodiment, an antigen binding domain against CEA is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Chmielewski et al., Gastoenterology 143(4): 1095-1107 (2012). 
     In one embodiment, an antigen binding domain against EPCAM is an antigen binding portion, e.g., CDRS, of an antibody selected from MT110, EpCAM-CD3 bispecific Ab (see, e.g., clinicaltrials.gov/ct2/show/NCT00635596); Edrecolomab; 3622W94; ING-1; and adecatumumab (MT201). 
     In one embodiment, an antigen binding domain against KIT is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., U.S. Pat. No. 7,915,391, US20120288506, and several commercial catalog antibodies. 
     In one embodiment, an antigen binding domain against IL-13Ra2 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., WO2008/146911, WO2004087758, several commercial catalog antibodies, and WO2004087758. 
     In one embodiment, an antigen binding domain against CD171 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Hong et al., J Immunother 37(2):93-104 (2014). 
     In one embodiment, an antigen binding domain against PSCA is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Morgenroth et al., Prostate 67(10): 1121-1131 (2007) (scFv 7F5); Nejatollahi et al., J of Oncology 2013(2013), article ID 839831 (scFv C5-II); and US Pat Publication No. 20090311181. 
     In one embodiment, an antigen binding domain against MAD-CT-2 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., PMID: 2450952; U.S. Pat. No. 7,635,753. 
     In one embodiment, an antigen binding domain against Folate receptor alpha is an antigen binding portion, e.g., CDRs, of the antibody IMGN853, or an antibody described in US20120009181; U.S. Pat. No. 4,851,332, LK26: U.S. Pat. No. 5,952,484. 
     In one embodiment, an antigen binding domain against ERBB2 (Her2/neu) is an antigen binding portion, e.g., CDRs, of the antibody trastuzumab, or pertuzumab. 
     In one embodiment, an antigen binding domain against MUC1 is an antigen binding portion, e.g., CDRs, of the antibody SAR566658. 
     In one embodiment, the antigen binding domain against EGFR is antigen binding portion, e.g., CDRs, of the antibody cetuximab, panitumumab, zalutumumab, nimotuzumab, or matuzumab. 
     In one embodiment, an antigen binding domain against NCAM is an antigen binding portion, e.g., CDRs, of the antibody clone 2-2B: MAB5324 (EMD Millipore) In one embodiment, an antigen binding domain against CAIX is an antigen binding portion, e.g., CDRs, of the antibody clone 303123 (R&amp;D Systems). 
     In one embodiment, an antigen binding domain against Fos-related antigen 1 is an antigen binding portion, e.g., CDRs, of the antibody 12F9 (Novus Biologicals). 
     In one embodiment, an antigen binding domain against SSEA-4 is an antigen binding portion, e.g., CDRs, of antibody MC813 (Cell Signaling), or other commercially available antibodies. 
     In one embodiment, an antigen binding domain against PDGFR-beta is an antigen binding portion, e.g., CDRs, of an antibody Abcam ab32570. 
     In one embodiment, an antigen binding domain against ALK is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Mino-Kenudson et al., Clin Cancer Res 16(5):1561-1571 (2010). 
     In one embodiment, an antigen binding domain against plysialic acid is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Nagae et al., J Biol Chem 288(47):33784-33796 (2013). 
     In one embodiment, an antigen binding domain against PLAC1 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Ghods et al., Biotechnol Appl Biochem 2013 doi:10.1002/bab.1177. 
     In one embodiment, an antigen binding domain against GloboH is an antigen binding portion of the antibody VK9; or an antibody described in, e.g., Kudryashov V et al, Glycoconj J. 15(3):243-9 (1998), Lou et al., Proc Natl Acad Sci USA 111(7):2482-2487 (2014); MBrl: Bremer E-G et al. J Biol Chem 259:14773-14777 (1984). 
     In one embodiment, an antigen binding domain against NY-BR-1 is an antigen binding portion, e.g., CDRs of an antibody described in, e.g., Jager et al., Appl Immunohistochem Mol Morphol 15(1):77-83 (2007). 
     In one embodiment, an antigen binding domain against sperm protein 17 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Song et al., Target Oncol 2013 Aug. 14 (PMID: 23943313), Song et al., Med Oncol 29(4):2923-2931 (2012). 
     In one embodiment, an antigen binding domain against TRP-2 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Wang et al, J Exp Med. 184(6):2207-16 (1996). 
     In one embodiment, an antigen binding domain against CYPB1 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Maecker et al, Blood 102 (9): 3287-3294 (2003). 
     In one embodiment, an antigen binding domain against RAGE-1 is an antigen binding portion, e.g., CDRs, of the antibody MAB5328 (EMD Millipore). 
     In one embodiment, an antigen binding domain against human telomerase reverse transcriptase is an antigen binding portion, e.g., CDRs, of the antibody cat no: LS-B95-100 (Lifespan Biosciences) In one embodiment, an antigen binding domain against intestinal carboxyl esterase is an antigen binding portion, e.g., CDRs, of the antibody 4F12: cat no: LS-B6190-50 (Lifespan Biosciences). 
     In one embodiment, an antigen binding domain against mut hsp70-2 is an antigen binding portion, e.g., CDRs, of the antibody Lifespan Biosciences: monoclonal: cat no: LS-C133261-100 (Lifespan Biosciences). 
     In one embodiment, an antigen binding domain against MAD-CT-2 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., PMID: 2450952; U.S. Pat. No. 7,635,753. 
     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 above. 
     Myeloid Tumor Antigens 
     The present disclosure provides immune effector cells (e.g., T cells, NK cells) that are engineered to contain (in addition to one or more BCA CAR molecules) one or more CAR molecules that target a tumor antigen. In one aspect the tumor antigen is an antigen expressed on a myeloid tumor (either a surface antigen or as a comples with MHC), and the cells of the invention comprise a CAR that recognizes a myeloid tumor antigen. 
     In an embodiment, the myeloid tumor antigen is an antigen that is preferentially or specifically expressed on the surface of a myeloid tumor cell. 
     The present disclosure provides CARs that can target the following myeloid tumor antigens: CD123, CD34, Flt3, CD33 and CLL-1. In embodiments, the myeloid tumor antigen is selected from CD123, CD33 and CLL-1. In embodiments, the myeloid tumor antigen is CD123. In embodiments, the myeloid tumor antigen is CD33. In embodiments, the myeloid tumor antigen is CD34. In embodiments, the myeloid tumor antigen is Flt3. In embodiments, the myeloid tumor antigen is CLL-1. In embodiments, the antigen binding domain targets the human antigen. 
     In one embodiment, the antigen-binding domain of a TA CAR, e.g., the TA CAR expressed by a cell of the invention (e.g., a cell that also expresses a BCA CAR), can be chosen such that a myeloid tumor population is targeted. Alternatively, when targeting of more than one type of myeloid tumor is desired, an antigen binding domain that targets a myeloid tumor antigen that is expressed by more than one, e.g., all, of the myeloid tumors to be targeted can be selected. 
     In one aspect, the antigen-binding domain of a TA CAR, e.g., the TA CAR expressed by a cell of the invention, binds to CD123, e.g., human CD123. Any known CD123 binding domain may be used in the invention. In one embodiment, an antigen binding domain against CD123 is an antigen binding portion, e.g., CDRs or VH and VL, of an antibody, antigen-binding fragment or CAR described in, e.g., PCT publication WO2014/130635. In one embodiment, an antigen binding domain against CD123 is an antigen binding portion, e.g., CDRs or VH and VL, of an antibody, antigen-binding fragment or CAR described in, e.g., PCT publication WO/2016/028896. In one embodiment, an antigen binding domain against CD123 is an antigen binding portion, e.g., CDRs, of an antibody, antigen-binding fragment, or CAR described in, e.g., PCT publication WO1997/024373, WO2008/127735 (e.g., a CD123 binding domain of 26292, 32701, 37716 or 32703), WO2014/138805 (e.g., a CD123 binding domain of CSL362), WO2014/138819, WO2013/173820, WO2014/144622, WO2001/66139, WO2010/126066 (e.g., the CD123 binding domain of any of Old4, Old5, Old17, Old19, New102, or Old6), WO2014/144622, or US2009/0252742. In embodiments, the antigen binding domain is or is derived from a murine anti-human CD123 binding domain. In embodiments, the antigen binding domain is a humanized antibody or antibody fragment, e.g., scFv domain. In an embodiment, the antigen binding domain is a human antibody or antibody fragment that binds to human CD123. In embodiments, the antigen binding domain is an scFv domain which includes a light chain variable region (VL) and a heavy chain variable region (VH). The VL and VH may attached by a linker described herein, e.g., comprising the sequence GGGGSGGGGSGGGGS (SEQ ID NO: 30), and may be in any orientation, e.g., VL-linker-VH, or VH-linker-VL. 
     In one aspect, the antigen-binding domain of a TA CAR, e.g., the TA CAR expressed by a cell of the invention, binds to CD33, e.g., human CD33. Any known CD33 binding domain may be used in the invention. In one embodiment, an antigen binding domain against CD33 is an antigen binding portion, e.g., CDRs or VH and VL, of an antibody, antigen-binding fragment or CAR described in, e.g., PCT publication WO2016/014576, the contents of which are incorporated herein in their entirety. In one embodiment, an antigen binding domain against CD33 is an antigen binding portion of or derived from Gemtuzumab ozogamicin (e.g., comprising an antigen binding domain comprising one or more, e.g., one, two, or three, CDRs of the heavy chain variable domain and/or one or more, e.g., one, two, or three, CDRs of the light chain variable domain, or the VH or VL, or the scFv sequence, of the scFv sequence of Gemtuzumab ozogamicin) (previously marketed as Mylotarg), e g., Bross et al., Clin Cancer Res 7(6):1490-1496 (2001) (Gemtuzumab Ozogamicin, hP67.6). In one embodiment, an antigen binding domain against CD33 is an antigen binding portion of or derived from (e.g., comprising an antigen binding domain comprising one or more, e.g., one, two, or three, CDRs of the heavy chain variable domain and/or one or more, e.g., one, two, or three, CDRs of the light chain variable domain, or the VH or VL, or the scFv sequence) of the scFv sequence encoded by GenBank reference no. AM402974.1 (See, Wang et al., Mol. Ther., vol. 23:1, pp. 184-191 (2015), hereby incorporated by reference. In one embodiment, an antigen binding domain against CD33 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Caron et al., Cancer Res 52(24):6761-6767 (1992) (Lintuzumab, HuM195), Lapusan et al., Invest New Drugs 30(3): 1121-1131 (2012) (AVE9633), Aigner et al., Leukemia 27(5): 1107-1115 (2013) (AMG330, CD33 BiTE), Dutour et al., Adv hematol 2012:683065 (2012), and Pizzitola et al., Leukemia doi: 10.1038/Lue.2014.62 (2014). In embodiments, the antigen binding domain is or is derived from a murine anti-human CD33 binding domain. In embodiments, the antigen binding domain is a humanized antibody or antibody fragment, e.g., scFv domain. In an embodiment, the antigen binding domain is a human antibody or antibody fragment that binds to human CD33. In embodiments, the antigen binding domain is an scFv domain which includes a light chain variable region (VL) and a heavy chain variable region (VH). The VL and VH may attached by a linker described herein, e.g., comprising the sequence GGGGSGGGGSGGGGS (SEQ ID NO: 30), and may be in any orientation, e.g., VL-linker-VH, or VH-linker-VL. 
     In one aspect, the antigen-binding domain of a TA CAR, e.g., the TA CAR expressed by a cell of the invention, binds to CLL-1, e.g., human CLL-1. Any known CLL-1 binding domain may be used in the invention. In one embodiment, an antigen binding domain against CLL-1 is an antigen binding portion, e.g., CDRs or VH and VL, of an antibody, antigen-binding fragment or CAR described in, e.g., PCT publication WO2016/014535, the contents of which are incorporated herein in their entirety. In one embodiment, an antigen binding domain against CLL-1 is an antigen binding portion, e.g., CDRs, of an antibody available from R&amp;D, ebiosciences, Abcam, for example, PE-CLL1-hu Cat #353604 (BioLegend); and PE-CLL1 (CLEC12A) Cat #562566 (BD). In embodiments, the antigen binding domain is or is derived from a murine anti-human CLL-1 binding domain. In embodiments, the antigen binding domain is a humanized antibody or antibody fragment, e.g., scFv domain. In an embodiment, the antigen binding domain is a human antibody or antibody fragment that binds to human CLL-1. In embodiments, the antigen binding domain is an scFv domain which includes a light chain variable region (VL) and a heavy chain variable region (VH). The VL and VH may attached by a linker described herein, e.g., comprising the sequence GGGGSGGGGSGGGGS (SEQ ID NO: 30), and may be in any orientation, e.g., VL-linker-VH, or VH-linker-VL. 
     B Cell Antigens 
     The present disclosure provides immune effector cells (e.g., T cells, NK cells) that are engineered to contain (in addition to one or more TA CAR molecules) one or more CAR molecules that target a B-Cell antigen. This is achieved through an antigen binding domain on the CAR that is specific for a B cell antigen. Such a CAR may be referred to herein as a BCA CAR. 
     In an embodiment, the B cell antigen is an antigen that is preferentially or specifically expressed on the surface of the B cell. The antigen can be expressed on the surface of any one of the following types of B cells: progenitor B cells (e.g., pre-B cells or pro-B cells), early pro-B cells, late pro-B cells, large pre-B cells, small pre-B cells, immature B cells, e.g., naïve B cells, mature B cells, plasma B cells, plasmablasts, memory B cells, B-1 cells, B-2 cells, marginal-zone B cells, follicular B cells, germinal center B cells, or regulatory B cells (Bregs). 
     The present disclosure provides CARs that can target the following B cell antigens: CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD37, CD38, CD53, CD72, CD73, CD74, CD75, CD77, CD79a, CD79b, CD80, CD81, CD82, CD83, CD84, CD85, ROR1, BCMA, CD86, and CD179b. Other B cell antigens that can be targeted by a CAR described herein include: CD1a, CD1b, CD1c, CD1d, CD2, CD5, CD6, CD9, CD11a, CD11b, CD11c, CD17, CD18, CD26, CD27, CD29, CD30, CD31, CD32a, CD32b, CD35, CD38, CD39, CD40, CD44, CD45, CD45RA, CD45RB, CD45RC, CD45RO, CD46, CD47, CD48, CD49b, CD49c, CD49d, CD50, CD52, CD54, CD55, CD58, CD60a, CD62L, CD63, CD63, CD68 CD69, CD70, CD85E, CD85I, CD85J, CD92, CD95, CD97, CD98, CD99, CD100, CD102, CD108, CD119, CD120a, CD120b, CD121b, CD122, CD124, CD125, CD126, CD130, CD132, CD137, CD138, CD139, CD147, CD148, CD150, CD152, CD162, CD164, CD166, CD167a, CD170, CD175, CD175s, CD180, CD184, CD185, CD192, CD196, CD197, CD200, CD205, CD210a, CDw210b, CD212, CD213a1, CD213a2, CD215, CD217, CD218a, CD218b, CD220, CD221, CD224, CD225, CD226, CD227, CD229, CD230, CD232, CD252, CD253, CD257, CD258, CD261, CD262, CD263, CD264, CD267, CD268, CD269, CD270, CD272, CD274, CD275, CD277, CD279, CD283, CD289, CD290, CD295, CD298, CD300a, CD300c, CD305, CD306, CD307a, CD307b, CD307c, CD307d, CD307e, CD314, CD315, CD316, CD317, CD319, CD321, CD327, CD328, CD329, CD338, CD351, CD352, CD353, CD354, CD355, CD357, CD358, CD360, CD361, CD362, and CD363. 
     In another embodiment, the B cell antigen targeted by the BCA CAR is chosen from CD19, BCMA, CD20, CD22, FcRn5, FcRn2, CS-1 and CD138. In an embodiment, the B-Cell antigen targeted by the BCA CAR is CD19. In an embodiment, the B-Cell antigen targeted by the BCA CAR is CD20. In an embodiment, the B-Cell antigen targeted by the BCA CAR is CD22. In an embodiment, the B-Cell antigen targeted by the BCA CAR is BCMA. In an embodiment, the B-Cell antigen targeted by the BCA CAR is FcRn5. In an embodiment, the B-Cell antigen targeted by the BCA CAR is FcRn2. In an embodiment, the B-Cell antigen targeted by the BCA CAR is CS-1. In an embodiment, the B-Cell antigen targeted by the BCA CAR is CD138. 
     In one embodiment, the antigen-binding domain of a BCA CAR, e.g., the BCA CAR expressed by a cell of the invention (e.g., a cell that also expresses a TA CAR), can be chosen such that a preferred B cell population is targeted. For example, in an embodiment where targeting of B regulatory cells is desired, an antigen binding domain is selected that targets a B cell antigen that is expressed on regulatory B cells and not on other B cell populations, e.g., plasma B cells and memory B cells. Cell surface markers expressed on regulatory B cells include: CD19, CD24, CD25, CD38, or CD86, or markers described in He et al., 2014, J Immunology Research, Article ID 215471. When targeting of more than one type of B cells is desired, an antigen binding domain that targets a B cell antigen that is expressed by all of the B cells to be targeted can be selected. 
     In an embodiment, the antigen-binding domain of a BCA CAR, e.g., the BCA CAR expressed by a cell of the invention, binds to CD19. CD19 is found on B cells throughout differentiation of the lineage from the pro/pre-B cell stage through the terminally differentiated plasma cell stage. In an embodiment, the antigen binding domain is a murine scFv domain that binds to human CD19, e.g., CTL019 (e.g., SEQ ID NO: 95). In an embodiment, the antigen binding domain is a humanized antibody or antibody fragment, e.g., scFv domain, derived from the murine CTL019 scFv. In an embodiment, the antigen binding domain is a human antibody or antibody fragment that binds to human CD19. Exemplary scFv domains (and their sequences, e.g., CDRs, VL and VH sequences) that bind to CD19 are provided in Table 6. The scFv domain sequences provided in Table 6 include a light chain variable region (VL) and a heavy chain variable region (VH). The VL and VH are attached by a linker comprising the sequence GGGGSGGGGSGGGGS (SEQ ID NO: 30), e.g., in the following orientation: VL-linker-VH. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Antigen binding domains that bind B cell antigen CD19 
               
            
           
           
               
               
               
               
            
               
                 B cell 
                   
                   
                   
               
               
                 antigen 
                 Name 
                 Amino Acid Sequence 
                 SEQ ID NO: 
               
               
                   
               
               
                 CD19 
                 muCTL 
                 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVK 
                 95 
               
               
                   
                 019 
                 LLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQ 
                   
               
               
                   
                   
                 GNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQESGPGLVA 
                   
               
               
                   
                   
                 PSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTY 
                   
               
               
                   
                   
                 YNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGG 
                   
               
               
                   
                   
                 SYAMDYWGQGTSVTVSS 
                   
               
               
                   
               
               
                 CD19 
                 huscFv1 
                 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPR 
                 83 
               
               
                   
                   
                 LLIHYTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQ 
                   
               
               
                   
                   
                 GNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVK 
                   
               
               
                   
                   
                 PSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTY 
                   
               
               
                   
                   
                 YSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGG 
                   
               
               
                   
                   
                 SYAMDYWGQGTLVTVSS 
                   
               
               
                   
               
               
                 CD19 
                 huscFv2 
                 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPR 
                 84 
               
               
                   
                   
                 LLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYVCQQ 
                   
               
               
                   
                   
                 GNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVK 
                   
               
               
                   
                   
                 PSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTY 
                   
               
               
                   
                   
                 YQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGG 
                   
               
               
                   
                   
                 SYAMDYGQGTLVTVSS 
                   
               
               
                   
               
               
                 CD19 
                 huscFv3 
                 QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGL 
                 85 
               
               
                   
                   
                 EWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADT 
                   
               
               
                   
                   
                 AVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGS 
                   
               
               
                   
                   
                 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPR 
                   
               
               
                   
                   
                 LLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQ 
                   
               
               
                   
                   
                 GNTLPYTFGQGTKLEIK 
                   
               
               
                   
               
               
                 CD19 
                 huscFv4 
                 QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGL 
                 86 
               
               
                   
                   
                 EWIGVIWGSETTYYQSSLKSRVTISDKNSKNQVSLKLSSVTAADT 
                   
               
               
                   
                   
                 AVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGS 
                   
               
               
                   
                   
                 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPR 
                   
               
               
                   
                   
                 LLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQ 
                   
               
               
                   
                   
                 GNTLPYTFGQGTKLEIK 
                   
               
               
                   
               
               
                 CD19 
                 huscFv5 
                 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPR 
                 87 
               
               
                   
                   
                 LLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQ 
                   
               
               
                   
                   
                 GNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESG 
                   
               
               
                   
                   
                 PGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWG 
                   
               
               
                   
                   
                 SETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKH 
                   
               
               
                   
                   
                 YYYGGSYAMDYWGQGTLVTVSS 
                   
               
               
                   
               
               
                 CD19 
                 huscFv6 
                 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPR 
                 88 
               
               
                   
                   
                 LLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQ 
                   
               
               
                   
                   
                 GNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESG 
                   
               
               
                   
                   
                 PGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWG 
                   
               
               
                   
                   
                 SETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKH 
                   
               
               
                   
                   
                 YYYGGSYAMDYWGQGTLVTVSS 
                   
               
               
                   
               
               
                 CD19 
                 huscFv7 
                 QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGL 
                 89 
               
               
                   
                   
                 EWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADT 
                   
               
               
                   
                   
                 AVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGS 
                   
               
               
                   
                   
                 GGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKP 
                   
               
               
                   
                   
                 GQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAV 
                   
               
               
                   
                   
                 YFCQQGNTLPYTFGQGTKLEIK 
                   
               
               
                   
               
               
                 CD19 
                 huscFv8 
                 QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGL 
                 90 
               
               
                   
                   
                 EWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADT 
                   
               
               
                   
                   
                 AVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGS 
                   
               
               
                   
                   
                 GGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKP 
                   
               
               
                   
                   
                 GAPERLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAV 
                   
               
               
                   
                   
                 YFCQQGNTLPYTFGQGTKLEIK 
                   
               
               
                   
               
               
                 CD19 
                 huscFv9 
                 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPR 
                 91 
               
               
                   
                   
                 LLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQ 
                   
               
               
                   
                   
                 GNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESG 
                   
               
               
                   
                   
                 PGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWG 
                   
               
               
                   
                   
                 SETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKH 
                   
               
               
                   
                   
                 YYYGGSYAMDYWGOGTLVTVSS 
                   
               
               
                   
               
               
                 CD19 
                 Hu 
                 QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGL 
                 92 
               
               
                   
                 scFv10 
                 EWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADT 
                   
               
               
                   
                   
                 AVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGS 
                   
               
               
                   
                   
                 GGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKP 
                   
               
               
                   
                   
                 GQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAV 
                   
               
               
                   
                   
                 YFCQQGNTLPYTFGQGTKLEIK 
                   
               
               
                   
               
               
                 CD19 
                 Hu 
                 EIVMTQSPATLSLSPGERATLSCRASQDISKYNLWYQQKPGQAPR 
                 93 
               
               
                   
                 scFv11 
                 LLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQEPDFAVYFCQQ 
                   
               
               
                   
                   
                 GNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVK 
                   
               
               
                   
                   
                 PSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTY 
                   
               
               
                   
                   
                 YNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGG 
                   
               
               
                   
                   
                 SYAMDYWGQGTLVTVSS 
                   
               
               
                   
               
               
                 CD19 
                 Hu 
                 QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGL 
                 94 
               
               
                   
                 scFv12 
                 EWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADT 
                   
               
               
                   
                   
                 AVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGS 
                   
               
               
                   
                   
                 EIVTMQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPR 
                   
               
               
                   
                   
                 LLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQ 
                   
               
               
                   
                   
                 GNTLPYTFGQGTKLEIK 
                   
               
               
                   
               
            
           
         
       
     
     The sequences of the CDR sequences of the scFv domains of the CD19 antigen binding domains provided in Table 6 are shown in Table 7 for the heavy chain variable domains and in Table 8 for the light chain variable domains. “ID” stands for the respective SEQ ID NO for each CDR. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Heavy Chain Variable Domain CDRs 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Description 
                 FW 
                 HCDR1 
                 ID 
                 HCDR2 
                 ID 
                 HCDR3 
                 ID 
               
               
                   
               
               
                 murine_CART19 
                   
                 GVSLPDYGVS 
                 255 
                 VIWGSETTYYNSALKS 
                 256 
                 HYYYGGSYAMDY 
                 260 
               
               
                   
               
               
                 humanized_CART19 a 
                 VH4 
                 GCSLPDYGVS 
                 255 
                 VIWGSETTYY  S  LKS 
                 257 
                 HYYYGGSYAMDY 
                 260 
               
               
                   
               
               
                 humanized_CART19 b 
                 VH4 
                 GVSLPDYGVS 
                 255 
                 VIWGSETTYY  S  LKS 
                 258 
                 HYYYGGSYAMDY 
                 260 
               
               
                   
               
               
                 humanized_CART19 c 
                 VH4 
                 GVSLPDYGVS 
                 255 
                 VIWGSETTYYNS  LKS 
                 259 
                 HYYYGGSYAMDY 
                 260 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Light Chain Variable Domain CDRs 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Description 
                 FW 
                 CDR1 
                 ID 
                 LCDR2 
                 ID 
                 LCDR3 
                 ID 
               
               
                   
               
               
                 murine_CART19 
                   
                 RASQDISKYLN 
                 261 
                 HTSRLHS 
                 262 
                 QQGNTLPYT 
                 263 
               
               
                   
               
               
                 humanized_CART19 a 
                 VK3 
                 RASQDISKYLN 
                 261 
                 HTSRLHS 
                 262 
                 QQGNTLPYT 
                 263 
               
               
                   
               
               
                 humanized_CART19 b 
                 VK3 
                 RASQDISKYLN 
                 261 
                 HTSRLHS 
                 262 
                 QQGNTLPYT 
                 263 
               
               
                   
               
               
                 humanized_CART19 c 
                 VK3 
                 RASQDISKYLN 
                 261 
                 HTSRLHS 
                 262 
                 QQGNTLPYT 
                 263 
               
               
                   
               
            
           
         
       
     
     In an embodiment, the antigen binding domain comprises an anti-CD19 antibody, or fragment thereof, e.g., an scFv. For example, the antigen binding domain comprises a variable heavy chain and a variable light chain listed in Table 9. The linker sequence joining the variable heavy and variable light chains can be any of the linker sequences described herein, or alternatively, can be GSTSGSGKPGSGEGSTKG (SEQ ID NO: 81). 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. 
     
       
         
           
               
             
               
                 TABLE 9 
               
               
                   
               
               
                 Additional Anti-CD19 antibody binding domains 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 Ab Name 
                 VH Sequence 
                 VL Sequence 
               
               
                   
               
               
                 SJ25-C1 
                 QVQLLESGAELVRPGSSVKISCKASGYAFSSYWMN 
                 ELVLTQSPKFMSTSVGDRVSVTCKASQNVGTN 
               
               
                   
                 WVKQRPGQGLEWIGQIYPGDGDTNYNGKFKGQATL 
                 VAWYQQKPGQSPKPLIYSATRYNSGVPDRFTG 
               
               
                   
                 TADKSSSTAYMQLSGLTSEDSAVYSCARKTISSVV 
                 SGSGTDFTLTITNVQSKDLADYFYFCQYNRYP 
               
               
                   
                 DFYFDYWGQGTTVT (SEQ ID NO: 96) 
                 YTSGGGTKLEIKRRS (SEQ ID NO: 97) 
               
               
                   
               
            
           
           
               
               
            
               
                   
                 ScFv Sequence 
               
               
                   
               
               
                 SJ25-C1 
                 QVQLLESGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIYPGDGDTNYNGKFKGQA 
               
               
                 scFv 
                 TLTADKSSSTAYMQLSGLTSEDSAVYSCARKTISSVVDFYFDYGQGTTVTGSTSGSGKPGSGEGSTKG 
               
               
                   
                 ELVLTQSPKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKPLIYSATYRNSGVPDRFTGSGSG 
               
               
                   
                 TDFTLTITNVQSKDLADYFYFCQYNRYPYTSGGGTKLEIKRRS (SEQ ID NO: 112) 
               
               
                   
               
            
           
         
       
     
     In one embodiment, the 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 CD19 binding domain described herein, e.g., provided in Table 6 or 7, 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 CD19 binding domain described herein, e.g., provided in Table 6 or 8. In one embodiment, the mesothelin binding domain comprises one, two, or all of LC CDR1, LC CDR2, and LC CDR3 of any amino acid sequences as provided in Table 8, incorporated herein by reference; and one, two or all of HC CDR1, HC CDR2, and HC CDR3 of any amino acid sequences as provided in Table 7. 
     In one embodiment, the CD19 antigen binding domain comprises:
         (i) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 261, a LC CDR2 amino acid sequence of SEQ ID NO: 262, and a LC CDR3 amino acid sequence of SEQ ID NO: 263; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 255, a HC CDR2 amino acid sequence of SEQ ID NO: 256, and a HC CDR3 amino acid sequence of SEQ ID NO: 260   (ii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 261, a LC CDR2 amino acid sequence of SEQ ID NO: 262, and a LC CDR3 amino acid sequence of SEQ ID NO: 263; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 255, a HC CDR2 amino acid sequence of SEQ ID NO: 257, and a HC CDR3 amino acid sequence of SEQ ID NO: 260;   (iii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 261, a LC CDR2 amino acid sequence of SEQ ID NO: 262, and a LC CDR3 amino acid sequence of SEQ ID NO: 263; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 255, a HC CDR2 amino acid sequence of SEQ ID NO: 258, and a HC CDR3 amino acid sequence of SEQ ID NO: 260; or   (iv) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 261, a LC CDR2 amino acid sequence of SEQ ID NO: 262, and a LC CDR3 amino acid sequence of SEQ ID NO: 263; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 255, a HC CDR2 amino acid sequence of SEQ ID NO: 259, and a HC CDR3 amino acid sequence of SEQ ID NO: 260.       

     In one embodiment, the CD19 binding domain comprises a light chain variable region described herein (e.g., in Table 6 or 9) and/or a heavy chain variable region described herein (e.g., in Table 6 or 9). In one embodiment, the mesothelin binding domain is a scFv comprising a light chain and a heavy chain of an amino acid sequence listed in Table 3 or 4. 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, 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 6 or 9, or a sequence with 95-99% identity with an amino acid sequence provided in Table 6 or 9; 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 6 or 9, or a sequence with 95-99% identity to an amino acid sequence provided in Table 6 or 9. 
     In one embodiment, the CD19 binding domain comprises an amino acid sequence selected from a group consisting of SEQ ID NO: 83; SEQ ID NO: 84, SEQ ID NO: 85; SEQ ID NO: 86; SEQ ID NO: 87; SEQ ID NO: 88; SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, and SEQ ID NO: 112; or 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) to any of the aforesaid sequences; or a sequence with 95-99% identity to any of the aforesaid sequences. In one embodiment, the CD19 binding domain is a scFv, and a light chain variable region comprising an amino acid sequence described herein, e.g., in Table 6 or 9, is attached to a heavy chain variable region comprising an amino acid sequence described herein, e.g., in Table 6 or 9, via a linker, e.g., a linker described herein. In one embodiment, the CD19 binding domain includes a (Gly4-Ser)n linker, wherein n is 1, 2, 3, 4, 5, or 6, preferably 4 (SEQ ID NO: 80). 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. 
     Any known CD19 CAR, e.g., the CD19 antigen binding domain of any known CD19 CAR, in the art can be used in accordance with the instant invention to construct a CAR. For example, LG-740; CD19 CAR described in the 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. In one embodiment, an antigen binding domain against CD19 is an antigen binding portion, e.g., CDRs, of a CAR, antibody or antigen-binding fragment thereof described in, e.g., PCT publication WO2012/079000; PCT publication WO2014/153270; Kochenderfer, J. N. et al., J. Immunother. 32 (7), 689-702 (2009); Kochenderfer, J. N., et al., Blood, 116 (20), 4099-4102 (2010); PCT publication WO2014/031687; Bejcek, Cancer Research, 55, 2346-2351, 1995; or U.S. Pat. No. 7,446,190. 
     In an embodiment, the antigen-binding domain of a BCA CAR, e.g., the BCA CAR expressed by a cell of the invention, binds to BCMA. BCMA is found preferentially expressed in mature B lymphocytes. In an embodiment, the antigen binding domain is a murine scFv domain that binds to human BCMA. In an embodiment, the antigen binding domain is a humanized antibody or antibody fragment, e.g., scFv domain, that binds human BCMA. In an embodiment, the antigen binding domain is a human antibody or antibody fragment that binds to human BCMA. Exemplary scFv domains (and their sequences, e.g., CDRs, VL and VH sequences) that bind to BCMA are provided in Table 12, Table 13, Table 14 and Table 15. The scFv domain sequences provided in Table 12 and Table 13 include a light chain variable region (VL) and a heavy chain variable region (VH). The VL and VH are attached by a linker, e.g., in the following orientation: VH-linker-VL. 
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Antigen Binding domains that bind the B-Cell antigen BCMA 
               
               
                 The amino acid sequences variable heavy chain and variable light 
               
               
                 chain sequences for each scFv is also provided. 
               
            
           
           
               
               
               
            
               
                 Name/ 
                   
                   
               
               
                 Description 
                 SEQ ID NO: 
                 Sequence 
               
               
                   
               
            
           
           
               
            
               
                 139109 
               
            
           
           
               
               
               
            
               
                 139109-aa 
                 349 
                 EVQLVESGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGL 
               
               
                 ScFv 
                   
                 EWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDT 
               
               
                 domain 
                   
                 AIYYCSAHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGSDIQ 
               
               
                   
                   
                 LTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLI 
               
               
                   
                   
                 YAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYS 
               
               
                   
                   
                 TPYTFGQGTKVEIK 
               
               
                 139109-nt 
                 364 
                 GAAGTGCAATTGGTGGAATCAGGGGGAGGACTTGTGCAGCCTGGA 
               
               
                 ScFv 
                   
                 GGATCGCTGAGACTGTCATGTGCCGTGTCCGGCTTTGCCCTGTCC 
               
               
                 domain 
                   
                 AACCACGGGATGTCCTGGGTCCGCCGCGCGCCTGGAAAGGGCCTC 
               
               
                   
                   
                 GAATGGGTGTCGGGTATTGTGTACAGCGGTAGCACCTACTATGCC 
               
               
                   
                   
                 GCATCCGTGAAGGGGAGATTCACCATCAGCCGGGACAACTCCAGG 
               
               
                   
                   
                 AACACTCTGTACCTCCAAATGAATTCGCTGAGGCCAGAGGACACT 
               
               
                   
                   
                 GCCATCTACTACTGCTCCGCGCATGGCGGAGAGTCCGACGTCTGG 
               
               
                   
                   
                 GGACAGGGGACCACCGTGACCGTGTCTAGCGCGTCCGGCGGAGGC 
               
               
                   
                   
                 GGCAGCGGGGGTCGGGCATCAGGGGGCGGCGGATCGGACATCCAG 
               
               
                   
                   
                 CTCACCCAGTCCCCGAGCTCGCTGTCCGCCTCCGTGGGAGATCGG 
               
               
                   
                   
                 GTCACCATCACGTGCCGCGCCAGCCAGTCGATTTCCTCCTACCTG 
               
               
                   
                   
                 AACTGGTACCAACAGAAGCCCGGAAAAGCCCCGAAGCTTCTCATC 
               
               
                   
                   
                 TACGCCGCCTCGAGCCTGCAGTCAGGAGTGCCCTCACGGTTCTCC 
               
               
                   
                   
                 GGCTCCGGTTCCGGTACTGATTTCACCCTGACCATTTCCTCCCTG 
               
               
                   
                   
                 CAACCGGAGGACTTCGCTACTTACTACTGCCAGCAGTCGTACTCC 
               
               
                   
                   
                 ACCCCCTACACTTTCGGACAAGGCACCAAGGTCGAAATCAAG 
               
               
                 139109-aa 
                 379 
                 EVQLVESGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGL 
               
               
                 VH 
                   
                 EWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDT 
               
               
                   
                   
                 AIYYCSAHGGESDVWGQGTTVTVSS 
               
               
                 139109-aa 
                 394 
                 DIQLTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPK 
               
               
                 VL 
                   
                 LLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ 
               
               
                   
                   
                 SYSTPYTFGQGTKVEIK 
               
               
                   
               
            
           
           
               
            
               
                 139103 
               
            
           
           
               
               
               
            
               
                 139103-aa 
                 339 
                 QVQLVESGGGLVQPGRSLRLSCAASGFTFSNYAMSWVRQAPGKGL 
               
               
                 ScFv 
                   
                 GWVSGISRSGENTYYADSVKGRFTISRDNSKKTLYLQMNSLRDED 
               
               
                 domain 
                   
                 TAVYYCARSPAHYYGGMDVWGQGTTVTVSSASGGGGSGGRASGGG 
               
               
                   
                   
                 GSDIVLTQSPGTLSLSPGERATLSCRASQSISSSFLAWYQQKPGQ 
               
               
                   
                   
                 APRLLIYGASRRATGIPDRFSGSGSGTDFTLTISRLEPEDSAVYY 
               
               
                   
                   
                 CQGYHSSPSWTFGQGTKLEIK 
               
               
                 139103-nt 
                 354 
                 CAAGTGCAACTCGTGGAATCTGGTGGAGGACTCGTGCAACCCGGA 
               
               
                 ScFv 
                   
                 AGATCGCTTAGACTGTCGTGTGCCGCCAGCGGGTTCACTTTCTCG 
               
               
                 domain 
                   
                 AACTACGCGATGTCCTGGGTCCGCCAGGCACCCGGAAAGGGACTC 
               
               
                   
                   
                 GGTTGGGTGTCCGGCATTTCCCGGTCCGGCGAAAATACCTACTAC 
               
               
                   
                   
                 GCCGACTCCGTGAAGGGCCGCTTCACCATCTCAAGGGACAACAGC 
               
               
                   
                   
                 AAAAACACCCTGTACTTGCAAATGAACTCCCTGCGGGATGAAGAT 
               
               
                   
                   
                 ACAGCCGTGTACTATTGCGCCCGGTCGCCTGCCCATTACTACGGC 
               
               
                   
                   
                 GGAATGGACGTCTGGGGACAGGGAACCACTGTGACTGTCAGCAGC 
               
               
                   
                   
                 GCGTCGGGTGGCGGCGGCTCAGGGGGTCGGGCCTCCGGGGGGGGA 
               
               
                   
                   
                 GGGTCCGACATCGTGCTGACCCAGTCCCCGGGAACCCTGAGCCTG 
               
               
                   
                   
                 AGCCCGGGAGAGCGCGCGACCCTGTCATGCCGGGCATCCCAGAGC 
               
               
                   
                   
                 ATTAGCTCCTCCTTTCTCGCCTGGTATCAGCAGAAGCCCGGACAG 
               
               
                   
                   
                 GCCCCGAGGCTGCTGATCTACGGCGCTAGCAGAAGGGCTACCGGA 
               
               
                   
                   
                 ATCCCAGACCGGTTCTCCGGCTCCGGTTCCGGGACCGATTTCACC 
               
               
                   
                   
                 CTTACTATCTCGCGCCTGGAACCTGAGGACTCCGCCGTCTACTAC 
               
               
                   
                   
                 TGCCAGCAGTACCACTCATCCCCGTCGTGGACGTTCGGACAGGGC 
               
               
                   
                   
                 ACCAAGCTGGAGATTAAG 
               
               
                 139103-aa 
                 369 
                 QVQLVESGGGLVQPGRSLRLSCAASGFTFSNYAMSWVRQAPGKGL 
               
               
                 VH 
                   
                 GWVSGISRSGENTYYADSVKGRFTISRDNSKNTLYLQMNSLRDED 
               
               
                   
                   
                 TAVYYCARSPAHYYGGMDVWGQGTTVTVSS 
               
               
                 139103-aa 
                 384 
                 DIVLTQSPGTLSLSPGERATLSCRASQSISSSLFAWYQQKPGQAP 
               
               
                 VL 
                   
                 RLLIYGASRRATGIPDRFSGSGSGTDFTLTISRLEPEDSAVYYCQ 
               
               
                   
                   
                 QYHSSPSWTFGQGTKLEIK 
               
               
                   
               
            
           
           
               
            
               
                 139105 
               
            
           
           
               
               
               
            
               
                 139105-aa 
                 340 
                 QVQLVESGGGLVQPGRSLRLSCAASGFTFDDYQMHWVRQAPGKGL 
               
               
                 ScFv 
                   
                 EWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLQLQMNSLRAED 
               
               
                 domain 
                   
                 TALYYCSVHSFLAYWGQGTLVTVSSASGGGGSGGRASGGGGSDIV 
               
               
                   
                   
                 MTQTPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLKQPGQS 
               
               
                   
                   
                 PQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC 
               
               
                   
                   
                 MQALQTPYTFGQGTKVEIK 
               
               
                 139105-nt 
                 355 
                 CAAGTGCAACTCGTCGAATCCGGTGGAGGTCTGGTCCAACCTGGT 
               
               
                 ScFv 
                   
                 AGAAGCCTGAGACTGTCGTGTGCGGCCAGCGGATTCACCTTTGAT 
               
               
                 domain 
                   
                 GACTATGCTATGCACTGGGTGCGGCAGGCCCCAGGAAAGGGCCTG 
               
               
                   
                   
                 GAATGGGTGTCGGGAATTAGCTGGAACTCCGGGTCCATTGGCTAC 
               
               
                   
                   
                 GCCGACTCCGTGAAGGGCCGCTTCACCATCTCCCGCGACAACGCA 
               
               
                   
                   
                 AAGAACTCCCTGTACTTGCAAATGAACTCGCTCAGGGCTGAGGAT 
               
               
                   
                   
                 ACCGCGCTGTACTACTGCTCCGTGCATTCCTTCCTGGCCTACTGG 
               
               
                   
                   
                 GGACAGGGAACTCTGGTCACCGTGTCGAGCGCCTCCGGCGGCGGG 
               
               
                   
                   
                 GGCTCGGGTGGACGGGCCTCGGGCGGAGGGGGGTCCGACATCGTG 
               
               
                   
                   
                 ATGACCCAGACCCCGCTGAGCTTGCCCGTGACTCCCGGAGAGCCT 
               
               
                   
                   
                 GCATCCATCTCCTGCCGGTCATCCCAGTCCCTTCTCCACTCCAAC 
               
               
                   
                   
                 GGATACAACTACCTCGACTGGTACCTCCAGAAGCCGGGACAGAGC 
               
               
                   
                   
                 CCTCAGCTTCTGATCTACCTGGGGTCAAATAGAGCCTCAGGAGTG 
               
               
                   
                   
                 CCGGATCGGTTCAGCGGATCTGGTTCGGGAACTGATTTCACTCTG 
               
               
                   
                   
                 AAGATTTCCCGCGTGGAAGCCGAGGACGTGGGCGTCTACTACTGT 
               
               
                   
                   
                 ATGCAGGCGCTGCAGACCCCCTATACCTTCGGCCAAGGGACGAAA 
               
               
                   
                   
                 GTGGAGATCAAG 
               
               
                 139105-aa 
                 370 
                 QVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGL 
               
               
                 VH 
                   
                 EWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAED 
               
               
                   
                   
                 TALYYCSVHSFLAYWGQGTLVTVSS 
               
               
                 139105-aa 
                 385 
                 DIVMTQTPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKP 
               
               
                 VL 
                   
                 GQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGV 
               
               
                   
                   
                 YYCMQALQTPYTFGQGTKVEIK 
               
               
                   
               
            
           
           
               
            
               
                 139111 
               
            
           
           
               
               
               
            
               
                 139111-aa 
                 341 
                 EVQLLESGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGL 
               
               
                 ScFv 
                   
                 EWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDT 
               
               
                 domain 
                   
                 AIYYCSAHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGSDIV 
               
               
                   
                   
                 MTQTPLSLSVTPGQPASISCKSSQSLLRNDGKTPLYWYLQKAGQP 
               
               
                   
                   
                 PQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGAYYC 
               
               
                   
                   
                 MQNIQFPSFGGGTKLEIK 
               
               
                 139111-nt 
                 356 
                 GAAGTGCAATTGTTGGAATCTGGAGGAGGACTTGTGCAGCCTGGA 
               
               
                 ScFv 
                   
                 GGATCACTGAGACTTTCGTGTGCGGTGTCAGGCTTCGCCCTGAGC 
               
               
                 domain 
                   
                 AACCACGGCATGAGCTGGGTGCGGAGAGCCCCGGGGAAGGGTCTG 
               
               
                   
                   
                 GAATGGGTGTCCGGGATCGTCTACTCCGGTTCAACTTACTACGCC 
               
               
                   
                   
                 GCAAGCGTGAAGGGTCGCTTCACCATTTCCCGCGATAACTCCCGG 
               
               
                   
                   
                 AACACCCTGTACCTCCAAATGAACTCCCTGCGGCCCGAGGACACC 
               
               
                   
                   
                 GCCATCTACTACTGTTCCGCGCATGGAGGAGAGTCCGATGTCTGG 
               
               
                   
                   
                 GGACAGGGCACTACCGTGACCGTGTCGAGCGCCTCGGGGGGAGGA 
               
               
                   
                   
                 GGCTCCGGCGGTCGCGCCTCCGGGGGGGGTGGCAGCGACATTGTG 
               
               
                   
                   
                 ATGACGCAGACTCCACTCTCGCTGTCCGTGACCCCGGGACAGCCC 
               
               
                   
                   
                 GCGTCCATCTCGTGCAAGAGCTCCCAGAGCCTGCTGAGGAACGAC 
               
               
                   
                   
                 GGAAAGACTCCTCTGTATTGGTACCTCCAGAAGGCTGGACAGCCC 
               
               
                   
                   
                 CCGCAACTGCTCATCTACGAAGTGTCAAATCGCTTCTCCGGGGTG 
               
               
                   
                   
                 CCGGATCGGTTTTCCGGCTCGGGATCGGGCACCGACTTCACCCTG 
               
               
                   
                   
                 AAAATCTCCAGGGTCGAGGCCGAGGACGTGGGAGCCTACTACTGC 
               
               
                   
                   
                 ATGCAAAACATCCAGTTCCCTTCCTTCGGCGGCGGCACAAAGCTG 
               
               
                   
                   
                 GAGATTAAG 
               
               
                 139111-aa 
                 371 
                 EVQLLESGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGL 
               
               
                 VH 
                   
                 EWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDT 
               
               
                   
                   
                 AIYYCSAHGGESDVWGQGTTVTVSS 
               
               
                 139111-aa 
                 386 
                 DIVMTQTPLSLSVTPGQPASISCKSSQSLLRNDGKTPLYWYLQKA 
               
               
                 VL 
                   
                 GQPPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGA 
               
               
                   
                   
                 YYCMQNIQFPSFGGGTKLEIK 
               
               
                   
               
            
           
           
               
            
               
                 139100 
               
            
           
           
               
               
               
            
               
                 139100-aa 
                 342 
                 QVQLVQSGAEVRKTGASVKVSCKASGYIFDNFGINWVRQAPGQGL 
               
               
                 ScFv 
                   
                 EWMGWINPKNNNTNYAQKFQGRVTITADESTNTAYMEVSSLRSED 
               
               
                 domain 
                   
                 TAVYYCARGPYYYQSYMDVWGQGTMVTVSSASGGGGSGGRASGGG 
               
               
                   
                   
                 GSDIVMTQTPLSLPVTPGEPASISCRSSQSLLHSNGYNYLNWYLQ 
               
               
                   
                   
                 KPGQSPQLLIYLGSKRASGVPDRFSGSGSGTDFTLHITRVGAEDV 
               
               
                   
                   
                 GVYYCMQALQTPYTFGQGTKLEIK 
               
               
                 139100-nt 
                 357 
                 CAAGTCCAACTCGTCCAGTCCGGCGCAGAAGTCAGAAAAACCGGT 
               
               
                 ScFv 
                   
                 GCTAGCGTGAAAGTGTCCTGCAAGGCCTCCGGCTACATTTTCGAT 
               
               
                 domain 
                   
                 AACTTCGGAATCAACTGGGTCAGACAGGCCCCGGGCCAGGGGCTG 
               
               
                   
                   
                 GAATGGATGGGATGGATCAACCCCAAGAACAACAACACCAACTAC 
               
               
                   
                   
                 GCACAGAAGTTCCAGGGCCGCGTGACTATCACCGCCGATGAATCG 
               
               
                   
                   
                 ACCAATACCGCCTACATGGAGGTGTCCTCCCTGCGGTCGGAGGAC 
               
               
                   
                   
                 ACTGCCGTGTATTACTGCGCGAGGGGCCCATACTACTACCAAAGC 
               
               
                   
                   
                 TACATGGACGTCTGGGGACAGGGAACCATGGTGACCGTGTCATCC 
               
               
                   
                   
                 GCCTCCGGTGGTGGAGGCTCCGGGGGGCGGGCTTCAGGAGGCGGA 
               
               
                   
                   
                 GGAAGCGATATTGTGATGACCCAGACTCCGCTTAGCCTGCCCGTG 
               
               
                   
                   
                 ACTCCTGGAGAACCGGCCTCCATTTCCTGCCGGTCCTCGCAATCA 
               
               
                   
                   
                 CTCCTGCATTCCAACGGTTACAACTACCTGAATTGGTACCTCCAG 
               
               
                   
                   
                 AAGCCTGGCCAGTCGCCCCAGTTGCTGATCTATCTGGGCTCGAAG 
               
               
                   
                   
                 CGCGCCTCCGGGGTGCCTGACCGGTTTAGCGGATCTGGGAGCGGC 
               
               
                   
                   
                 ACGGACTTCACTCTCCACATCACCCGCGTGGGAGCGGAGGACGTG 
               
               
                   
                   
                 GGAGTGTACTACTGTATGCAGGCGCTGCAGACTCCGTACACATTC 
               
               
                   
                   
                 GGACAGGGCACCAAGCTGGAGATCAAG 
               
               
                 139100-aa 
                 372 
                 QVQLVQSGAEVRKTGASVKVSCKASGYIFDNFGINWVRQAPGQGL 
               
               
                 VH 
                   
                 EWMGWINPKNNNTNYAQKFQGRVTITADESTNTAYMEVSSLRSED 
               
               
                   
                   
                 TAVYYCARGPYYYQSYMDVWGQGTMVTVSS 
               
               
                 139100-aa 
                 387 
                 DIVMTQTPLSLPVTPGEPASISCRSSQSLLHSNGYNYLNWYLQKP 
               
               
                 VL 
                   
                 GQSPQLLIYLGSKRASGVPDRFSGSGSGTDFTLHITRVGAEDVGV 
               
               
                   
                   
                 YYCMQALQTPYTFGQGTKLEIK 
               
               
                   
               
            
           
           
               
            
               
                 139101 
               
            
           
           
               
               
               
            
               
                 139101-aa 
                 343 
                 QVQLQESGGGLVQPGGSLRLSCAASGFTFSSDAMTWVRQAPGKGL 
               
               
                 ScFv 
                   
                 EWVSVISGSGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED 
               
               
                 domain 
                   
                 TAVYYCAKLDSSGYYYARGPRYWGQGTLVTVSSASGGGGSGGRAS 
               
               
                   
                   
                 GGGGSDIQLTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKP 
               
               
                   
                   
                 GKAPKLLIYGASTLASGVPARFSGSGSGTHFTLTINSLQSEDSAT 
               
               
                   
                   
                 YYCQQSYKRASFGQGTKVEIK 
               
               
                 139101-nt 
                 358 
                 CAAGTGCAACTTCAAGAATCAGGCGGAGGACTCGTGCAGCCCGGA 
               
               
                 ScFv 
                   
                 GGATCATTGCGGCTCTCGTGCGCCGCCTCGGGCTTCACCTTCTCG 
               
               
                 domain 
                   
                 AGCGACGCCATGACCTGGGTCCGCCAGGCCCCGGGGAAGGGGCTG 
               
               
                   
                   
                 GAATGGGTGTCTGTGATTTCCGGCTCCGGGGGAACTACGTACTAC 
               
               
                   
                   
                 GCCGATTCCGTGAAAGGTCGCTTCACTATCTCCCGGGACAACAGC 
               
               
                   
                   
                 AAGAACACCCTTTATCTGCAAATGAATTCCCTCCGCGCCGAGGAC 
               
               
                   
                   
                 ACCGCCGTGTACTACTGCGCCAAGCTGGACTCCTCGGGCTACTAC 
               
               
                   
                   
                 TATGCCCGGGGTCCGAGATACTGGGGACAGGGAACCCTCGTGACC 
               
               
                   
                   
                 GTGTCCTCCGCGTCCGGCGGAGGAGGGTCGGGAGGGCGGGCCTCC 
               
               
                   
                   
                 GGCGGCGGCGGTTCGGACATCCAGCTGACCCAGTCCCCATCCTCA 
               
               
                   
                   
                 CTGAGCGCAAGCGTGGGCGACAGAGTCACCATTACATGCAGGGCG 
               
               
                   
                   
                 TCCCAGAGCATCAGCTCCTACCTGAACTGGTACCAACAGAAGCCT 
               
               
                   
                   
                 GGAAAGGCTCCTAAGCTGTTGATCTACGGGGCTTCGACCCTGGCA 
               
               
                   
                   
                 TCCGGGGTGCCCGCGAGGTTTAGCGGAAGCGGTAGCGGCACTCAC 
               
               
                   
                   
                 TTCACTCTGACCATTAACAGCCTCCAGTCCGAGGATTCAGCCACT 
               
               
                   
                   
                 TACTACTGTCAGCAGTCCTACAAGCGGGCCAGCTTCGGACAGGGC 
               
               
                   
                   
                 ACTAAGGTCGAGATCAAG 
               
               
                 139101-aa 
                 373 
                 QVQLQESGGGLVQPGGSLRLSCAASGFTFSSDAMTWCRQAPGKGL 
               
               
                 VH 
                   
                 EWVSVISGSGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED 
               
               
                   
                   
                 TAVYYCAKLDSSGYYYARGPRYWGQGTLVTVSS 
               
               
                 139101-aa 
                 388 
                 DIQLTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPK 
               
               
                 VL 
                   
                 LLIYGASTLASGVPARFSGSGSGTHFTLTINSLQSEDSATYYCQQ 
               
               
                   
                   
                 SYKRASFGQGTKVEIK 
               
               
                   
               
            
           
           
               
            
               
                 139102 
               
            
           
           
               
               
               
            
               
                 139102-aa 
                 344 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGITWVRQAPGQGL 
               
               
                 ScFv 
                   
                 EWMGWISAYNGNTNYAQKFQGRVTMTRNTSISTAYMELSSLRSED 
               
               
                 domain 
                   
                 TAVYYCARGPYYYYMDVWGKGTMVTVSSASGGGGSGGRASGGGGS 
               
               
                   
                   
                 EIVMTQSPLSLPVTPGEPASISCRSSQSLLYSNGYNYVDWYLQKP 
               
               
                   
                   
                 GQSPQLLIYLGSNRASGVPDRFSGSGSGTDFKLQISRVEAEDVGI 
               
               
                   
                   
                 YYCMQGRQFPYSFGQGTKVEIK 
               
               
                 139102-nt 
                 359 
                 CAAGTCCAACTGGTCCAGAGCGGTGCAGAAGTGAAGAAGCCCGGA 
               
               
                 ScFv 
                   
                 GCGAGCGTGAAAGTGTCCTGCAAGGCTTCCGGGTACACCTTCTCC 
               
               
                 domain 
                   
                 AACTACGGCATCACTTGGGTGCGCCAGGCCCCGGGACAGGGCCTG 
               
               
                   
                   
                 GAATGGATGGGGTGGATTTCCGCGTACAACGGCAATACGAACTAC 
               
               
                   
                   
                 GCTCAGAAGTTCCAGGGTAGAGTGACCATGACTAGGAACACCTCC 
               
               
                   
                   
                 ATTTCCACCGCCTACATGGAACTGTCCTCCCTGCGGAGCGAGGAC 
               
               
                   
                   
                 ACCGCCGTGTACTATTGCGCCCGGGGACCATACTACTACTACATG 
               
               
                   
                   
                 GATGTCTGGGGGAAGGGGACTATGGTCACCGTGTCATCCGCCTCG 
               
               
                   
                   
                 GGAGGCGGCGGATCAGGAGGACGCGCCTCTGGTGGTGGAGGATCG 
               
               
                   
                   
                 GAGATCGTGATGACCCAGAGCCCTCTCTCCTTGCCCGTGACTCCT 
               
               
                   
                   
                 GGGGAGCCCGCATCCATTTCATGCCGGAGCTCCCAGTCACTTCTC 
               
               
                   
                   
                 TACTCCAACGGCTATAACTACGTGGATTGGTACCTCCAAAAGCCG 
               
               
                   
                   
                 GGCCAGAGCCCGCAGCTGCTGATCTACCTGGGCTCGAACAGGGCC 
               
               
                   
                   
                 AGCGGAGTGCCTGACCGGTTCTCCGGGTCGGGAAGCGGGACCGAC 
               
               
                   
                   
                 TTCAAGCTGCAAATCTCGAGAGTGGAGGCCGAGGACGTGGGAATC 
               
               
                   
                   
                 TACTACTGTATGCAGGGCCGCCAGTTTCCGTACTCGTTCGGACAG 
               
               
                   
                   
                 GGCACCAAAGTGGAAATCAAG 
               
               
                 139102-aa 
                 374 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGITWVRQAPGQGL 
               
               
                 VH 
                   
                 EWMGWISAYNGNTNYAQKFQGRVTMTRNTSISTAYMELSSLRSED 
               
               
                   
                   
                 TAVYYCARGPYYYYMDVWGKGTMVTVSS 
               
               
                 139102-aa 
                 389 
                 EIVMTQSPLSLPVTPGEPASISCRSSQSLLYSNGYNYVDWYLQKP 
               
               
                 VL 
                   
                 GQSPQLLIYLGSNRASGVPDRFSGSGSGTDFKLQISRVEAEDVGI 
               
               
                   
                   
                 YYCMQGRQFPYSFGQGTKVEIK 
               
               
                   
               
            
           
           
               
            
               
                 139104 
               
            
           
           
               
               
               
            
               
                 139104-aa 
                 345 
                 EVQLLETGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGL 
               
               
                 ScFv 
                   
                 EWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDT 
               
               
                 domain 
                   
                 AIYYCSAHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGSEIV 
               
               
                   
                   
                 LTQSPATLSVSPGESATLSCRASQSVSSNLAWYQQKPGQAPRLLI 
               
               
                   
                   
                 YGASTRASGIPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYGS 
               
               
                   
                   
                 SLTFGGGTKVEIK 
               
               
                 139104-nt 
                 360 
                 GAAGTGCAATTGCTCGAAACTGGAGGAGGTCTGGTGCAACCTGGA 
               
               
                 ScFv 
                   
                 GGATCACTTCGCCTGTCCTGCGCCGTGTCGGGCTTTGCCCTGTCC 
               
               
                 domain 
                   
                 AACCATGGAATGAGCTGGGTCCGCCGCGCGCCGGGGAAGGGCCTC 
               
               
                   
                   
                 GAATGGGTGTCCGGCATCGTCTACTCCGGCTCCACCTACTACGCC 
               
               
                   
                   
                 GCGTCCGTGAAGGGCCGGTTCACGATTTCACGGGACAACTCGCGG 
               
               
                   
                   
                 AACACCCTGTACCTCCAAATGAATTCCCTTCGGCCGGAGGATACT 
               
               
                   
                   
                 GCCATCTACTACTGCTCCGCCCACGGTGGCGAATCCGACGTCTGG 
               
               
                   
                   
                 GGCCAGGGAACCACCGTGACCGTGTCCAGCGCGTCCGGGGGAGGA 
               
               
                   
                   
                 GGAAGCGGGGGTAGAGCATCGGGTGGAGGCGGATCAGAGATCGTG 
               
               
                   
                   
                 CTGACCCAGTCCCCCGCCACCTTGAGCGTGTCACCAGGAGAGTCC 
               
               
                   
                   
                 GCCACCCTGTCATGCCGCGCCAGCCAGTCCGTGTCCTCCAACCTG 
               
               
                   
                   
                 GCTTGGTACCAGCAGAAGCCGGGGCAGGCCCCTAGACTCCTGATC 
               
               
                   
                   
                 TATGGGGCGTCGACCCGGGCATCTGGAATTCCCGATAGGTTCAGC 
               
               
                   
                   
                 GGATCGGGCTCGGGCACTGACTTCACTCTGACCATCTCCTCGCTG 
               
               
                   
                   
                 CAAGCCGAGGACGTGGCTGTGTACTACTGTCAGCAGTACGGAAGC 
               
               
                   
                   
                 TCCCTGACTTTCGGTGGCGGGACCAAAGTCGAGATTAAG 
               
               
                 139104-aa 
                 375 
                 EVQLLETGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGL 
               
               
                 VH 
                   
                 EWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDT 
               
               
                   
                   
                 AIYYCSAHGGESDVWGQGTTVTVSS 
               
               
                 139104-aa 
                 390 
                 EIVLTQSPATLSVSPGESATLSCRASQSVSSNLAWYQQKPGQAPR 
               
               
                 VL 
                   
                 LLIYGASTRASGIPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQ 
               
               
                   
                   
                 YGSSLTFGGGTKVEIK 
               
               
                   
               
            
           
           
               
            
               
                 139106 
               
            
           
           
               
               
               
            
               
                 139106-aa 
                 346 
                 EVQLVETGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGL 
               
               
                 ScFv 
                   
                 EWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDT 
               
               
                 domain 
                   
                 AIYYCSAHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGSEIV 
               
               
                   
                   
                 MTQSPATLSVSPGERATLSCRASQSVSSKLAWYQQKPGQAPRLLM 
               
               
                   
                   
                 YGASIRATGIPDRFSGSGSGTEFTLTISSLEPEDFAVYYCQQYGS 
               
               
                   
                   
                 SSWTFGQGTKVEIK 
               
               
                 139106-nt 
                 361 
                 GAAGTGCAATTGGTGGAAACTGGAGGAGGACTTGTGCAACCTGGA 
               
               
                 ScFv 
                   
                 GGATCATTGAGACTGAGCTGCGCAGTGTCGGGATTCGCCCTGAGC 
               
               
                 domain 
                   
                 AACCATGGAATGTCCTGGGTCAGAAGGGCCCCTGGAAAAGGCCTC 
               
               
                   
                   
                 GAATGGGTGTCAGGGATCGTGTACTCCGGTTCCACTTACTACGCC 
               
               
                   
                   
                 GCCTCCGTGAAGGGGCGCTTCACTATCTCACGGGATAACTCCCGC 
               
               
                   
                   
                 AATACCCTGTACCTCCAAATGAACAGCCTGCGGCCGGAGGATACC 
               
               
                   
                   
                 GCCATCTACTACTGTTCCGCCCACGGTGGAGAGTCTGACGTCTGG 
               
               
                   
                   
                 GGCCAGGGAACTACCGTGACCGTGTCCTCCGCGTCCGGCGGTGGA 
               
               
                   
                   
                 GGGAGCGGCGGCCGCGCCAGCGGCGGCGGAGGCTCCGAGATCGTG 
               
               
                   
                   
                 ATGACCCAGAGCCCCGCTACTCTGTCGGTGTCGCCCGGAGAAAGG 
               
               
                   
                   
                 GCGACCCTGTCCTGCCGGGCGTCGCAGTCCGTGAGCAGCAAGCTG 
               
               
                   
                   
                 GCTTGGTACCAGCAGAAGCCGGGCCAGGCACCACGCCTGCTTATG 
               
               
                   
                   
                 TACGGTGCCTCCATTCGGGCCACCGGAATCCCGGACCGGTTCTCG 
               
               
                   
                   
                 GGGTCGGGGTCCGGTACCGAGTTCACACTGACCATTTCCTCGCTC 
               
               
                   
                   
                 GAGCCCGAGGACTTTGCCGTCTATTACTGCCAGCAGTACGGCTCC 
               
               
                   
                   
                 TCCTCATGGACGTTCGGCCAGGGGACCAAGGTCGAAATCAAG 
               
               
                 139106-aa 
                 376 
                 EVQLVETGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGL 
               
               
                 VH 
                   
                 EWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDT 
               
               
                   
                   
                 AIYYCSAHGGESDVWGQGTTVTVSS 
               
               
                 139106-aa 
                 391 
                 EIVMTQSPATLSVSPGERATLSCRASQSVSSKLAWYQQKPGQAPR 
               
               
                 VL 
                   
                 LLMYGASIRATGIPDRFSGSGSGTEFTLTISSLEPEDFAVYYCQQ 
               
               
                   
                   
                 YGSSSWTFGQGTKVEIK 
               
               
                   
               
            
           
           
               
            
               
                 139107 
               
            
           
           
               
               
               
            
               
                 139107-aa 
                 347 
                 EVQLVETGGGVVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGL 
               
               
                 ScFv 
                   
                 EWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDT 
               
               
                 domain 
                   
                 AIYYCSAHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGSEIV 
               
               
                   
                   
                 LTQSPGTLSLSPGERATLSCRASQSVGSTNLAWYQQKPGQAPRLL 
               
               
                   
                   
                 IYDASNRATGIPDRFSGGGSGTDFTLTISRLEPEDFAVYYCQQYG 
               
               
                   
                   
                 SSPPWTFGQGTKVEIK 
               
               
                 139107-nt 
                 362 
                 GAAGTGCAATTGGTGGAGACTGGAGGAGGAGTGGTGCAACCTGGA 
               
               
                 ScFv 
                   
                 GGAAGCCTGAGACTGTCATGCGCGGTGTCGGGCTTCGCCCTCTCC 
               
               
                 domain 
                   
                 AACCACGGAATGTCCTGGGTCCGCCGGGCCCCTGGGAAAGGACTT 
               
               
                   
                   
                 GAATGGGTGTCCGGCATCGTGTACTCGGGTTCCACCTACTACGCG 
               
               
                   
                   
                 GCGTCAGTGAAGGGCCGGTTTACTATTAGCCGCGACAACTCCAGA 
               
               
                   
                   
                 AACACACTGTACCTCCAAATGAACTCGCTGCGGCCGGAAGATACC 
               
               
                   
                   
                 GCTATCTACTACTGCTCCGCCCATGGGGGAGAGTCGGACGTCTGG 
               
               
                   
                   
                 GGACAGGGCACCACTGTCACTGTGTCCAGCGCTTCCGGCGGTGGT 
               
               
                   
                   
                 GGAAGCGGGGGACGGGCCTCAGGAGGCGGTGGCAGCGAGATTGTG 
               
               
                   
                   
                 CTGACCCAGTCCCCCGGGACCCTGAGCCTGTCCCCGGGAGAAAGG 
               
               
                   
                   
                 GCCACCCTCTCCTGTCGGGCATCCCAGTCCGTGGGGTCTACTAAC 
               
               
                   
                   
                 CTTGCATGGTACCAGCAGAAGCCCGGCCAGGCCCCTCGCCTGCTG 
               
               
                   
                   
                 ATCTACGACGCGTCCAATAGAGCCACCGGCATCCCGGATCGCTTC 
               
               
                   
                   
                 AGCGGAGGCGGATCGGGCACCGACTTCACCCTCACCATTTCAAGG 
               
               
                   
                   
                 CTGGAACCGGAGGACTTCGCCGTGTACTACTGCCAGCAGTATGGT 
               
               
                   
                   
                 TCGTCCCCACCCTGGACGTTCGGCCAGGGGACTAAGGTCGAGATC 
               
               
                   
                   
                 AAG 
               
               
                 139107-aa 
                 377 
                 EVQLVETGGGVVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGL 
               
               
                 VH 
                   
                 EWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDT 
               
               
                   
                   
                 AIYYCSAKGGESDVWGQGTTVTVSS 
               
               
                 139107-aa 
                 392 
                 EIVLTQSPGTLSLSPGERATLSCRASQSVGSTNLAWYQQKPGQAP 
               
               
                 VL 
                   
                 RLLIYDASNRATGIPDRFSGGGSGTDFTLTISRLEPEDFACYYCQ 
               
               
                   
                   
                 QYGSSPPWTFGQGTKVEIK 
               
               
                   
               
            
           
           
               
            
               
                 139108 
               
            
           
           
               
               
               
            
               
                 139108-aa 
                 348 
                 QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGL 
               
               
                 ScFv 
                   
                 EWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAED 
               
               
                 domain 
                   
                 TAVYYCARESGDGMDVWGQGTTVTVSSASGGGGSGGRASGGGGSD 
               
               
                   
                   
                 IQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKL 
               
               
                   
                   
                 LIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQS 
               
               
                   
                   
                 YTLAFGQGTKVDIK 
               
               
                 139108-nt 
                 363 
                 CAAGTGCAACTCGTGGAATCTGGTGGAGGACTCGTGAAACCTGGA 
               
               
                 ScFv 
                   
                 GGATCATTGAGACTGTCATGCGCGGCCTCGGGATTCACGTTCTCC 
               
               
                 domain 
                   
                 GATTACTACATGAGCTGGATTCGCCAGGCTCCGGGGAAGGGACTG 
               
               
                   
                   
                 GAATGGGTGTCCTACATTTCCTCATCCGGCTCCACCATCTACTAC 
               
               
                   
                   
                 GCGGACTCCGTGAAGGGGAGATTCACCATTAGCCGCGATAACGCC 
               
               
                   
                   
                 AAGAACAGCCTGTACCTTCAGATGAACTCCCTGCGGGCTGAAGAT 
               
               
                   
                   
                 ACTGCCGTCTACTACTGCGCAAGGGAGAGCGGAGATGGGATGGAC 
               
               
                   
                   
                 GTCTGGGGACAGGGTACCACTGTGACCGTGTCGTCGGCCTCCGGC 
               
               
                   
                   
                 GGAGGGGGTTCGGGTGGAAGGGCCAGCGGCGGCGGAGGCAGCGAC 
               
               
                   
                   
                 ATCCAGATGACCCAGTCCCCCTCATCGCTGTCCGCCTCCGTGGGC 
               
               
                   
                   
                 GACCGCGTCACCATCACATGCCGGGCCTCACAGTCGATCTCCTCC 
               
               
                   
                   
                 TACCTCAATTGGTATCAGCAGAAGCCCGGAAAGGCCCCTAAGCTT 
               
               
                   
                   
                 CTGATCTACGCAGCGTCCTCCCTGCAATCCGGGGTCCCATCTCGG 
               
               
                   
                   
                 TTCTCCGGCTCGGGCAGCGGTACCGACTTCACTCTGACCATCTCG 
               
               
                   
                   
                 AGCCTGCAGCCGGAGGACTTCGCCACTTACTACTGTCAGCAAAGC 
               
               
                   
                   
                 TACACCCTCGCGTTTGGCCAGGGCACCAAAGTGGACATCAAG 
               
               
                 139108-aa 
                 378 
                 QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGL 
               
               
                 VL 
                   
                 EWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAED 
               
               
                   
                   
                 TAVYYCARESGDGMDVWGQGTTVTVSS 
               
               
                 139108-aa 
                 393 
                 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPK 
               
               
                 VL 
                   
                 LLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ 
               
               
                   
                   
                 SYTLAFGQGTKVDIK 
               
               
                   
               
            
           
           
               
            
               
                 139110 
               
            
           
           
               
               
               
            
               
                 139110-aa 
                 350 
                 QVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGL 
               
               
                 ScFv 
                   
                 EWVSYISSSGNTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAED 
               
               
                 domain 
                   
                 TAVYYCARSTMVREDYWGQGTLVTVSSASGGGGSGGRASGGGGSD 
               
               
                   
                   
                 IVLTQSPLSLPVTLGQPASISCKSSESLVHNSGKTYLNWFHQRPG 
               
               
                   
                   
                 QSPRRLIYEVSNRDSGVPDRFTGSGSGTDFTLKISRVEAEDVGVY 
               
               
                   
                   
                 YCMQGTHWPGTFGQGTKLEIK 
               
               
                 139110-nt 
                 365 
                 CAAGTGCAACTGGTGCAAAGCGGAGGAGGATTGGTCAAACCCGGA 
               
               
                 ScFv 
                   
                 GGAAGCCTGAGACTGTCATGCGCGGCCTCTGGATTCACCTTCTCC 
               
               
                 domain 
                   
                 GATTACTACATGTCATGGATCAGACAGGCCCCGGGGAAGGGCCTC 
               
               
                   
                   
                 GAATGGGTGTCCTACATCTCGTCCTCCGGGAACACCATCTACTAC 
               
               
                   
                   
                 GCCGACAGCGTGAAGGGCCGCTTTACCATTTCCCGCGACAACGCA 
               
               
                   
                   
                 AAGAACTCGCTGTACCTTCAGATGAATTCCCTGCGGGCTGAAGAT 
               
               
                   
                   
                 ACCGCGGTGTACTATTGCGCCCGGTCCACTATGGTCCGGGAGGAC 
               
               
                   
                   
                 TACTGGGGACAGGGCACACTCGTGACCGTGTCCAGCGCGAGCGGG 
               
               
                   
                   
                 GGTGGAGGCAGCGGTGGACGCGCCTCCGGCGGCGGCGGTTCAGAC 
               
               
                   
                   
                 ATCGTGCTGACTCAGTCGCCCCTGTCGCTGCCGGTCACCCTGGGC 
               
               
                   
                   
                 CAACCGGCCTCAATTAGCTGCAAGTCCTCGGAGAGCCTGGTGCAC 
               
               
                   
                   
                 AACTCAGGAAAGACTTACCTGAACTGGTTCCATCAGCGGCCTGGA 
               
               
                   
                   
                 CAGTCCCCACGGAGGCTCATCTATGAAGTGTCCAACAGGGATTCG 
               
               
                   
                   
                 GGGGTGCCCGACCGCTTCACTGGCTCCGGGTCCGGCACCGACTTC 
               
               
                   
                   
                 ACCTTGAAAATCTCCAGAGTGGAAGCCGAGGACGTGGGCGTGTAC 
               
               
                   
                   
                 TACTGTATGCAGGGTACCCACTGGCCTGGAACCTTTGGACAAGGA 
               
               
                   
                   
                 ACTAAGCTCGAGATTAAG 
               
               
                 139110-aa 
                 380 
                 QVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGL 
               
               
                 VH 
                   
                 EWVSYISSSGNTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAED 
               
               
                   
                   
                 TAVYYCARSTMVREDYWGQGTLVTVSS 
               
               
                 139110-aa 
                 395 
                 DIVLTQSPLSLPVTLGQPASISCKSSELSVHNSGKTYLNWFHQRP 
               
               
                 VL 
                   
                 GQSPRRLIYEVSNRDSGVPDRFTGSGSGTDFTLKISRVEAEDVGV 
               
               
                   
                   
                 YYCMQGTHWPGTFGQGTKLEIK 
               
               
                   
               
            
           
           
               
            
               
                 139112 
               
            
           
           
               
               
               
            
               
                 139112-aa 
                 351 
                 QVQLVESGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGL 
               
               
                 ScFv 
                   
                 EWVSGIVYSGSTYYAASVKGRFTISRDKSRNTLYLQMNSLRPEDT 
               
               
                 domain 
                   
                 AIYYCSAHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGSDIR 
               
               
                   
                   
                 LTQSPSPLSASVGDRVTITCQASEDINKFLNWYHQTPGKAPKLLI 
               
               
                   
                   
                 YDASTLQTGVPSRFSGSGSGTDFTLTINSLQPEDIGTYYCQQYES 
               
               
                   
                   
                 LPLTFGGGTKVEIK 
               
               
                 139112-nt 
                 366 
                 CAAGTGCAACTCGTGGAATCTGGTGGAGGACTCGTGCAACCCGGT 
               
               
                 ScFv 
                   
                 GGAAGCCTTAGGCTGTCGTGCGCCGTCAGCGGGTTTGCTCTGAGC 
               
               
                 domain 
                   
                 AACCATGGAATGTCCTGGGTCCGCCGGGCACCGGGAAAAGGGCTG 
               
               
                   
                   
                 GAATGGGTGTCCGGCATCGTGTACAGCGGGTCAACCTATTACGCC 
               
               
                   
                   
                 GCGTCCGTGAAGGGCAGATTCACTATCTCAAGAGACAACAGCCGG 
               
               
                   
                   
                 AACACCCTGTACTTGCAAATGAATTCCCTGCGCCCCGAGGACACC 
               
               
                   
                   
                 GCCATCTACTACTGCTCCGCCCACGGAGGAGAGTCGGACGTGTGG 
               
               
                   
                   
                 GGCCAGGGAACGACTGTGACTGTGTCCAGCGCATCAGGAGGGGGT 
               
               
                   
                   
                 GGTTCGGGCGGCCGGGCCTCGGGGGGAGGAGGTTCCGACATTCGG 
               
               
                   
                   
                 CTGACCCAGTCCCCGTCCCCACTGTCGGCCTCCGTCGGCGACCGC 
               
               
                   
                   
                 GTGACCATCACTTGTCAGGCGTCCGAGGACATTAACAAGTTCCTG 
               
               
                   
                   
                 AACTGGTACCACCAGACCCCTGGAAAGGCCCCCAAGCTGCTGATC 
               
               
                   
                   
                 TACGATGCCTCGACCCTTCAAACTGGAGTGCCTAGCCGGTTCTCC 
               
               
                   
                   
                 GGGTCCGGCTCCGGCACTGATTTCACTCTGACCATCAACTCATTG 
               
               
                   
                   
                 CAGCCGGAAGATATCGGGACCTACTATTGCCAGCAGTACGAATCC 
               
               
                   
                   
                 CTCCCGCTCACATTCGGCGGGGGAACCAAGGTCGAGATTAAG 
               
               
                 139112-aa 
                 381 
                 QVQLVESGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGL 
               
               
                 VH 
                   
                 EWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDT 
               
               
                   
                   
                 AIYYCSAHGGE3DVWGQGTTVTVSS 
               
               
                 139112-aa 
                 396 
                 DIRLTQSPSPLSASVGDRVTITCQASEDINKFLNWYHQTPGKAPK 
               
               
                 VL 
                   
                 LLIYDASTLQTGVPSRFSGSGSGTDFTLTINSLQPEDIGTYYCQQ 
               
               
                   
                   
                 YESLPLTFGGGTKVEIK 
               
               
                   
               
            
           
           
               
            
               
                 139113 
               
            
           
           
               
               
               
            
               
                 139113-aa 
                 352 
                 EVQLVETGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGL 
               
               
                 ScFv 
                   
                 EWVSGIVYSGSTYYAASVKGRFTI3RDKSRNTLYLQMNSLRPEDT 
               
               
                 domain 
                   
                 AIYYCSAHGGE3DVWGQGTTVTVSSASGGGGSGGRASGGGGSETT 
               
               
                   
                   
                 LTQSPATLSVSPGERATLSCRASQSVGSNLAWYQQKPGQGPRLLI 
               
               
                   
                   
                 YGASTRATGIPARFSGSGSGTEFTLTISSLQPEDFAVYYCQQYND 
               
               
                   
                   
                 WLPVTFGQGTKVEIK 
               
               
                 139113-nt 
                 367 
                 GAAGTGCAATTGGTGGAAACTGGAGGAGGACTTGTGCAACCTGGA 
               
               
                 ScFv 
                   
                 GGATCATTGCGGCTCTCATGCGCTGTCTCCGGCTTCGCCCTGTCA 
               
               
                 domain 
                   
                 AATCACGGGATGTCGTGGGTCAGACGGGCCCCGGGAAAGGGTCTG 
               
               
                   
                   
                 GAATGGGTGTCGGGGATTGTGTACAGCGGCTCCACCTACTACGCC 
               
               
                   
                   
                 GCTTCGGTCAAGGGCCGCTTCACTATTTCACGGGACAACAGCCGC 
               
               
                   
                   
                 AACACCCTCTATCTGCAAATGAACTCTCTCCGCCCGGAGGATACC 
               
               
                   
                   
                 GCCATCTACTACTGCTCCGCACACGGCGGCGAATCCGACGTGTGG 
               
               
                   
                   
                 GGACAGGGAACCACTGTCACCGTGTCGTCCGCATCCGGTGGCGGA 
               
               
                   
                   
                 GGATCGGGTGGCCGGGCCTCCGGGGGCGGCGGCAGCGAGACTACC 
               
               
                   
                   
                 CTGACCCAGTCCCCTGCCACTCTGTCCGTGAGCCCGGGAGAGAGA 
               
               
                   
                   
                 GCCACCCTTAGCTGCCGGGCCAGCCAGAGCGTGGGCTCCAACCTG 
               
               
                   
                   
                 GCCTGGTACCAGCAGAAGCCAGGACAGGGTCCCAGGCTGCTGATC 
               
               
                   
                   
                 TACGGAGCCTCCACTCGCGCGACCGGCATCCCCGCGAGGTTCTCC 
               
               
                   
                   
                 GGGTCGGGTTCCGGGACCGAGTTCACCCTGACCATCTCCTCCCTC 
               
               
                   
                   
                 CAACCGGAGGACTTCGCGGTGTACTACTGTCAGCAGTACAACGAT 
               
               
                   
                   
                 TGGCTGCCCGTGACATTTGGACAGGGGACGAAGGTGGAAATCAAA 
               
               
                 139113-aa 
                 382 
                 EVQLVETGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGL 
               
               
                 VH 
                   
                 EWVSGIVYSGSTYYAASVKGRFTISRDKSRNTLYLQMNSLRPEDT 
               
               
                   
                   
                 AIYYCSAKGGESDVWGQGTTVTVSS 
               
               
                 139113-aa 
                 397 
                 ETTLTQSPATLSVSPGERATLSCRASQSVGSNLAWYQQKPGQGPR 
               
               
                 VL 
                   
                 LLIYGASTRATGIPARFSGSGSGTEFTLTISSLQPEDFAVYYCQQ 
               
               
                   
                   
                 YNDWLPVTFGQGTKVEIK 
               
               
                   
               
            
           
           
               
            
               
                 139114 
               
            
           
           
               
               
               
            
               
                 139114-aa 
                 353 
                 EVQLVESGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGL 
               
               
                 ScFv 
                   
                 EWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDT 
               
               
                 domain 
                   
                 AIYYCSAHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGSEIV 
               
               
                   
                   
                 LTQSPGTLSLSPGERATLSCRASQSIGSSSLAWYQQKPGQAPRLL 
               
               
                   
                   
                 MYGASSRASGIFDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYA 
               
               
                   
                   
                 GSPPFTFGQGTKVEIK 
               
               
                 139114-nt 
                 368 
                 GAAGTGCAATTGGTGGAATCTGGTGGAGGACTTGTGCAACCTGGA  
               
               
                 ScFv 
                   
                 GGATCACTGAGACTGTCATGCGCGGTGTCCGGTTTTGCCCTGAGC 
               
               
                 domain 
                   
                 AATCATGGGATGTCGTGGGTCCGGCGCGCCCCCGGAAAGGGTCTG 
               
               
                   
                   
                 GAATGGGTGTCGGGTATCGTCTACTCCGGGAGCACTTACTACGCC 
               
               
                   
                   
                 GCGAGCGTGAAGGGCCGCTTCACCATTTCCCGCGATAACTCCCGC 
               
               
                   
                   
                 AACACCCTGTACTTGCAAATGAACTCGCTCCGGCCTGAGGACACT 
               
               
                   
                   
                 GCCATCTACTACTGCTCCGCACACGGAGGAGAATCCGACGTGTGG 
               
               
                   
                   
                 GGCCAGGGAACTACCGTGACCGTCAGCAGCGCCTCCGGCGGCGGG 
               
               
                   
                   
                 GGCTCAGGCGGACGGGCTAGCGGCGGCGGTGGCTCCGAGATCGTG 
               
               
                   
                   
                 CTGACCCAGTCGCCTGGCACTCTCTCGCTGAGCCCCGGGGAAAGG 
               
               
                   
                   
                 GCAACCCTGTCCTGTCGGGCCAGCCAGTCCATTGGATCATCCTCC 
               
               
                   
                   
                 CTCGCCTGGTATCAGCAGAAACCGGGACAGGCTCCGCGGCTGCTT 
               
               
                   
                   
                 ATGTATGGGGCCAGCTCAAGAGCCTCCGGCATTCCCGACCGGTTC 
               
               
                   
                   
                 TCCGGGTCCGGTTCCGGCACCGATTTCACCCTGACTATCTCGAGG 
               
               
                   
                   
                 CTGGAGCCAGAGGACTTCGCCGTGTACTACTGCCAGCAGTACGCG 
               
               
                   
                   
                 GGGTCCCCGCCGTTCACGTTCGGACAGGGAACCAAGGTCGAGATC 
               
               
                   
                   
                 AAG 
               
               
                 139114-aa 
                 383 
                 EVQLVESGGGLVQPGGSLRLSCAVSGFALSNHGMSWVRRAPGKGL 
               
               
                 VH 
                   
                 EWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQMNSLRPEDT 
               
               
                   
                   
                 ATYYCSAHGGESDVWGQGTTVTVSS 
               
               
                 139114-aa 
                 398 
                 EIVLTQSPGTLSLSPGERATLSCRASQSIGSSSLAWYQQKPGQAP 
               
               
                 VL 
                   
                 RLLMYGASSRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQ 
               
               
                   
                   
                 QYAGSPPFTFGQGTKVEIK 
               
               
                   
               
            
           
           
               
            
               
                 149362 
               
            
           
           
               
               
               
            
               
                 149362-aa 
                 429 
                 QVQLQESGPGLVKPSETLSLTCTVSGGSISSSYYYWGWIRQPPGK 
               
               
                 ScFv 
                   
                 GLEWIGSIYYSGSAYYNPSLKSRVTISVDTSKNQFSLRLSSVTAA 
               
               
                 domain 
                   
                 DTAVYYCARHWQEWPDAFDIWGQGTMVTVSSGGGGSGGGGSGGGG 
               
               
                   
                   
                 SETTLTQSPAFMSATPGDKVIISCKASQDIDDAMNWYQQKPGEAP 
               
               
                   
                   
                 LFIIQSATSPVPGIPPRFSGSGFGTDFSLTINNIESEDAAYYFCL 
               
               
                   
                   
                 QHDNFPLTFGQGTKLEIK 
               
               
                 149362-nt 
                 450 
                 CAAGTGCAGCTTCAGGAAAGCGGACCGGGCCTGGTCAAGCCATCC 
               
               
                 ScFv 
                   
                 GAAACTCTCTCCCTGACTTGCACTGTGTCTGGCGGTTCCATCTCA 
               
               
                 domain 
                   
                 TCGTCGTACTACTACTGGGGCTGGATTAGGCAGCCGCCCGGAAAG 
               
               
                   
                   
                 TACAACCCTAGCCTCAAGTCGAGAGTGACCATCTCCGTGGATACC 
               
               
                   
                   
                 GGACTGGAGTGGATCGGAAGCATCTACTATTCCGGCTCGGCGTAC 
               
               
                   
                   
                 TCCAAGAACCAGTTTTCCCTGCGCCTGAGCTCCGTGACCGCCGCT 
               
               
                   
                   
                 GACACCGCCGTGTACTACTGTGCTCGGCATTGGCAGGAATGGCCC 
               
               
                   
                   
                 GATGCCTTCGACATTTGGGGCCAGGGCACTATGGTCACTGTGTCA 
               
               
                   
                   
                 TCCGGGGGTGGAGGCAGCGGGGGAGGAGGGTCCGGGGGGGGAGGT 
               
               
                   
                   
                 TCAGAGACAACCTTGAGCCAGTCACCCGCATTCATGTCCGCCACT 
               
               
                   
                   
                 CCGGGAGACAAGGTCATCATCTCGTGCAAAGCGTCCCAGGATATC 
               
               
                   
                   
                 GACGATGCCATGAATTGGTACCAGCAGAAGCCTGGCGAAGCGCCG 
               
               
                   
                   
                 CTGTTCATTATCCAATCCGCAACCTCGCCCGTGCCTGGAATCCCA 
               
               
                   
                   
                 CCGCGGTTCAGCGGCAGCGGTTTCGGAACCGACTTTTCCCTGACC 
               
               
                   
                   
                 ATTAACAACATTGAGTCCGAGGACGCCGCCTACTACTTCTGCCTG 
               
               
                   
                   
                 CAACACGACAACTTCCCTCTCACGTTCGGCCAGGGAACCAAGCTG 
               
               
                   
                   
                 GAAATCAAG 
               
               
                 149362-aa 
                 471 
                 QVQLQESGPGLVKPSETLSLTCTVSGGSISSSYYYWGWIRQPPGK 
               
               
                 VH 
                   
                 GLEWIGSIYYSGSAYYNPSLKSRVTISVDTSKNQFSLRLSSVTAA 
               
               
                   
                   
                 DTAVYYCARHWQEWPDAFDIWGQGTMVTVSS 
               
               
                 149362-aa 
                 492 
                 ETTLTQSPAFMSATPGDKVIISCKASQDIDDAMNWYQQKPGEAPL 
               
               
                 VL 
                   
                 FIIQSATSPVPGIPPRFSGSGFGTDFSLTINNIESEDAAYYFCLQ 
               
               
                   
                   
                 HDNFPLTFGQGTKLEIK 
               
               
                   
               
            
           
           
               
            
               
                 149363 
               
            
           
           
               
               
               
            
               
                 149363-aa 
                 430 
                 QVNLRESGPALVKPTQTLTLTCTFSGFSLRTSGMCVSWIRQPPGK 
               
               
                 ScFv 
                   
                 ALEWLARIDWDEDKFYSTSLKTRLTISKDTSDNQVVLRMTNMDPA 
               
               
                 domain 
                   
                 DTATYYCARSGAGGTSATAFDIWGPGTMVTVSSGGGGSGGGGSGG 
               
               
                   
                   
                 GGSDIQMTQSPSSLSASVGDRVTITCRASQDIYNNLAWFQLKPGS 
               
               
                   
                   
                 APRSLMYAANKSQSGVPSRFSGSASGTDFTLTISSLQPEDFATYY 
               
               
                   
                   
                 CQHYYRFPYSFGQGTKLEIK 
               
               
                 149363-nt 
                 451 
                 CAAGTCAATCTGCGCGAATCCGGCCCCGCCTTGGTCAAGCCTACC 
               
               
                 ScFv 
                   
                 CAGACCCTCACTCTGACCTGTACTTTCTCCGGCTTCTCCCTGCGG 
               
               
                 domain 
                   
                 ACTTCCGGGATGTGCGTGTCCTGGATCAGACAGCCTCCGGGAAAG 
               
               
                   
                   
                 GCCCTGGAGTGGCTCGCTCGCATTGACTGGGATGAGGACAAGTTC 
               
               
                   
                   
                 TACTCCACCTCACTCAAGACCAGGCTGACCATCAGCAAAGATACC 
               
               
                   
                   
                 TCTGACAACCAAGTGGTGCTCCGCATGACCAACATGGACCCAGCC 
               
               
                   
                   
                 GACACTGCCACTTACTACTGCGCGAGGAGCGGAGCGGGCGGAACC 
               
               
                   
                   
                 TCCGCCACCGCCTTCGATATTTGGGGCCCGGGTACCATGGTCACC 
               
               
                   
                   
                 GTGTCAAGCGGAGGAGGGGGGTCCGGGGGCGGCGGTTCCGGGGGA 
               
               
                   
                   
                 GGCGGATCGGACATTCAGATGACTCAGTCACCATCGTCCCTGAG 
               
               
                   
                   
                 GCTAGCGTGGGCGACAGAGTGACAATCACTTGCCGGGCATCCCAG 
               
               
                   
                   
                 GACATCTATAACAACCTTGCGTGGTTCCAGCTGAAGCCTGGTTCC 
               
               
                   
                   
                 GCACCGCGGTCACTTATGTACGCCGCCAACAAGAGCCAGTCGGGA 
               
               
                   
                   
                 GTGCCGTCCCGGTTTTCCGGTTCGGCCTCGGGAACTGACTTCACC 
               
               
                   
                   
                 CTGACGATCTCCAGCCTGCAACCCGAGGATTTCGCCACCTACTAG 
               
               
                   
                   
                 TGCCAGCACTACTAGCGCTTTCCCTACTCGTTCGGACAGGGAACC 
               
               
                   
                   
                 AAGCTGGAAATCAAG 
               
               
                 149363-aa 
                 472 
                 QVNLRESGPALVKPTQTLTLTCTFSGFSLRTSGMCVSWIRQPPGK 
               
               
                 VH 
                   
                 ALEWLARIDWDEDKFYSTSLKTRLTISKDTSDNQVVLRMTNMDPA 
               
               
                   
                   
                 DTATYYCARSGAGGTSATAFPIWGPGTMVTVSS 
               
               
                 149363-aa 
                 493 
                 DIQMTQSPSSLSASVGDRVTITCRASQDIYNNLAWFQLKPGSAPR 
               
               
                 VL 
                   
                 SLMYAANKSQSGVPSRFSGSASGTDFTLTISSLQPEDFATYYCQH 
               
               
                   
                   
                 YYRFPYSFGQGTKLEIK 
               
               
                   
               
            
           
           
               
            
               
                 149364 
               
            
           
           
               
               
               
            
               
                 149364-aa 
                 431 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGL 
               
               
                 ScFv 
                   
                 EWVSSISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAED 
               
               
                 domain 
                   
                 TAVYYCAKTIAAVYAFDIWGQGTTVTVSSGGGGSGGGGSGGGGSE 
               
               
                   
                   
                 IVLTQSPLSLPVTPEEPASISCRSSQSLLHSNGYNYLDWYLQKPG 
               
               
                   
                   
                 QSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVY 
               
               
                   
                   
                 YCMQALOTPYTFGQGTKLEIK 
               
               
                 149364-nt 
                 452 
                 GAAGTGCAGCTTGTCGAATCCGGGGGGGGACTGGTCAAGCCGGGC 
               
               
                 ScFv 
                   
                 GGATCACTGAGACTGTCCTGCGCCGCGAGCGGCTTCACGTTCTCC 
               
               
                 domain 
                   
                 TCCTACTCCATGAACTGGGTCCGCCAAGCCCCCGGGAAGGGACTG 
               
               
                   
                   
                 GAATGGGTGTCCTCTATCTCCTCGTCGTCGTCCTACATCTACTAC 
               
               
                   
                   
                 GCCGACTCCGTGAAGGGAAGATTCACCATTTCCCGCGACAACGCA 
               
               
                   
                   
                 AAGAACTCACTGTACTTGCAAATGAACTCACTCCGGGCCGAAGAT 
               
               
                   
                   
                 ACTGCTGTGTACTATTGCGCCAAGACTATTGCCGCCGTCTACGCT 
               
               
                   
                   
                 TTCGACATCTGGGGCCAGGGAACCACCGTGACTGTGTCGTCCGGT 
               
               
                   
                   
                 GGTGGTGGCTCGGGCGGAGGAGGAAGCGGCGGCGGGGGGTCCGAG 
               
               
                   
                   
                 ATTGTGCTGACCCAGTCGCCACTGAGCCTCCCTGTGACCCCCGAG 
               
               
                   
                   
                 GAACCCGCCAGCATCAGCTGCCGGTCCAGCCAGTCCCTGCTCCAC 
               
               
                   
                   
                 TCCAACGGATACAATTACCTCGATTGGTACCTTCAGAAGCCTGGA 
               
               
                   
                   
                 CAAAGCCCGCAGCTGCTCATCTACTTGGGATCAAACCGCGCGTCA 
               
               
                   
                   
                 GGAGTGCCTGACCGGTTCTCCGGCTCGGGCAGCGGTACCGATTTC 
               
               
                   
                   
                 ACCCTGAAAATCTCCAGGGTGGAGGCAGAGGACGTGGGAGTGTAT 
               
               
                   
                   
                 TACTGTATGCAGGCGCTGCAGACTCCGTACACATTTGGGCAGGGC 
               
               
                   
                   
                 ACCAAGCTGGAGATCAAG 
               
               
                 149364-aa 
                 473 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGL 
               
               
                 VH 
                   
                 SWVSSISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAED 
               
               
                   
                   
                 TAVYYCAKTIAAVYAFDIWGQGTTVTVSS 
               
               
                 149364-aa 
                 494 
                 EIVLTQSPLSLPVTPEEPASISCRSSQSLLHSNGYNYLDWYLQKP 
               
               
                 VL 
                   
                 GQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGV 
               
               
                   
                   
                 YYCMQALQTPYTFGQGTKLEIK 
               
               
                   
               
            
           
           
               
            
               
                 149365 
               
            
           
           
               
               
               
            
               
                 149365-aa 
                 432 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGL 
               
               
                 ScFv 
                   
                 EWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAED 
               
               
                 domain 
                   
                 TAVYYCARDLRGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSSYV 
               
               
                   
                   
                 LTQSPSVSAAPGYTATISCGGNNIGTKSVHWYQQKPGQAPLLVIR 
               
               
                   
                   
                 DDSVRPSKIPGRFSGSNSGNMATLTISGVQAGDEADFYCQVWDSD 
               
               
                   
                   
                 SEHVVFGGGTKLTVL 
               
               
                 149365-nt 
                 453 
                 GAAGTCCAGCTCGTGGAGTCCGGCGGAGGCCTYGTGAAGCCTGGA 
               
               
                 ScFv 
                   
                 GGTTCGCTGAGACTGTCCTGCGCCGCCTCCGGCTTCACCTTCTCC 
               
               
                 domain 
                   
                 GACTACTACATGTCCTGGATCAGACAGGCCCCGGGAAAGGGCCTG 
               
               
                   
                   
                 GAATGGGTGTCCTACATCTCGTCATCGGGCAGCACTATCTACTAC 
               
               
                   
                   
                 GCGGACTCAGTGAAGGGGCGGTTCACCATTTCCCGGGATAACGCG 
               
               
                   
                   
                 AAGAACTCGCTGTATCTGCAAATGAACTCACTGAGGGCCGAGGAC 
               
               
                   
                   
                 ACCGCCGTGTACTACTGCGCCCGCGATCTCCGCGGGGCATTTGAC 
               
               
                   
                   
                 ATCTGGGGACAGGGAACCATGGTCACAGTGTCCAGCGGAGGGGGA 
               
               
                   
                   
                 GGATCGGGTGGCGGAGGTTCCGGGGGTGGAGGCTCCTCCTACGTG 
               
               
                   
                   
                 CTGACTCAGAGCCCAAGCGTCAGCGCTGCGCCCGGTTACACGGCA 
               
               
                   
                   
                 ACCATCTCCTGTGGCGGAAACAACATTGGGACCAAGTCTGTGCAC 
               
               
                   
                   
                 TGGTATCAGCAGAAGCCGGGCCAAGCTCCCCTGTTGGTGATCCGC 
               
               
                   
                   
                 GATGACTCCGTGCGGCCTAGCAAAATTCCGGGACGGTTCTCCGGC 
               
               
                   
                   
                 TCCAACAGCGGCAATATGGCCACTCTCACCATCTCGGGAGTGCAG 
               
               
                   
                   
                 GCCGGAGATGAAGCCGACTTCTACTGCCAAGTCTGGGACTCAGAC 
               
               
                   
                   
                 TCCGAGCATGTGGTGTTCGGGGGCGGAACCAAGCTGACTGTGCTC 
               
               
                 149365-aa 
                 474 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGL 
               
               
                 VH 
                   
                 EWVSYISSSGSTIYYADSVKGRFTISRDMAKNSLYLQMNSLRAED 
               
               
                   
                   
                 TAVYYCARDLRGAFDIWGQGTMVTVSS 
               
               
                 149365-aa 
                 495 
                 SYVLTQSPSVSAAPGYTATISCGGNNIGTKSVHWYQQKPGQAPLL 
               
               
                 VL 
                   
                 VIRDDSVRPSKIPGRFSGSNSGNMATLTISGVQAGDEADFYCQVW 
               
               
                   
                   
                 DSDSEHVVFGGGTKLTVL 
               
               
                   
               
            
           
           
               
            
               
                 149366 
               
            
           
           
               
               
               
            
               
                 149366-aa 
                 433 
                 QVQLVQSGAEVKKPGASVKVSCKPSGYTVTSHYIHWVRRAPGQGL 
               
               
                 ScFv 
                   
                 EWMGMINPSGGVTAYSQTLQGRVTMTSDTSSSTVYMELSSLRSED 
               
               
                 domain 
                   
                 TAMYYCAREGSGSGWYFDFWGRGTLVTVSSGGGGSGGGGSGGGGS 
               
               
                   
                   
                 SYVLTQPPSVSVSPGQTASITCSGDGLSKKYVSWYQQKAGQSPVV 
               
               
                   
                   
                 LISRDKERPSGIPDRFSGSNSADTATLTISGTQAMDEADYYCQAW 
               
               
                   
                   
                 DDTTVVFGGGTKLTVL 
               
               
                 149366-nt 
                 454 
                 CAAGTGCAGCTGGTGCAGAGCGGGGCCGAAGTCAAGAAGCCGGGA 
               
               
                 ScFv 
                   
                 GCCTCCGTGAAAGTGTCCTGCAAGCCTTCGGGATACACCGTGACC 
               
               
                 domain 
                   
                 TCCCACTACATTCATTGGGTCCGCCGCGCCCCCGGCCAAGGACTC 
               
               
                   
                   
                 GAGTGGATGGGCATGATCAACCCTAGCGGCGGAGTGACCGCGTAC 
               
               
                   
                   
                 AGCCAGACGCTGCAGGGACGCGTGACTATGACCTCGGATACCTCC 
               
               
                   
                   
                 TCCTCCACCGTCTATATGGAACTGTCCAGCCTGCGGTCCGAGGAT 
               
               
                   
                   
                 ACCGCCATGTACTACTGCGCCCGGGAAGGATCAGGCTCCGGGTGG 
               
               
                   
                   
                 TATTTCGACTTCTGGGGAAGAGGCACCCTCGTGACTGTGTCATCT 
               
               
                   
                   
                 GGGGGAGGGGGTTCCGGTGGTGGCGGATCGGGAGGAGGCGGTTCA 
               
               
                   
                   
                 TCCTACGTGCTGACCCAGCCACCCTCCGTGTCCGTGAGCCCCGGC 
               
               
                   
                   
                 CAGACTGCATCGATTACATGTAGCGGCGACGGCCTCTCCAAGAAA 
               
               
                   
                   
                 TACGTGTCGTGGTACCAGCAGAAGGCCGGACAGAGCCCGGTGGTG 
               
               
                   
                   
                 CTGATCTCAAGAGATAAGGAGCGGCCTAGCGGAATCCCGGACAGG 
               
               
                   
                   
                 TTCTCGGGTTCCAACTCCGCGGACACTGCTACTCTGACCATCTCG 
               
               
                   
                   
                 GGGACCCAGGCTATGGACGAAGCCGATTACTACTGCCAAGCCTGG 
               
               
                   
                   
                 GACGACACTACTGTCGTGTTTGGAGGGGGCACCAAGTTGACCGTC 
               
               
                   
                   
                 CTT 
               
               
                 149366-aa 
                 475 
                 QVQLVQSGAEVKKPGASVKVSCKPSGYTVTSHYIHWVRRAPGQGL 
               
               
                 VH 
                   
                 EMWGMINPSGGTVAYSQTLQGRVTMTSDTSSSTVYMELSSLRSED 
               
               
                   
                   
                 TAMYYCAREGSGSGWYFDFWGRGTLVTVSS 
               
               
                 149366-aa 
                 496 
                 SYVLTQPPSVSVSPGQTASITCSGDGLSKKYVSWYQQKAGQSPVV 
               
               
                 VL 
                   
                 LISRDKERPSGIPDRFSGSNSADTATLTISGTQAMDEADYYCQAW 
               
               
                   
                   
                 DDTTVVFGGGTKLTVL 
               
               
                   
               
            
           
           
               
            
               
                 149367 
               
            
           
           
               
               
               
            
               
                 149367-aa 
                 434 
                 QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGK 
               
               
                 ScFv 
                   
                 GLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAA 
               
               
                 domain 
                   
                 DTAVYYCARAGIAARLRGAFDIWGQGTMVTVSSGGGGSGGGGSGG 
               
               
                   
                   
                 GGSDIVMTQSPSSVSASVGDRVIITCRASQGIRNWLAWYQQKPGK 
               
               
                   
                   
                 APNLLIYAASNLQSGVPSRFSGSGSGADFTLTISSLQPEDVATYY 
               
               
                   
                   
                 CQKYNSAPFTFGPGTKVDIK 
               
               
                 149367-nt 
                 455 
                 CAAGTGCAGCTTCAGGAGAGCGGCCCGGGACTCGTGAAGCCGTCC 
               
               
                 ScFv 
                   
                 CAGACCCTGTCCCTGACTTGCACCGTGTCGGGAGGAAGCATCTCG 
               
               
                 domain 
                   
                 AGCGGAGGCTACTATTGGTCGTGGATTCGGCAGCACCCTGGAAAG 
               
               
                   
                   
                 GGCCTGGAATGGATCGGCTACATCTACTACTCCGGCTCGACCTAC 
               
               
                   
                   
                 TACAACCCATCGCTGAAGTCCAGAGTGACAATCTCAGTGGACACG 
               
               
                   
                   
                 TCCAAGAATCAGTTCAGCCTGAAGCTCTCTTCCGTGACTGCGGCC 
               
               
                   
                   
                 GACACCGCCGTGTACTACTGCGCACGCGCTGGAATTGCCGCCCGG 
               
               
                   
                   
                 CTGAGGGGTGCCTTCGACATTTGGGGACAGGGCACCATGGTCACC 
               
               
                   
                   
                 GTGTCCTCCGGCGGCGGAGGTTCCGGGGGTGGAGGCTCAGGAGGA 
               
               
                   
                   
                 GGGGGGTCCGACATCGTCATGACTCAGTCGCCCTCAAGCGTCAGC 
               
               
                   
                   
                 GCGTCCGTCGGGGACAGAGTGATCATCACCTGTCGGGCGTCCCAG 
               
               
                   
                   
                 GGAATTCGCAACTGGCTGGCCTGGTATCAGCAGAAGCCCGGAAAG 
               
               
                   
                   
                 GCCCCCAACCTGTTGATCTACGCCGCCTCAAACCTCCAATCCGGG 
               
               
                   
                   
                 GTGCCGAGCCGCTTCAGCGGCTCCGGTTCGGGTGCCGATTTCACT 
               
               
                   
                   
                 CTGACCATCTCCTCCCTGCAACCTGAAGATGTGGCTACCTACTAC 
               
               
                   
                   
                 TGCCAAAAGTACAACTCCGCACCTTTTACTTTCGGACCGGGGACC 
               
               
                   
                   
                 AAAGTGGACATTAAG 
               
               
                 149367-aa 
                 476 
                 QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGK 
               
               
                 VH 
                   
                 GLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAA 
               
               
                   
                   
                 DTAVYYCARAGIAARLRGAFDIWGQGTMVTVSS 
               
               
                 149367-aa 
                 497 
                 DIVMTQSPSSVSASVGDRVIITCRASQGIRNWLAWYQQKPGKAPN 
               
               
                 VL 
                   
                 LLIYAASNLQSGVPSRFSGSGSGADFTLTISSLQPEDVATYYCQK 
               
               
                   
                   
                 YNSAPFTFGPGTKVDIK 
               
               
                   
               
            
           
           
               
            
               
                 149368 
               
            
           
           
               
               
               
            
               
                 149368-aa 
                 435 
                 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGL 
               
               
                 ScFv 
                   
                 EWMGGIIPIFGTAKYAQKFQGRVTITADESTSTAYMELSSLRSED 
               
               
                 domain 
                   
                 TAVYYCARRGGYQLLRWDVGLLRSAFDIWGQGTMVTVSSGGGGSG 
               
               
                   
                   
                 GGGSGGGGSSYVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQ 
               
               
                   
                   
                 QKPGQAPVLVLYGKNNRPSGVPDRFSGSRSGTTASLTITGAQAED 
               
               
                   
                   
                 EADYYCSSRDSSGDHLRVFGTGTKVTVL 
               
               
                 149368-nt 
                 456 
                 CAAGTGCAGCTGGTCCAGTCGGGCGCCGAGGTCAAGAAGCCCGGG 
               
               
                 ScFv 
                   
                 AGCTCTGTGAAAGTGTCCTGCAAGGCCTCCGGGGGCACCTTTAGC 
               
               
                 domain 
                   
                 TCCTACGCCATCTCCTGGGTCCGCCAAGCACCGGGTCAAGGCCTG 
               
               
                   
                   
                 GAGTGGATGGGGGGAATTATCCCTATCTTCGGCACTGCCAACTAC 
               
               
                   
                   
                 GCCCAGAAGTTCCAGGGACGCGTGACCATTACCGCGGACGAATCC 
               
               
                   
                   
                 ACCTCCACCGCTTATATGGAGCTGTCCAGCTTGCGCTCGGAAGAT 
               
               
                   
                   
                 ACCGCCGTGTACTACTGCGCCCGGAGGGGTGGATACCAGCTGCTG 
               
               
                   
                   
                 AGATGGGACGTGGGCCTCCTGCGGTCGGCGTTCGACATCTGGGGC 
               
               
                   
                   
                 CAGGGCACTATGGTCACTGTGTCCAGCGGAGGAGGCGGATCGGGA 
               
               
                   
                   
                 GGCGGCGGATCAGGGGGAGGCGGTTCCAGCTACGTGCTTACTCAA 
               
               
                   
                   
                 CCCCCTTCGGTGTCCGTGGCCCCGGGACAGACCGCCAGAATCACT 
               
               
                   
                   
                 TGCGGAGGAAACAACATTGGGTCCAAGAGCGTGCATTGGTACCAG 
               
               
                   
                   
                 CAGAAGCCAGGACAGGCCCCTGTGCTGGTGCTCTACGGGAAGAAC 
               
               
                   
                   
                 AATCGGCCCAGCGGAGTGCCGGACAGGTTCTCGGGTTCACGCTCC 
               
               
                   
                   
                 GGTACAACCGCTTCACTGACTATCACCGGGGCCCAGGCAGAGGAT 
               
               
                   
                   
                 GAAGCGGACTACTACTGTTCCTCCCGGGATTCATCCGGCGACCAC 
               
               
                   
                   
                 CTCCGGGTGTTCGGAACCGGAACGAAGGTCACCGTGCTG 
               
               
                 149368-aa 
                 477 
                 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGL 
               
               
                 VH 
                   
                 EWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSED 
               
               
                   
                   
                 TAVYYCARRGGYQLLRWDVGLLRSAFDIWGQGTMVTVSS 
               
               
                 149368-aa 
                 498 
                 SYVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVL 
               
               
                 VL 
                   
                 VLYGKNNRPSGVPDRFSGSRSGTTASLTITGAQAEDEADYYCSSR 
               
               
                   
                   
                 DSSGDKLRVFGTGTKVTVL 
               
               
                   
               
            
           
           
               
            
               
                 149369 
               
            
           
           
               
               
               
            
               
                 149369-aa 
                 436 
                 EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSR 
               
               
                 ScFv 
                   
                 GLEWLGRTYYRSKWYSFYAISLKSRIIINPDTSKKQFSLQLKSVT 
               
               
                 domain 
                   
                 PEDTAVYYCARSSPEGLFLYWFDPWGQGTLVTVSSGGDGSGGGGS 
               
               
                   
                   
                 GGGGSSSELTQDPAVSVALGQTIRITCQGDSLGNYYATWYQQKPG 
               
               
                   
                   
                 QAPVLVIYGTNNRPSGIPDRFSASSSGNTASLTITGAQAEDEADY 
               
               
                   
                   
                 YCNSRDSSGHHLLFGTGTKVTVL 
               
               
                 149369-nt 
                 457 
                 GAAGTGCAGCTCCAACAGTCAGGACCGGGGCTCGTGAAGCCATCC 
               
               
                 ScFv 
                   
                 CAGACCCTGTCCCTGACTTGTGCCATCTCGGGAGATAGCGTGTCA 
               
               
                 domain 
                   
                 TCGAACTCCGCCGCCTGGAACTGGATTCGGCAGAGCCCGTCCCGC 
               
               
                   
                   
                 GGACTGGAGTGGCTTGGAAGGACCTACTACCGGTCCAAGTGGTAC 
               
               
                   
                   
                 TCTTTCTACGCGATCTCGCTGAAGTCCCGCATTATCATTAACCCT 
               
               
                   
                   
                 GATACCTCCAAGAATCAGTTCTCCCTCCAACTGAAATCCGTCACC 
               
               
                   
                   
                 CCCGAGGACACAGCAGTGTATTACTGCGCACGGAGCAGCCCCGAA 
               
               
                   
                   
                 GGACTGTTCCTGTATTGGTTTGACCCCTGGGGCCAGGGGACTCTT 
               
               
                   
                   
                 GTGACCGTGTCGAGCGGCGGAGATGGGTCCGGTGGCGGTGGTTCG 
               
               
                   
                   
                 GGGGGCGGCGGATCATCATCCGAACTGACCCAGGACCCGGCTGTG 
               
               
                   
                   
                 TCCGTGGCGCTGGGACAAACCATCCGCATTACGTGCCAGGGAGAC 
               
               
                   
                   
                 TCCCTGGGCAACTACTACGCCACTTGGTACCAGCAGAAGCCGGGC 
               
               
                   
                   
                 CAAGCCCCTGTGTTGGTCATCTACGGGACCAACAACAGACCTTCC 
               
               
                   
                   
                 GGCATCCCCGACCGGTTCAGCGCTTCGTCCTCCGGCAACACTGCC 
               
               
                   
                   
                 AGCCTGACCATCACTGGAGCGCAGGCCGAAGATGAGGCCGACTAG 
               
               
                   
                   
                 TACTGCAACAGCAGAGACTCCTCGGGTCATCACCTCTTGTTCGGA 
               
               
                   
                   
                 ACTGGAACCAAGGTCACCGTGCTG 
               
               
                 149369-aa 
                 478 
                 EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSR 
               
               
                 VH 
                   
                 GLEWLGRTYYRSKWYSFYAISLKSRIIINPDTSKNQFSLQLKSVT 
               
               
                   
                   
                 PEDTAVYYCARSSPEGLFLYWFDPWGQGTLVTVSS 
               
               
                 149369-aa 
                 499 
                 SSELTQDPAVSVALGQTIRITCQGDSLGNYYATWYQQKPGQAPVL 
               
               
                 VL 
                   
                 VIYGTNNRPSGIPDRFSASSSGMTASLTITGAQAEDEADYYCNSR 
               
               
                   
                   
                 DSSGHHLLFGTGTKVTVL 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-A4 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                 437 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 C1978-A4-aa 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED 
               
               
                 ScFv 
                   
                 TAVYYCAKVEGSGSLDYWGQGTLVTVSSGGGGSGGGGSGGGGSEI 
               
               
                 domain 
                   
                 VMTQSPGTLSLSPGERATLSCRASQSVSSAYLAWYQQKPGQPPRL 
               
               
                   
                   
                 LISGASTRATGIPDRFGGSGSGTDFTLTISRLEPEDFAVYYCQHY 
               
               
                   
                   
                 GSSFNGSSLFTFGQGTRLEIK 
               
               
                 BCMA_EBB- 
                 458 
                 GAAGTGCAGCTCGTGGAGTCAGGAGGCGGCCTGGTCCAGCCGGGA 
               
               
                 C1978-A4-nt 
                   
                 GGGTCCCTTAGACTGTCA7GCGCCGCAAGCGGATTCACTTTCTCC 
               
               
                 ScFv 
                   
                 TCCTATGCCATGAGCTGGGTCCGCCAAGCCCCCGGAAAGGGACTG 
               
               
                 domain 
                   
                 GAATGGGTGTCCGCCATCTCGGGGTCTGGAGGCTCAACTTACTAC 
               
               
                   
                   
                 GCTGACTCCGTGAAGGGACGGTTCACCATTAGCCGCGACAACTCC 
               
               
                   
                   
                 AAGAACACCCTCTAGCTCCAAATGAACTCCCTGCGGGCCGAGGAT 
               
               
                   
                   
                 ACCGCCGTCTACTACTGCGCCAAAGTGGAAGGTTCAGGATCGCTG 
               
               
                   
                   
                 GACTACTGGGGACAGGGTACTCTCGTGACCGTGTCATCGGGCGGA 
               
               
                   
                   
                 GGAGGTTCCGGCGGTGGCGGCTCCGGCGGCGGAGGGTCGGAGATC 
               
               
                   
                   
                 GTGATGACCCAGAGCCCTGGTACTCTGAGCCTTTCGCCGGGAGAA 
               
               
                   
                   
                 AGGGCCACCCTGTCCTGCCGCGCTTCCCAATCCGTGTCCTCCGCG 
               
               
                   
                   
                 TACTTGGCGTGGTACCAGCAGAAGCCGGGACAGCCCCCTCGGCTG 
               
               
                   
                   
                 CTGATCAGCGGGGCCAGCACCCGGGCAACCGGAATCCCAGACAGA 
               
               
                   
                   
                 TTCGGGGGTTCCGGCAGCGGCACAGATTTCACCCTGACTATTTCG 
               
               
                   
                   
                 AGGTTGGAGCCCGAGGACTTTGCGGTGTATTACTGTCAGCACTAC 
               
               
                   
                   
                 GGGTCGTCCTTTAATGGCTCCAGCCTGTTCACGTTCGGACAGGGG 
               
               
                   
                   
                 ACCCGCCTGGAAATCAAG 
               
               
                 BCMA_EBB- 
                 479 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 C1978-A4-aa 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED 
               
               
                 VH 
                   
                 TAVYYCAKVEGSGSLDYWGQGTLVTVSS 
               
               
                 BCMA_EBB- 
                 500 
                 EIVMTQSPGTLSLSPGERATLSCRASQSVSSAYLAWYQQKPGQPP 
               
               
                 C1978-A4-aa 
                   
                 RLLISGASTRATGIPDRFGGSGSGTDFTLTISRLEPEDFAVYYCQ 
               
               
                 VL 
                   
                 HYGSSFNGSSLFTFGQGTRLEIK 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-G1 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                 438 
                 EVQLVETGGGLVQPGGSLRLSCAASGITFSRYPMSWVRQAPGKGL   
               
               
                 C1978-G1-aa 
                   
                 EWVSGISDSGVSTYYADSAKGRFTISRDNSKNTLFLQMSSLRDED 
               
               
                 ScFv 
                   
                 TAVYYCVTRAGSEASDIWGQGTMVTVSSGGGGSGGGGSGGGGSEI 
               
               
                 domain 
                   
                 VLTQSPATLSLSPGERATLSCRASQSVSNSLAWYQQKPGQAPRLL 
               
               
                   
                   
                 IYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAIYYCQQFG 
               
               
                   
                   
                 TSSGLTFGGGTKLEIK 
               
               
                 BCMA_EBB- 
                 459 
                 GAAGTGCAACTGGTGGAAACCGGTGGCGGCCTGGTGCAGCCTGGA 
               
               
                 C1978-G1-nt 
                   
                 GGATCATTGAGGCTGTCATGCGCGGCCAGCGGTATTACCTTCTCC 
               
               
                 ScFv 
                   
                 CGGTACCCCATGTCCTGGGTCAGACAGGCCCCGGGGAAAGGGCTT 
               
               
                 domain 
                   
                 GAATGGGTGTCCGGGATCTCGGACTCCGGTGTCAGCACTTACTAC 
               
               
                   
                   
                 GCCGACTCCGCCAAGGGACGCTTCACCA7TTCCCGGGACAACTCG 
               
               
                   
                   
                 AAGAACACCCTGTTCCTCCAAATGAGCTCCCTCCGGGACGAGGAT 
               
               
                   
                   
                 ACTGCAGTGTACTACTGCGTGACCCGCGCCGGGTCCGAGGCGTCT 
               
               
                   
                   
                 GACATTTGGGGACAGGGCACTATGGTCACCGTGTCGTCCGGCGGA 
               
               
                   
                   
                 GGGGGCTCGGGAGGCGGTGGCAGCGGAGGAGGAGGGTCCGAGATC 
               
               
                   
                   
                 GTGCTGACCCAATCCCCGGCCACCCTCTCGCTGAGCCCTGGAGAA 
               
               
                   
                   
                 AGGGCAACCTTGTCCTGTCGCGCGAGCCAGTCCGTGAGCAACTCC 
               
               
                   
                   
                 CTGGCCTGGTACCAGCAGAAGCCCGGACAGGCTCCGAGACTTCTG 
               
               
                   
                   
                 ATCTACGACGCTTCGAGCCGGGCCACTGGAATCCCCGACCGCTTT 
               
               
                   
                   
                 TCGGGGTCCGGCTCAGGAACCGATTTCACCCTGACAATCTCACGG 
               
               
                   
                   
                 CTGGAGCCAGAGGATTTCGCCATCTATTACTGCCAGCAGTTCGGT 
               
               
                   
                   
                 ACTTCCTCCGGCCTGACTTTCGGAGGCGGCACGAAGCTCGAAATC 
               
               
                   
                   
                 AAG 
               
               
                 BCMA_EBB- 
                 480 
                 EVQLVETGGGLVQPGGSLRLSCAASGITFSRYPMSWVRQAPGKGL 
               
               
                 C1978-G1-aa 
                   
                 EWVSGISDSGVSTYYADSAKGRFTISRDNSKNTLFLQMSSLRDED 
               
               
                 VH 
                   
                 TAVYYCVTRAGSEASDIWGQGTMVTVSS 
               
               
                 BCMA_EBB- 
                 501 
                 EIVLTQSPATLSLSPGERATLSCRASQSVSNSLAWYQQKPGQAPR 
               
               
                 C1978-G1-aa 
                   
                 LLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAIYYCQQ 
               
               
                 VL 
                   
                 FGTSSGLTFGGGTKLEIK 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1979-C1 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                 439 
                 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 C1979-C1-aa 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNAKNSLYLQMNSLRAED 
               
               
                 ScFv 
                   
                 TAIYYCARATYKRELRYYYGMDVWGQGTMVTVSSGGGGSGGGGSG 
               
               
                 domain 
                   
                 GGGSEIVMTQSPGTVSLSPGERATLSCRASQSVSSSFLAWYQQKP 
               
               
                   
                   
                 GQAPRLLIYGASSRATGIFDRFSGSGSGTDFTLTISRLEPEDSAV 
               
               
                   
                   
                 YYCQQYHSSPSWTFGQGTRLEIK 
               
               
                 BCMA_EBB- 
                 460 
                 CAAGTGCAGCTCGTGGAATCGGGTGGCGGACTGGTGCAGCCGGGG 
               
               
                 C1979-C1-nt 
                   
                 GGCTCACTTAGACTGTCCTGCGCGGCCAGCGGATTCACTTTCTCC 
               
               
                 ScFv 
                   
                 TCCTACGCCATGTCCTGGGTCAGACAGGCCCCTGGAAAGGGCCTG 
               
               
                 domain 
                   
                 GAATGGGTGTCCGCAATCAGCGGCAGCGGCGGCTCGACCTATTAC 
               
               
                   
                   
                 GCGGATTCAGTGAAGGGCAGATTCACCATTTCCCGGGACAACGCC 
               
               
                   
                   
                 AAGAACTCCTTGTACCTTCAAATGAACTCCCTCCGCGCGGAAGAT 
               
               
                   
                   
                 ACCGCAATCTAGTACTGCGCTCGGGCCACTTACAAGAGGGAACTG 
               
               
                   
                   
                 CGCTACTACTACGGGATGGACGTCTGGGGCCAGGGAACCATGGTC 
               
               
                   
                   
                 ACCGTGTCCAGCGGAGGAGGAGGATCGGGAGGAGGCGGTAGCGGG 
               
               
                   
                   
                 GGTGGAGGGTCGGAGATCGTGATGACCCAGTCCCCCGGCACTGTG 
               
               
                   
                   
                 TCGCTGTCCCCCGGCGAACGGGCCACCCTGTCATGTCGGGCCAGC 
               
               
                   
                   
                 CAGTCAGTGTCGTCAAGCTTCCTCGCCTGGTACCAGCAGAAACCG 
               
               
                   
                   
                 GGACAAGCTCCCCGCCTGCTGATCTACGGAGCCAGCAGCCGGGCC 
               
               
                   
                   
                 ACCGGTATTCCTGACCGGTTCTCCGGTTCGGGGTCCGGGACCGAC 
               
               
                   
                   
                 TTTACTCTGACTATCTCTCGCCTCGAGCCAGAGGACTCCGCCGTG 
               
               
                   
                   
                 TATTACTGCCAGCAGTACCACTCCTCCCCGTCCTGGACGTTCGGA 
               
               
                   
                   
                 CAGGGCACAAGGCTGGAGATTAAG 
               
               
                 BCMA_EBB- 
                 481 
                 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 C1979-C1-aa 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNAKNSLYLQMNSLRAED 
               
               
                 VH 
                   
                 TAIYYCARATYKRELRYYYGMDVWGQGTMVTVSS 
               
               
                 BCMA_EBB- 
                 502 
                 EIVMTQSPGTVSLSPGERATLSCRASQSVSSSFLAWYQQKPGQAP 
               
               
                 C1979-C1-aa 
                   
                 RLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDSAVYYCQ 
               
               
                 VL 
                   
                 QYHSSPSWTFGQGTRLEIK 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-C7 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                 440 
                 EVQLVETGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 C1978-C7-aa 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNTLKAED 
               
               
                 ScFv 
                   
                 TAVYYCARATYKRELRYYYGMDVWGQGTTVTVSSGGGGSGGGGSG 
               
               
                 domain 
                   
                 GGGSEIVLTQSPSTLSLSPGESATLSCRASQSVSTTFLAWYQQKP 
               
               
                   
                   
                 GQAPRLLIYGSSNRATGIPDRFSGSGSGTDFTLTIRRLEPEDFAV 
               
               
                   
                   
                 YYCQQYHSSPSWTFGQGTKVEIK 
               
               
                 BCMA_EBB- 
                 461 
                 GAGGTGCAGCTTGTGGAAACCGGTGGCGGACTGGTGCAGCCCGGA 
               
               
                 C1978-C7-nt 
                   
                 GGAAGCCTCAGGCTGTCCTGCGCCGCGTCCGGCTTCACCTTCTCC 
               
               
                 ScFv 
                   
                 TCGTACGCCATGTCCTGGGTCCGCCAGGCCCCCGGAAAGGGCCTG 
               
               
                 domain 
                   
                 GAATGGGTGTCCGCCATCTCTGGAAGCGGAGGTTCCACGTACTAC 
               
               
                   
                   
                 GCGGACAGCGTCAAGGGAAGGTTCACAATCTCCCGCGATAATTCG 
               
               
                   
                   
                 AAGAACACTCTGTACCTTCAAATGAACACCCTGAAGGCCGAGGAC 
               
               
                   
                   
                 ACTGCTGTGTACTACTGCGCACGGGCCACCTACAAGAGAGAGCTC 
               
               
                   
                   
                 CGGTACTACTACGGAATGGACGTCTGGGGCCAGGGAACTACTGTG 
               
               
                   
                   
                 ACCGTGTCCTCGGGAGGGGGTGGCTCCGGGGGGGGCGGCTCCGGC 
               
               
                   
                   
                 GGAGGCGGTTCCGAGATTGTGCTGACCCAGTCACCTTCAACTCTG 
               
               
                   
                   
                 TCGCTGTCCCCGGGAGAGAGCGCTACTCTGAGCTGCCGGGCCAGC 
               
               
                   
                   
                 CAGTCCGTGTCCACCACCTTCCTCGCCTGGTATCAGCAGAAGCCG 
               
               
                   
                   
                 GGGCAGGCACCACGGCTCTTGATCTACGGGTCAAGCAACAGAGCG 
               
               
                   
                   
                 ACCGGAATTCCTGACCGCTTCTCGGGGAGCGGTTCAGGCACCGAC 
               
               
                   
                   
                 TTCACCCTGACTATCCGGCGCCTGGAACCCGAAGATTTCGCCGTG 
               
               
                   
                   
                 TATTACTGTCAACAGTACCACTCCTCGCCGTCCTGGACCTTTGGC 
               
               
                   
                   
                 CAAGGAACCAAAGTGGAAATCAAG 
               
               
                 BCMA_EBB- 
                 482 
                 EVQLVETGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 C1979-C7-aa 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNTLKAED 
               
               
                 VH 
                   
                 TAVYYCARATYKRELRYYYGMDVWGQGTTVTVSS 
               
               
                 BCMA_EBB- 
                 503 
                 EIVTLQSPSTLSLSPGESATLSCRASQSVSTTFLAWYQQKPGQAP 
               
               
                 C1979-C7-aa 
                   
                 RLLIYGSSNRATGIPDRFSGSGSGTDFTLTIRRLEPEDFAVYYCQ 
               
               
                 VL 
                   
                 QYHSSPWSTFGQGTKVEIK 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-D10 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                 441 
                 EVQLVETGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGL 
               
               
                 C1978-D10- 
                   
                 EWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRDED 
               
               
                 aa 
                   
                 TAVYYCARVGKAVFDVWGQGTTVTVSSGGGGSGGGGSGGGGSDIV 
               
               
                 ScFv 
                   
                 MTQTPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLI 
               
               
                 domain 
                   
                 YAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYS 
               
               
                   
                   
                 TPYSFGQGTRLEIK 
               
               
                 BCMA_EBB- 
                 462 
                 GAAGTGCAGCTCGTGGAAACTGGAGGTGGACTCGTGCAGCCTGGA 
               
               
                 C1978-D10- 
                   
                 CGGTCGCTGCGGCTGAGCTGCGCTGCATCCGGCTTCACCTTCGAC 
               
               
                 nt 
                   
                 GATTATGCCATGCACTGGGTCAGACAGGCGCCAGGGAAGGGACTT 
               
               
                 ScFv 
                   
                 GAGTGGGTGTCCGGTATCAGCTGGAATAGCGGCTCAATCGGATAC 
               
               
                 domain 
                   
                 GCGGACTCCGTGAAGGGAAGGTTCACCATTTCCCGCGACAACGCC 
               
               
                   
                   
                 AAGAACTCCCTGTACTTGCAAATGAACAGCCTCCGGGATGAGGAC 
               
               
                   
                   
                 ACTGCCGTGTACTACTGCGCCCGCGTCGGAAAAGCTGTGCCCGAC 
               
               
                   
                   
                 GTCTGGGGCCAGGGAACCACTGTGACCGTGTCCAGCGGCGGGGGT 
               
               
                   
                   
                 GGATCGGGCGGTGGAGGGTCCGGTGGAGGGGGCTCAGATATTGTG 
               
               
                   
                   
                 ATGACCCAGACCCCCTCGTCCCTGTCCGCCTCGGTCGGCGACCGC 
               
               
                   
                   
                 GTGACTATCACATGTAGAGCCTCGCAGAGCATCTCCAGCTACCTG 
               
               
                   
                   
                 AACTGGTATCAGCAGAAGCCGGGGAAGGCCCCGAAGCTCCTGATC 
               
               
                   
                   
                 TACGCGGCATCATCACTGCAATCGGGAGTGCCGAGCCGGTTTTCC 
               
               
                   
                   
                 GGGTCCGGCTCCGGCACCGACTTCACGCTGACCATTTCTTCCCTG 
               
               
                   
                   
                 CAACCCGAGGACTTCGCCACTTACTACTGCCAGCAGTCCTACTCC 
               
               
                   
                   
                 ACCCCTTACTCCTTCGGCCAAGGAACCAGGCTGGAAATCAAG 
               
               
                 BCMA_EBB- 
                 483 
                 EVQLVETGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGL 
               
               
                 C1978-D10- 
                   
                 EWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRDED 
               
               
                 aa 
                   
                 TAVYYCARVGKAVPDVWGQGTTVTVSS 
               
               
                 VH 
                   
                   
               
               
                 BCMA_EBB- 
                 504 
                 DIVMTQTPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPK 
               
               
                 C1978-D10- 
                   
                 LLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ 
               
               
                 aa 
                   
                 SYSTPYSFGQGTRLEIK 
               
               
                 VL 
                   
                   
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1979-C12 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                 442 
                 EVQLVESGGGLVQPGRSLRLSCTASGFTFDDYAMHWVRQRPGKGL 
               
               
                 C1979-C12- 
                   
                 EWVASINWKGNSLAYGDSVKGRFAISRDNAKNTVFLQMNSLRTED 
               
               
                 aa 
                   
                 TAVYYCASHQGVAYYNYAMDVWGRGTLVTVSSGGGGSGGGGSGGG 
               
               
                 ScFv 
                   
                 GSEIVLTQSPGTLSLSPGERATLSCRATQSIGSSFLAWYQQRPGQ 
               
               
                 domain 
                   
                 APRLLIYGASQRATGIPDRFSGRGSGTDFTLTISRVEPEDSAVYY 
               
               
                   
                   
                 CQHYESSPSWTFGQGTKVEIK 
               
               
                 BCMA_EBB- 
                 463 
                 GAAGTGCAGCTCGTGGAGAGCGGGGGAGGATTGGTGCAGCCCGGA 
               
               
                 C1979-C12- 
                   
                 AGGTCCCTGCGGCTCTCCTGCACTGCGTCTGGCTTCACCTTCGAC 
               
               
                 nt 
                   
                 GACTACGCGATGCACTGGGTCAGACAGCGCCCGGGAAAGGGCCTG 
               
               
                 ScFv 
                   
                 GAATGGGTCGCCTCAATCAACTGGAAGGGAAACTCCCTGGCCTAT 
               
               
                 domain 
                   
                 GGCGACAGCGTGAAGGGCCGCTTCGCCATTTCGCGCGACAACGCC 
               
               
                   
                   
                 AAGAACACCGTGTTTCTGCAAATGAATTCCCTGCGGACCGAGGAT 
               
               
                   
                   
                 ACCGCTGTGTACTACTGCGCCAGCCACCAGGGCGTGGCATACTAT 
               
               
                   
                   
                 AACTACGCCATGGACGTGTGGGGAAGAGGGACGCTCGTCACCGTG 
               
               
                   
                   
                 TCCTCCGGGGGCGGTGGATCGGGTGGAGGAGGAAGCGGTGGCGGG 
               
               
                   
                   
                 GGCAGCGAAATCGTGCTGACTCAGAGCCCGGGAACTCTTTCACTG 
               
               
                   
                   
                 TCCCCGGGAGAACGGGCCACTCTCTCGTGCCGGGCCACCCAGTCC 
               
               
                   
                   
                 ATCGGCTCCTCCTTCCTTGCCTGGTACCAGCAGAGGCCAGGACAG 
               
               
                   
                   
                 GCGCCCCGCCTGCTGATCTACGGTGCTTCCCAACGCGCCACTGGC 
               
               
                   
                   
                 ATTCCTGACCGGTTCAGCGGCAGAGGGTCGGGAACCGATTTCACA 
               
               
                   
                   
                 CTGACCATTTCCCGGGTGGAGCCCGAAGATTCGGCAGTCTACTAC 
               
               
                   
                   
                 TGTCAGCATTACGAGTCCTCCCCTTCATGGACCTTCGGTCAAGGG 
               
               
                   
                   
                 ACCAAAGTGGAGATCAAG 
               
               
                 BCMA_EBB- 
                 484 
                 EVQLVESGGGLVQPGRSLRLSCTASGFTFDDYAMHwVRQRPGKGL 
               
               
                 C1978-C12- 
                   
                 EWVASINWKGNSLAYGDSVKGRFAISRDNAKNTVFLQMNSLRTED 
               
               
                 aa 
                   
                 TAVYYCASHQGVAYYNYAMDVWGRGTLVTVSS 
               
               
                 VH 
                   
                   
               
               
                 BCMA_EBB- 
                 505 
                 EIVLTQSPGTLSLSPGERATLSCRATQSIGSSFLAWYQQRPGQAP 
               
               
                 C1978-C12- 
                   
                 RLLIYGASQRATGIPDRFSGRGSGTDFTLTISRVEPEDSAVYYCQ 
               
               
                 aa 
                   
                 HYESSPSWTFGQGTKVEIK 
               
               
                 VL 
                   
                   
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1980-G4 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                 443 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 C1980-G4-aa 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED 
               
               
                 ScFv 
                   
                 TAVYYCAKWRDGMDVWGQGTTVTVSSGGGGSGGGGSGGGGSEIV 
               
               
                 domain 
                   
                 LTQSPATLSLSPGEPATLSCRASQSVSSSYLAWYQQKPGQAPRLL 
               
               
                   
                   
                 IYGASSRATGIPDRFSGNGSGTDFTLTISRLEPEDFAVYYCQQYG 
               
               
                   
                   
                 SPPRFTFGPGTKVDIK 
               
               
                 BCMA_EBB- 
                 464 
                 GAGGTGCAGTTGGTCGAAAGCGGGGGCGGGCTTGTGCAGCCTGGC 
               
               
                 C1980-G4-nt 
                   
                 GGATCACTGCGGCTGTCCTGCGCGGCATCAGGCTTCACGTTTTCT 
               
               
                 ScFv 
                   
                 TCCTACGCCATGTCCTGGGTGCGCCAGGCCCCTGGAAAGGGACTG 
               
               
                 domain 
                   
                 GAATGGGTGTCCGCGATTTCGGGGTCCGGCGGGAGCACCTACTAC 
               
               
                   
                   
                 GCCGATTCCGTGAAGGGCCGCTTCACTATCTCGCGGGACAACTCC 
               
               
                   
                   
                 AAGAACACCCTCTACCTCCAAATGAATAGCCTGCGGGCCGAGGAT 
               
               
                   
                   
                 ACCGCCGTCTACTATTGCGCTAAGGTCGTGCGCGACGGAATGGAC 
               
               
                   
                   
                 GTGTGGGGACAGGGTACCACCGTGACAGTGTCCTCGGGGGGAGGC 
               
               
                   
                   
                 GGTAGCGGCGGAGGAGGAAGCGGTGGTGGAGGTTCCGAGATTGTG 
               
               
                   
                   
                 CTGACTCAATCACCCGCGACCCTGAGCCTGTCCCCCGGCGAAAGG 
               
               
                   
                   
                 GCCACTCTGTCCTGTCGGGCCAGCCAATCAGTCTCCTCCTCGTAC 
               
               
                   
                   
                 CTGGCCTGGTACCAGCAGAAGCCAGGACAGGCTCCGAGACTCCTT 
               
               
                   
                   
                 ATCTATGGCGCATCCTCCCGCGCCACCGGAATCCCGGATAGGTTC 
               
               
                   
                   
                 TCGGGAAACGGATCGGGGACCGACTTCACTCTCACCATCTCCCGG 
               
               
                   
                   
                 CTGGAACCGGAGGACTTCGCCGTGTACTACTGCCAGCAGTACGGC 
               
               
                   
                   
                 AGCCCGCCTAGATTCACTTTCGGCCCCGGCACCAAAGTGGACATC 
               
               
                   
                   
                 AAG 
               
               
                 BCMA_EBB- 
                 485 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 C1979-G4-aa 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLCMNSLRAED 
               
               
                 VH 
                   
                 TAVYYCAKWRDGMDVWGQGTTVTVSS 
               
               
                 BCMA_EBB- 
                 506 
                 EIVLTQSPATLSLSPGERATLSCRASQSVSSSYLAWYQQKPGOAP 
               
               
                 C1979-G4-aa 
                   
                 RLLIYGASSRATGIPDRFSGNGSGTDFTLTISRLEPEDFAVYYCQ 
               
               
                 VL 
                   
                 QYGSPPRFTFGPGTKVDIK 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1980-D2 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                 444 
                 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 C1980-D2-aa 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLCWNSLRAED 
               
               
                 ScFv 
                   
                 TAVYYCAKIPQTGTFDYWGQGTLVTVSSGGGGSGGGGSGGGGSEI 
               
               
                 domian 
                   
                 VLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQRPGQAPRL 
               
               
                   
                   
                 LIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQHY 
               
               
                   
                   
                 GSSPSWTFGQGTRLEIK 
               
               
                 BCMA_EBB- 
                 465 
                 GAAGTGCAGCTGCTGGAGTCCGGCGGTGGATTGGTGCAACCGGGG 
               
               
                 C1980-D2-nt 
                   
                 GGATCGCTCAGACTGTCCTGTGCGGCGTCAGGCTTCACCTTCTCG 
               
               
                 ScFv 
                   
                 AGCTACGCCATGTCATGGGTCAGACAGGCCCCTGGAAAGGGTCTG 
               
               
                 domain 
                   
                 GAATGGGTGTCCGCCATTTCCGGGAGCGGGGGATCTACATACTAC 
               
               
                   
                   
                 GCCGATAGCGTGAAGGGCCGCTTCACCATTTCCCGGGACAACTCC 
               
               
                   
                   
                 AAGAACACTCTCTATCTGCAAATGAACTCCCTCCGCGCTGAGGAC 
               
               
                   
                   
                 ACTGCCGTGTACTACTGCGCCAAAATCCCTCAGACCGGCACCTTC 
               
               
                   
                   
                 GAGTAGTGGGGAGAGGGGAGTCTGGTCACCGTCAGCAGCGGTGGC 
               
               
                   
                   
                 GGAGGTTCGGGGGGAGGAGGAAGCGGCGGCGGAGGGTCCGAGATT 
               
               
                   
                   
                 GTGCTGACCCAGTCACCCGGCACTTTGTCCCTGTCGCCTGGAGAA 
               
               
                   
                   
                 AGGGCCACCCTTTCCTGCCGGGCATCCCAATCCGTGTCCTCCTCG 
               
               
                   
                   
                 TACCTGGCCTGGTACCAGCAGAGGCCCGGACAGGCCCCACGGCTT 
               
               
                   
                   
                 CTGATCTACGGAGCAAGCAGCCGCGCGACCGGTATCCCGGACCGG 
               
               
                   
                   
                 TTTTCGGGCTCGGGCTCAGGAACTGACTTCACCCTCACCATCTCC 
               
               
                   
                   
                 CGCCTGGAACCCGAAGATTTCGCTGTGTATTACTGCCAGCACTAC 
               
               
                   
                   
                 GGCAGCTCCCCGTCCTGGACGTTCGGCCAGGGAACTCGGCTGGAG 
               
               
                   
                   
                 ATCAAG 
               
               
                 BCMA_EBB- 
                 486 
                 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 C1979-D2-aa 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED 
               
               
                 VH 
                   
                 TAVYYCAKIPQTGTFDYWGQGTLVTVSS 
               
               
                 BCMA_EBB- 
                 507 
                 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQRPGQAP 
               
               
                 C1979-D2-aa 
                   
                 RLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQ 
               
               
                 VL 
                   
                 HYGSSPSWTFGQGTRLEIK 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-A10 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                 445 
                 EVQLVETGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 C1978-A10- 
                   
                 EWVSAISGSGGSTYYADSVKGRFTMSRENDKNSVFLQMNSLRVED 
               
               
                 aa 
                   
                 TGVYYCARANYKRELRYYYGMDVWGQGTMVTVSSGGGGSGGGGSG 
               
               
                 ScFv 
                   
                 GGGSEIVMTQSPGTLSLSPGESATLSCRASQRVASNYLAWYQHKP 
               
               
                 domain 
                   
                 GQAPSLLISGASSRATGVPDRFSGSGSGTDFTLAISRLEPEDSAV 
               
               
                   
                   
                 YYCQHYDSSPSWTFGQGTKVEIK 
               
               
                 BCMA_EBB- 
                 466 
                 GAAGTGCAACTGGTGGAAACCGGTGGAGGACTCGTGCAGCCTGGC 
               
               
                 C1978-A10- 
                   
                 GGCAGCCTCCGGCTGAGCTGCGCCGCTTCGGGATTCACCTTTTCC 
               
               
                 nt 
                   
                 TCCTACGCGATGTCTTGGGTCAGACAGGCCCCCGGAAAGGGGCTG 
               
               
                 ScFv 
                   
                 GAATGGGTGTCAGCCATCTCCGGCTCCGGCGGATCAACGTACTAC 
               
               
                 domain 
                   
                 GCCGACTCCGTGAAAGGCCGGTTCACCATGTCGCGCGAGAATGAC 
               
               
                   
                   
                 AAGAACTCCGTGTTCCTGCAAATGAACTCCCTGAGGGTGGAGGAC 
               
               
                   
                   
                 ACCGGAGTGTACTATTGTGCGCGCGCCAACTACAAGAGAGAGCTG 
               
               
                   
                   
                 CGGTACTACTACGGAATGGACGTCTGGGGACAGGGAACTATGGTG 
               
               
                   
                   
                 ACCGTGTCATCCGGTGGAGGGGGAAGCGGCGGTGGAGGCAGCGGG 
               
               
                   
                   
                 GGCGGGGGTTCAGAAATTGTCATGACCCAGTCCCCGGGAACTCTT 
               
               
                   
                   
                 TCCCTCTCCCCCGGGGAATCCGCGACTTTGTCCTGCCGGGCCAGC 
               
               
                   
                   
                 CAGCGCGTGGCCTCGAACTACCTCGCATGGTACCAGCATAAGCCA 
               
               
                   
                   
                 GGCCAAGCCCCTTCCCTGCTGATTTCCGGGGCTAGCAGCCGCGCC 
               
               
                   
                   
                 ACTGGCGTGCCGGATAGGTTCTCGGGAAGCGGCTCGGGTACCGAT 
               
               
                   
                   
                 TTCACCCTGGCAATCTCGCGGCTGGAACCGGAGGATTCGGCCGTG 
               
               
                   
                   
                 TACTACTGCCAGCACTATGACTCATCCCCCTCCTGGACATTCGGA 
               
               
                   
                   
                 CAGGGCACCAAGGTCGAGATCAAG 
               
               
                 BCMA_EBB- 
                 487 
                 EVQLVETGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 C1978-A10- 
                   
                 EWVSAISGSGGSTYYADSVKGRFTMSRENDKNSVFLQMNSLRVED 
               
               
                 aa 
                   
                 TGVYYCARANYKRELRYYYGMDVWGQGTMVTVSS 
               
               
                 VH 
                   
                   
               
               
                 BCMA_EBB- 
                 508 
                 EIVMTQSPGTLSLSPGESATLSCRASQRVASNYLAWYQHKPGQAP 
               
               
                 C1978-A10- 
                   
                 SLLISGASSRATGVPDRFSGSGSGTDFTLAISRLEPEDSAVYYCQ 
               
               
                 aa 
                   
                 HYDSSPSWTFGQGTKVEIK 
               
               
                 VL 
                   
                   
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-D4 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                 446 
                 EVQLLETGGGLVQPGGSLRLSCAASGFSFSSYAMSWVRQAPGKGL 
               
               
                 C1978-D4-aa 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED 
               
               
                 ScFv 
                   
                 TAVYYCAKALVGATGAFDIWGQGTLVTVSSGGGGSGGGGSGGGGS 
               
               
                 domain 
                   
                 EIVLTQSPGTLSLSPGERATLSCRASQSLSSNFLAWYQQKPGQAP 
               
               
                   
                   
                 GLLIYGASNWATGTPDRFSGSGSGTDFTLTITRLEPEDFAVYYCQ 
               
               
                   
                   
                 YYGTSPMYTFGOGTKVEIK 
               
               
                 BCMA_EBB- 
                 467 
                 GAAGTGCAGCTGCTCGAAACCGGTGGAGGGCTGGTGCAGCCAGGG 
               
               
                 C1978-D4-nt 
                   
                 GGCTCCCTGAGGCTTTCATGCGCCGCTAGCGGATTCTCCTTCTCC 
               
               
                 ScFv 
                   
                 TCTTACGCCATGTCGTGGGTCCGCCAAGCCCCTGGAAAAGGCCTG 
               
               
                 domain 
                   
                 GAATGGGTGTCCGCGATTTCCGGGAGCGGAGGTTCGACCTATTAC 
               
               
                   
                   
                 GCCGACTCCGTGAAGGGCCGCTTTACCATCTCCCGGGATAACTCC 
               
               
                   
                   
                 AAGAACACTCTGTACCTCCAAATGAACTCGCTGAGAGCCGAGGAC 
               
               
                   
                   
                 ACCGCCGTGTATTACTGCGCGAAGGCGCTGGTCGGCGCGACTGGG 
               
               
                   
                   
                 GCATTCGACATCTGGGGACAGGGAACTCTTGTGACCGTGTCGAGC 
               
               
                   
                   
                 GGAGGCGGCGGCTCCGGCGGAGGAGGGAGCGGGGGCGGTGGTTCC 
               
               
                   
                   
                 GAAATCGTGTTGACTCAGTCCCCGGGAACCCTGAGCTTGTCACCC 
               
               
                   
                   
                 GGGGAGCGGGCCACTCTCTCCTGTCGCGCCTCCCAATCGCTCTCA 
               
               
                   
                   
                 TCCAATTTCCTGGCCTGGTACCAGCAGAAGCCCGGACAGGCCCCG 
               
               
                   
                   
                 GGCCTGCTCATCTACGGCGCTTCAAACTGGGCAACGGGAACCCCT 
               
               
                   
                   
                 GATCGGTTCAGCGGAAGCGGATCGGGTACTGACTTTACCCTGACC 
               
               
                   
                   
                 ATCACCAGACTGGAACCGGAGGACTTCGCCGTGTACTACTGCCAG 
               
               
                   
                   
                 TACTACGGCACCTCCCCCATGTACACATTCGGACAGGGTACCAAG 
               
               
                   
                   
                 GTCGAGATTAAG 
               
               
                 BCMA_EBB- 
                 488 
                 EVQLLETGGGLVQPGGSLRLSCAASGFSFSSYAMSWVRQAPGKGL 
               
               
                 C1979-D4-aa 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED 
               
               
                 VH 
                   
                 TAVYYCAKALVGATGAFDIWGQGTLVTVSS 
               
               
                 BCMA_EBB- 
                 509 
                 EIVLTQSPGTLSLSPGERATLSCRASQSLSSNFLAWYQQKPGQAP 
               
               
                 C1979-D4-aa 
                   
                 GLLIYGASNWATGTPDRFSGSGSGTDFTLTITRLEPEDFAVYYCQ 
               
               
                 VL 
                   
                 YYGTSPMYTFGQGTKVEIK 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1980-A2 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                 447 
                 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 C1980-A2-aa 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED 
               
               
                 ScFv 
                   
                 TAVYYCVLWFGEGFDPWGQGTLVTVSSGGGGSGGGGSGGGGSDIV 
               
               
                 domain 
                   
                 LTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQS 
               
               
                   
                   
                 PQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC 
               
               
                   
                   
                 MQALQTPLTFGGGTKVDIK 
               
               
                 BCMA_EBB- 
                 468 
                 GAAGTGCAGCTGCTTGAGAGCGGTGGAGGTCTGGTGCAGCCCGGG 
               
               
                 C1980-A2-nt 
                   
                 GGATCACTGCGCCTGTCCTGTGCCGCGTCCGGTTTCACTTTCTCC 
               
               
                 ScFv 
                   
                 TCGTACGCCATGTCGTGGGTCAGACAGGCACCGGGAAAGGGACTG 
               
               
                 domain 
                   
                 GAATGGGTGTCAGCCATTTCGGGTTCGGGGGGCAGCACCTACTAC 
               
               
                   
                   
                 GCTGACTCCGTGAAGGGCCGGTTCACCATTTCCCGCGACAACTCC 
               
               
                   
                   
                 AAGAACACCTTGTACCTCCAAATGAACTCCCTGCGGGCCGAAGAT 
               
               
                   
                   
                 ACCGCCGTGTATTACTGCGTGCTGTGGTTCGGAGAGGGATTCGAC 
               
               
                   
                   
                 CCGTGGGGACAAGGAACACTCGTGACTGTGTCATCCGGCGGAGGC 
               
               
                   
                   
                 GGCAGCGGTGGCGGCGGTTCCGGCGGCGGCGGATCTGACATCGTG 
               
               
                   
                   
                 TTGACCCAGTCCCCTCTGAGCCTGCCGGTCACTCCTGGCGAACCA 
               
               
                   
                   
                 GCCAGCATCTCCTGCCGGTCGAGCCAGTCCCTCCTGCACTCCAAT 
               
               
                   
                   
                 GGGTACAACTACCTCGATTGGTATCTGCAAAAGCCGGGCCAGAGC 
               
               
                   
                   
                 CCCCAGCTGCTGATCTACCTTGGGTCAAACCGCGCTTCCGGGGTG 
               
               
                   
                   
                 CCTGATAGATTCTCCGGGTCCGGGAGCGGAACCGACTTTACCCTG 
               
               
                   
                   
                 AAAATCTCGAGGGTGGAGGCCGAGGACGTCGGAGTGTACTACTGC 
               
               
                   
                   
                 ATGCAGGCGCTCCAGACTCCCCTGACCTTCGGAGGAGGAACGAAG 
               
               
                   
                   
                 GTCGACATCAAGA 
               
               
                 BCMA_EBB- 
                 489 
                 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 C1979-A2-aa 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED 
               
               
                 VH 
                   
                 TAVYYCVLWFGEGFDPWGQGTLVTV3S 
               
               
                 BCMA_EBB- 
                 510 
                 DIVLTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKP 
               
               
                 C1979-A2-aa 
                   
                 GQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGV 
               
               
                 VL 
                   
                 YYCMQALQTPLTFGGGTKVDIK 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1981-C3 
               
            
           
           
               
               
               
            
               
                 BMCA_EBB- 
                 448 
                 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 C1981-C3-aa 
                   
                 SWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED 
               
               
                 ScFv 
                   
                 TAVYYCAKVGYDSSGYYRDYYGMDVWGQGTTVTVSSGGGGSGGGG 
               
               
                 domain 
                   
                 SGGGGSEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQ 
               
               
                   
                   
                 KPGQAPRLLIYGTSSRATGISDRFSGSGSGTDFTLTISRLEPEDF 
               
               
                   
                   
                 AVYYCQHYGNSPPKFTFGPGTKLEIK 
               
               
                 BCMA_EBB- 
                 469 
                 CAAGTGCAGCTCGTGGAGTCAGGCGGAGGACTGGTGCAGCCCGGG 
               
               
                 C1981-C3-nt 
                   
                 GGCTCCCTGAGACTTTCCTGCGCGGCATCGGGTTTTACCTTCTCC 
               
               
                 ScFv 
                   
                 TCCTATGCTATGTCCTGGGTGCGCCAGGCCCCGGGAAAGGGACTG 
               
               
                 domain 
                   
                 GAATGGGTGTCCGCAATCAGCGGTAGCGGGGGCTCAACATACTAC 
               
               
                   
                   
                 GCCGACTCCGTCAAGGGTCGCTTCACTATTTCCCGGGACAACTCC 
               
               
                   
                   
                 AAGAATACCCTGTACCTCCAAATGAACAGCCTCAGGGCCGAGGAT 
               
               
                   
                   
                 ACTGCCGTGTACTACTGCGCCAAAGTCGGATACGATAGCTCCGGT 
               
               
                   
                   
                 TACTACCGGGACTACTACGGAATGGACGTGTGGGGACAGGGCACC 
               
               
                   
                   
                 ACCGTGACCGTGTCAAGCGGCGGAGGCGGTTCAGGAGGGGGAGGC 
               
               
                   
                   
                 TCCGGCGGTGGAGGGTCCGAAATCGTCCTGACTCAGTCGCCTGGC 
               
               
                   
                   
                 ACTCTGTCGTTGTCCCCGGGGGAGCGCGCTACCCTGTCGTGTCGG 
               
               
                   
                   
                 GCGTCGCAGTCCCTGTCGAGCTCCTACCTCGCGTGGTACCAGCAG 
               
               
                   
                   
                 AAGCCCGGACAGGCCCCTAGACTTCTGATCTACGGCACTTCTTCA 
               
               
                   
                   
                 CGCGCCACCGGGATCAGCGACAGGTTCAGCGGCTCCGGCTCCGGG 
               
               
                   
                   
                 ACCGACTTCACCCTGACCATTAGCCGGCTGGAGCCTGAAGATTTC 
               
               
                   
                   
                 GCCGTGTATTACTGCCAACACTAGGGAAACTCGCCGCCAAAGTTC 
               
               
                   
                   
                 ACGTTCGGACCCGGAACCAAGCTGGAAATCAAG 
               
               
                 BCMA_EBB- 
                 490 
                 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWYRQAPGKGL 
               
               
                 C1979-C3-aa 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED 
               
               
                 VH 
                   
                 TAVYYCAKVGYDSSGYYRDYYGMDVWGQGTTVTVSS 
               
               
                 BCMA_EBB- 
                   
                 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAP 
               
               
                 C1979-C3-aa 
                 511 
                 RLLIYGTSSRATGISDRFSGSGSGTDFTLTISRLEPEDFAVYYCQ 
               
               
                 VL 
                   
                 HYGNSPPKFTFGPGTKLEIK 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-G4 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                 449 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 C1978-G4-aa 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED 
               
               
                 ScFv 
                   
                 TAVYYCAKMGWSSGYLGAFDIWGQGTTVTVSSGGGGSGGGGSGGG 
               
               
                 domain 
                   
                 GSEIVLTQSPGTLSLSPGERATLSCRASQSVASSFLAWYQQKPGQ 
               
               
                   
                   
                 APRLLIYGASGRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY 
               
               
                   
                   
                 CQHYGGSPRLTFGGGTKVDIK 
               
               
                 BCMA_EBB- 
                 470 
                 GAAGTCCAACTGGTGGAGTCCGGGGGAGGGCTCGTGCAGCCCGGA 
               
               
                 C1978-G4-nt 
                   
                 GGCAGCCTTCGGCTGTCGTGCGCCGCCTCCGGGTTCACGTTCTCA 
               
               
                 ScFv 
                   
                 TCCTACGCGATGTCGTGGGTCAGACAGGCACCAGGAAAGGGACTG 
               
               
                 domain 
                   
                 GAATGGGTGTCCGCCATTAGCGGCTCCGGCGGTAGCACCTACTAT 
               
               
                   
                   
                 GCCGACTCAGTGAAGGGAAGGTTCACTATCTCCCGCGACAACAGC 
               
               
                   
                   
                 AAGAACACCCTGTACCTCCAAATGAACTCTCTGCGGGCCGAGGAT 
               
               
                   
                   
                 ACCGCGGTGTACTATTGCGCCAAGATGGGTTGGTCCAGCGGATAC 
               
               
                   
                   
                 TTGGGAGCCTTCGACATTTGGGGACAGGGCACTACTGTGACCGTG 
               
               
                   
                   
                 TCCTCCGGGGGTGGCGGATCGGGAGGCGGCGGCTCGGGTGGAGGG 
               
               
                   
                   
                 GGTTCCGAAATCGTGTTGACCCAGTCACCGGGAACCCTCTCGCTG 
               
               
                   
                   
                 TCCCCGGGAGAACGGGCTACACTGTCATGTAGAGCGTCCCAGTCC 
               
               
                   
                   
                 GTGGCTTCCTCGTTCCTGGCCTGGTACCAGCAGAAGCCGGGACAG 
               
               
                   
                   
                 GCACCCCGCCTGCTCATCTACGGAGCCAGCGGCCGGGCGACCGGC 
               
               
                   
                   
                 ATCCCTGACCGCTTCTCCGGTTCCGGCTCGGGCACCGACTTTACT 
               
               
                   
                   
                 CTGACCATTAGCAGGCTTGAGCCCGAGGATTTTGCCGTGTACTAC 
               
               
                   
                   
                 TGCCAACACTACGGGGGGAGCCCTCGCCTGACCTTCGGAGGCGGA 
               
               
                   
                   
                 ACTAAGGTCGATATCAAAA 
               
               
                 BCMA_EBB- 
                 491 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGL 
               
               
                 C1979-G4-aa 
                   
                 EWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED 
               
               
                 VH 
                   
                 TAVYYCAKMGWSSGYLGAFDIWGQGTTVTVSS 
               
               
                 BCMA_EBB- 
                 512 
                 EIVLTQSPGTLSLSPGERATLSCRASQSVASSFLAWYQQKPGQAP 
               
               
                 C1979-G4-aa 
                   
                 RLLIYGASGRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQ 
               
               
                 VL 
                   
                 HYGGSPRLTFGGGTKVDIK 
               
               
                   
               
            
           
         
       
     
     In embodiments, additional exemplary BCMA CAR constructs are generated using the VH and VL sequences from PCT Publication WO2012/0163805 (the contents of which are hereby incorporated by reference in its entirety). In embodiments, additional exemplary BCMA CAR constructs are generated using the VH and VL sequences from PCT Publication WO2016/014565 (the contents of which are hereby incorporated by reference in its entirety). In embodiments, additional exemplary BCMA CAR constructs are generated using the VH and VL sequences from PCT Publication WO2014/122144 (the contents of which are hereby incorporated by reference in its entirety). In embodiments, additional exemplary BCMA CAR constructs are generated using the CAR molecules, and/or the VH and VL sequences from PCT Publication WO2016/014789 (the contents of which are hereby incorporated by reference in its entirety). In embodiments, additional exemplary BCMA CAR constructs are generated using the CAR molecules, and/or the VH and VL sequences from PCT Publication WO2014/089335 (the contents of which are hereby incorporated by reference in its entirety). In embodiments, additional exemplary BCMA CAR constructs are generated using the CAR molecules, and/or the VH and VL sequences from PCT Publication WO2014/140248 (the contents of which are hereby incorporated by reference in its entirety). 
     In embodiments, additional exemplary BCMA CAR constructs can also be generated using the VH and VL sequences found in Table 13. The amino acid sequences of exemplary scFv domains comprising the VH and VL domains and a linker sequence, and full-length CARs are also found in Table 13. 
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 Additional exemplary BCMA binding domain sequences 
               
            
           
           
               
               
               
            
               
                 Name 
                 Sequence 
                 SEQ ID NO: 
               
               
                   
               
               
                 A7D12.2 
                 QIQLVQSGPDLKKPGETVKLSCKASGYTFTNFGMNWVKQAPGKGFKWMAWINTYTGESYFA 
                 555 
               
               
                 VH 
                 DDFKGRFAFSVETSATTAYLQINNLKTEDTATYFCARGEIYYGYDGGFAYWGQGTLVTVSA 
                   
               
               
                   
               
               
                 A7D12.2 
                 DVVMTQSHRFMSTSVGDRVSITCRASQDVNTAVSWYQQKPGQSPKLLIFSASYRYTGVPDR 
                 559 
               
               
                 VL 
                 FTGSGSGADFTLTISSVQAEDLAVYYCQQHYSTPWTFGGGTKLDIK 
                   
               
               
                   
               
               
                 A7D12.2 
                 QIQLVQSGPDLKKPGETVKLSCKASGYTFTNFGMNWVKQAPGKGFKWMAWINTYTGESYFA 
                 563 
               
               
                 scFv 
                 DDFKGRFAFSVETSATTAYLQINNLKTEDTATYFCARGEIYYGYDGGFAYWGQGTLVTVSA 
                   
               
               
                 domain 
                 GGGGSGGGGSGGGGSDVVMTQSHRFMSTSVGDRVSITCRASQDVNTAVSWYQQKPGQSPKL 
                   
               
               
                   
                 LIFSASYRYTGVPDRFTGSGSGADFTLTISSVQAEDLAVYYCQQHYSTPWTFGGGTKLDIK 
                   
               
               
                   
               
               
                 C11D5.3 
                 QIQLVQSGPELKKPGETVKISCKASGYTFTDYSINWVKRAPGKGLKWMGWINTETREPAYA 
                 556 
               
               
                 VH 
                 YDFRGRFAFSLETSASTAYLQINNLKYEDTATYFCALDYSYAMDYWGQGTSVTVSS 
                   
               
               
                   
               
               
                 C11D5.3 
                 DIVLTQSPASLAMSLKGRATISCRASESVSVIGAHLIHWYQQKPGQPPKLLIYLASNLETG 
                 560 
               
               
                 VL 
                 VPARFSGSGSGTDFTLTIDPVEEDDVAIYSCLQSRIFPRTFGGGTKLEIK 
                   
               
               
                   
               
               
                 C11D5.3 
                 QIQLVQSGPELKKPGETVKISCKASGYTFTDYSINWVKRAPGKGLKWMGWINTETREPAYA 
                 564 
               
               
                 scFv 
                 YDFRGRFAFSLETSASTAYLQINNLKYEDTATYFCALDYSYAMDYWGQGTSVTVSSGGGGS 
                   
               
               
                 domain 
                 GGGGSGGGGSQIQLVQSGPELKKPGETVKISCKASGYTFTDYSINWVKRAPGKGLKWMGWI 
                   
               
               
                   
                 NTETREPAYAYDFRGRFAFSLETSASTAYLQINNLKYEDTATYFCALDYSYAMDYWGQGTS 
                   
               
               
                   
                 VTVSS 
                   
               
               
                   
               
               
                 C12A3.2 
                 QIQLVQSGPELKKPGETVKISCKASGYTFRHYSMNWVKQAPGKGLKWMGRINTESGVPIYA 
                 557 
               
               
                 VH 
                 DDFKGRFAFSVETSASTAYLNINNLKDEDTASYFCSNDYLYSLDFWGQGTALTVSS 
                   
               
               
                   
               
               
                 C12A3.2 
                 DIVLTQSPPSLAMSLGKRATISCRASESVTILGSHLIYWYQQKPGQPPTLLIQLASNVQTG 
                 561 
               
               
                 VL 
                 VPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPRTFGGGTKLEIK 
                   
               
               
                   
               
               
                 C12A3.2 
                 QIQLVQSGPELKKPGETVKISCKASGYTFRHYSMNWVKQAPGKGLKWMGRINTESGVPIYA 
                 565 
               
               
                 scFv 
                 DDFKGRFAFSVETSASTAYLVINNLKDEDTASYFCSNDYLYSLDFWGQGTALTVSSGGGGS 
                   
               
               
                 domain 
                 GGGGSGGGGSDIVLTQSPPSLAMSLGKRATISCRASESVTILGSHLIYWYQQKPGQPPTLL 
                   
               
               
                   
                 IQLASNVQTGVPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPRTFGGGTKLEIK 
                   
               
               
                   
               
               
                 C13F12.1 
                 QIQLVQSGPELKKPGETVKISCKASGYTFTHYSMNWVKQAPGKGLKWMGRINTETGEPLYA 
                 558 
               
               
                 VH 
                 DDFKGRFAFSLETSASTAYLVINNLKNEDTATFFCSNDYLYSCDYWGQGTTLTVSS 
                   
               
               
                   
               
               
                 C13F12.1 
                 DIVLTQSPPSLAMSLGKRATISCRASESVTILGSHLIYWYQQKPGQPPTLLIQLASNVQTG 
                 562 
               
               
                 VL 
                 VPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPRTFGGGTKLIEK 
                   
               
               
                   
               
               
                 C13F12.1 
                 QIQLVQSGPELKKPGETVKISCKASGYTFTHYSMNWVKQAPGKGLKWMGRINTETGEPLYA 
                 566 
               
               
                 scFv 
                 DDFKGRFAFSLETSASTAYLVINNLKNEDTATFFCSNDYLYSCDYWGQGTTLTVSSGGGGS 
                   
               
               
                 domain 
                 GGGGSGGGGSDIVLTQSPPSLAMSLGKRATISCRASESVTILGSHLIYWYQQKPQPPPTLL 
                   
               
               
                   
                 IQLASNVQTGVPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPRTFGGGTKLEIK 
               
               
                   
               
            
           
         
       
     
     The sequences of human CDR sequences of the scFv domains are shown in Table 14 for the heavy chain variable domains and in Table 15 for the light chain variable domains. “ID” stands for the respective SEQ ID NO for each CDR. The CDRs are shown according to the Kabat definition, however, the CDRs under other convention, for example, Chothia or the combined Kabat/Chothia definitions may be readily deduced based on the VH and VL sequences above. 
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 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 
                 694 
                 GIVYSGSTYYAASVKG 
                 734 
                 HGGESDV 
                 774 
               
               
                   
               
               
                 139103 
                 NYAMS 
                 684 
                 GISRSSGENTYYADSVKG 
                 724 
                 SPAHYYGGMDV 
                 764 
               
               
                   
               
               
                 139105 
                 DYAMH 
                 685 
                 GISWNSGSIGYADSVKG 
                 725 
                 HSFLAY 
                 765 
               
               
                   
               
               
                 139111 
                 NHGMS 
                 686 
                 GIVYSGSTYYAASVKG 
                 726 
                 HGGESDV 
                 766 
               
               
                   
               
               
                 139100 
                 NFGIN 
                 687 
                 WINPKNNNTNYAQKFQG 
                 727 
                 GPYYYQSYMDV 
                 767 
               
               
                   
               
               
                 139101 
                 SDAMT 
                 688 
                 VISGSGGTTYYADSVKG 
                 728 
                 LDSSGYYYARGPRY 
                 768 
               
               
                   
               
               
                 139102 
                 NYGIT 
                 689 
                 WISAYNGNTNYAQKFQG 
                 729 
                 GPYYYYMDV 
                 769 
               
               
                   
               
               
                 139104 
                 NHGMS 
                 690 
                 GIVYSGSTYYAASVKG 
                 730 
                 HGGESDV 
                 770 
               
               
                   
               
               
                 139106 
                 NHGMS 
                 691 
                 GIVYSGSTYYAASVKG 
                 731 
                 HGGESDV 
                 771 
               
               
                   
               
               
                 139107 
                 NHGMS 
                 692 
                 GIVYSGSTYYAASVKG 
                 732 
                 HGGESDV 
                 772 
               
               
                   
               
               
                 139108 
                 DYYMS 
                 693 
                 YISSSGSTIYYADSVKG 
                 733 
                 ESGDGMDV 
                 773 
               
               
                   
               
               
                 139110 
                 DYYMS 
                 695 
                 YISSSGNTIYYADSVKG 
                 735 
                 STMVREDY 
                 775 
               
               
                   
               
               
                 139112 
                 NHGMS 
                 696 
                 GIVYSGSTYYAASVKG 
                 736 
                 HGGESDV 
                 776 
               
               
                   
               
               
                 139113 
                 NHGMS 
                 697 
                 GIVYSGSTYYAASVKG 
                 737 
                 HGGESDV 
                 777 
               
               
                   
               
               
                 139114 
                 NHGMS 
                 698 
                 GIVYSGSTYYAASVKG 
                 738 
                 HGGESDV 
                 778 
               
               
                   
               
               
                 149362 
                 SSYYYWG 
                 699 
                 SIYYSGSAYYNPSLKS 
                 739 
                 HWQEWPDAFDI 
                 779 
               
               
                   
               
               
                 149363 
                 TSGMCVS 
                 700 
                 RIDWDEDKFYSTSLKT 
                 740 
                 SGAGGTSATAFDI 
                 780 
               
               
                   
               
               
                 149364 
                 SYSMN 
                 701 
                 SISSSSSYIYYADSVKG 
                 741 
                 TIAAVYAFDI 
                 781 
               
               
                   
               
               
                 149365 
                 DYYMS 
                 702 
                 YISSSGSTIYYADSVKG 
                 742 
                 DLRGAFDI 
                 782 
               
               
                   
               
               
                 149366 
                 SHYIH 
                 703 
                 MINPSGGVTAYSQTLQG 
                 743 
                 EGSGSGWYFDF 
                 783 
               
               
                   
               
               
                 149367 
                 SGGYYWS 
                 704 
                 YIYYSGSTYYNPSLKS 
                 744 
                 AGIAARLRGAFDI 
                 784 
               
               
                   
               
               
                 149368 
                 SYAIS 
                 705 
                 GIIPIFGTANYAQKFQG 
                 745 
                 FGGYQLLRWDVGLLRSAFDI 
                 785 
               
               
                   
               
               
                 149369 
                 SNSAAWN 
                 706 
                 RTYYRSKWYSFYAISLKS 
                 746 
                 SSPEGLFLYWFDP 
                 786 
               
               
                   
               
               
                 BCMA_EBB-C1978-A4 
                 SYAMS 
                 707 
                 AISGSGGSTYYADSVKG 
                 747 
                 VEGSGSLDY 
                 787 
               
               
                   
               
               
                 BCMA_EBB-C1978-G1 
                 RYPMS 
                 708 
                 GISDSGVSTYYADSVAKG 
                 748 
                 RAGSEASDI 
                 788 
               
               
                   
               
               
                 BCMA_EBB-C1979-C1 
                 SYAMS 
                 709 
                 AISGSGGSTYYADSVKG 
                 749 
                 ATYKRELRYYYGMDV 
                 789 
               
               
                   
               
               
                 BCMA_EBB-C1978-C7 
                 SYAMS 
                 710 
                 AISGSGGSTYYADSVKG 
                 750 
                 ATYKRELRYYYGMDV 
                 790 
               
               
                   
               
               
                 BCMA_EBB-C1978-D10 
                 DYAMH 
                 711 
                 GISWNSGSIGYADSVKG 
                 751 
                 VKGAVPDV 
                 791 
               
               
                   
               
               
                 BCMA_EBB-C1979-C12 
                 DYAMH 
                 712 
                 SINWKGNSLAYGDSVKG 
                 752 
                 HQGVAYYNYAMDV 
                 792 
               
               
                   
               
               
                 BCMA_EBB-C1980-G4 
                 SYAMS 
                 713 
                 AISGSGGSTYYADSVKG 
                 753 
                 VVRDGMDV 
                 793 
               
               
                   
               
               
                 BCMA_EBB-C1980-D2 
                 SYAMS 
                 714 
                 AISGSGGSTYYADSVKG 
                 754 
                 IPQTGTFDY 
                 794 
               
               
                   
               
               
                 BCMA_EBB-C1978-A10 
                 SYAMS 
                 715 
                 AISGSGGSTYYADSVKG 
                 755 
                 ANYKRELRYYYGMDV 
                 795 
               
               
                   
               
               
                 BCMA_EBB-C1978-D4 
                 SYAMS 
                 716 
                 AISGSGGSTYYADSVKG 
                 756 
                 ALVGATGAFDI 
                 796 
               
               
                   
               
               
                 BCMA_EBB-C1980-A2 
                 SYAMS 
                 717 
                 AISGSGGSTYYADSVKG 
                 757 
                 WFGEGFDP 
                 797 
               
               
                   
               
               
                 BCMA_EBB-C1981-C3 
                 SYAMS 
                 718 
                 AISGSGGSTYYADSVKG 
                 758 
                 VGYDSSGYYRDYYGMDV 
                 799 
               
               
                   
               
               
                 BCMA_EBB-C1978-G4 
                 SYAMS 
                 719 
                 AISGSGGSTYYADSVKG 
                 759 
                 MGWSSGYLGAFDI 
                 799 
               
               
                   
               
               
                 A7D12.2 
                 NFGMN 
                 720 
                 WINTYTGESYFADDFKG 
                 760 
                 GEIYYGYDGGFAY 
                 800 
               
               
                   
               
               
                 C11D5.3 
                 DYSIN 
                 721 
                 WINTETREPAYAYDFRG 
                 761 
                 DYSYAMDY 
                 801 
               
               
                   
               
               
                 C12A3.2 
                 HYSMN 
                 722 
                 RINTESGVPIYADDFKG 
                 762 
                 DYLYSLDF 
                 802 
               
               
                   
               
               
                 C13F12.1 
                 HYSMN 
                 723 
                 RINTETGEPLYADDFKG 
                 763 
                 DYLYSCDY 
                 803 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 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 
                 814 
                 AASSLQS 
                 854 
                 QQSYSTPYT 
                 894 
               
               
                   
               
               
                 139103 
                 RASQSISSSFLA 
                 804 
                 GASRRAT 
                 844 
                 QQYHSSPSWT 
                 884 
               
               
                   
               
               
                 139105 
                 RSSQSLLHSNGYNYLD 
                 805 
                 LGSNRAS 
                 845 
                 MQALQTPYT 
                 885 
               
               
                   
               
               
                 139111 
                 KSSQSLLRNDGKTPLY 
                 806 
                 EVSNRFS 
                 846 
                 MQNIQFPS 
                 886 
               
               
                   
               
               
                 139100 
                 RSSQSLLHSNGYNYLN 
                 807 
                 LGSKRAS 
                 847 
                 MQALQTPYT 
                 887 
               
               
                   
               
               
                 139101 
                 RASQSISSYLN 
                 808 
                 GASTLAS 
                 848 
                 QQSYKRAS 
                 888 
               
               
                   
               
               
                 139102 
                 RSSQSLLYSNGYNYVD 
                 809 
                 LGSNRAS 
                 849 
                 MQGRQFPYS 
                 889 
               
               
                   
               
               
                 139104 
                 RASQSVSSNLA 
                 810 
                 GASTRAS 
                 850 
                 QQYGSSLT 
                 890 
               
               
                   
               
               
                 139106 
                 RASQSVSSKLA 
                 811 
                 GASIRAT 
                 851 
                 QQYGSSSWT 
                 891 
               
               
                   
               
               
                 139107 
                 RASQSVGSTNLA 
                 812 
                 DASNRAT 
                 852 
                 QQYGSSPPWT 
                 892 
               
               
                   
               
               
                 139108 
                 RASQSISSYLN 
                 813 
                 AASSLQS 
                 853 
                 QQSYTLA 
                 893 
               
               
                   
               
               
                 139110 
                 KSSESLVHNSGKTYLN 
                 815 
                 EVSNRDS 
                 855 
                 MQGHTWPGT 
                 895 
               
               
                   
               
               
                 139112 
                 QASEDINKFLN 
                 816 
                 DASTLQT 
                 856 
                 QQYESLPLT 
                 896 
               
               
                   
               
               
                 139113 
                 RASQSVGSNLA 
                 817 
                 GASTRAT 
                 857 
                 QQYNDWLPVT 
                 897 
               
               
                   
               
               
                 139114 
                 RASQSIGSSSLA 
                 818 
                 GASSRAS 
                 858 
                 QQYAGSPPFT 
                 898 
               
               
                   
               
               
                 149362 
                 KASQDIDDAMN 
                 819 
                 SATSPVP 
                 859 
                 LQHDNFPLT 
                 899 
               
               
                   
               
               
                 149363 
                 RASQDIYNNLA 
                 820 
                 AANKSQS 
                 860 
                 QHYYRFPYS 
                 900 
               
               
                   
               
               
                 149364 
                 RSSQSLLHSNGYNYLD 
                 821 
                 LGSNRAS 
                 861 
                 MQALQTPYT 
                 901 
               
               
                   
               
               
                 149365 
                 GGNNIGTKSVH 
                 822 
                 DDSVRPS 
                 862 
                 QVWDSDSEHVV 
                 902 
               
               
                   
               
               
                 149366 
                 SGDGLSKKYVS 
                 823 
                 RDKERPS 
                 863 
                 QASDDTTVV 
                 903 
               
               
                   
               
               
                 149367 
                 RASQGIRNWLA 
                 824 
                 AASNLQS 
                 864 
                 QKYNSAPFT 
                 904 
               
               
                   
               
               
                 149368 
                 GGNNIGKSKSVH 
                 825 
                 GKNNRPS 
                 865 
                 SSRDSSGDHLRV 
                 905 
               
               
                   
               
               
                 149369 
                 QGDSLGNYYAT 
                 826 
                 GTNNRPS 
                 866 
                 NSRDSSGHHLL 
                 906 
               
               
                   
               
               
                 BCMA_EBB-C1978-A4 
                 RASQSVSSAYLA 
                 827 
                 GASTRAT 
                 867 
                 QHYGSSFNGSSLFT 
                 907 
               
               
                   
               
               
                 BCMA_EBB-C1978-G1 
                 RASQSVSNSLA 
                 828 
                 DASSRAT 
                 868 
                 QQFGTSSGLT 
                 908 
               
               
                   
               
               
                 BCMA_EBB-C1979-C1 
                 RASQSVSSSFLA 
                 829 
                 GASSRAT 
                 869 
                 QQYHSSPSWT 
                 909 
               
               
                   
               
               
                 BCMA_EBB-C1978-C7 
                 RASQSVSTTFLA 
                 830 
                 GSSNRAT 
                 870 
                 QQYHSSPSWT 
                 910 
               
               
                   
               
               
                 BCMA_EBB-C1978-D10 
                 RASQSISSYLN 
                 831 
                 AASSLQS 
                 871 
                 QQSYSTPYS 
                 911 
               
               
                   
               
               
                 BCMA_EBB-C1979-C12 
                 RATQSIGSSFLA 
                 832 
                 GASQRAT 
                 872 
                 QHYESSPSWT 
                 912 
               
               
                   
               
               
                 BCMA_EBB-C1980-G4 
                 RASQSVSSSYLA 
                 833 
                 GASSRAT 
                 873 
                 QQYGSPPRFT 
                 913 
               
               
                   
               
               
                 BCMA_EBB-C1980-D2 
                 RASQSVSSSYLA 
                 834 
                 GASSRAT 
                 874 
                 QHYGSSPSWT 
                 914 
               
               
                   
               
               
                 BCMA_EBB-C1978-A10 
                 RASQRVASNYLA 
                 835 
                 GASSRAT 
                 875 
                 QHYDSSPSWT 
                 915 
               
               
                   
               
               
                 BCMA_EBB-C1978-D4 
                 RASQSLSSNFLA 
                 836 
                 GASNWAT 
                 876 
                 QYYGTSPMYT 
                 916 
               
               
                   
               
               
                 BCMA_EBB-C1980-A2 
                 RSSQSLLHSNGYNYLD 
                 837 
                 LGSNRAS 
                 877 
                 MQALQTPLT 
                 917 
               
               
                   
               
               
                 BCMA_EBB-C1981-C3 
                 RASQSVSSSYLA 
                 838 
                 GTSSRAT 
                 878 
                 QHYGNSPPKFT 
                 918 
               
               
                   
               
               
                 BCMA_EBB-C1978-G4 
                 RASQSVASSFLA 
                 839 
                 GASGRAT 
                 879 
                 QHYGGSPRLT 
                 919 
               
               
                   
               
               
                 A7D12.2 
                 RASQDVNTAVS 
                 840 
                 SASYRYT 
                 880 
                 QQHYSTPWT 
                 920 
               
               
                   
               
               
                 C11D5.3 
                 RASESVSVIGAHLIH 
                 841 
                 LASNLET 
                 881 
                 LQSRIFPRT 
                 921 
               
               
                   
               
               
                 C12A3.2 
                 RASESVTILGSHLIY 
                 842 
                 LASNVQT 
                 882 
                 LSQRTIPRT 
                 922 
               
               
                   
               
               
                 C13F12.1 
                 RASESVTILGSHLIY 
                 843 
                 LASNVQT 
                 883 
                 LSQRTIPRT 
                 923 
               
               
                   
               
            
           
         
       
     
     In one embodiment, the BCMA 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 BCMA binding domain described herein, e.g., provided in Table 12, 13 or 15, 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 BCMA binding domain described herein, e.g., provided in Table 12, 13 or 14. In one embodiment, the BCMA binding domain comprises one, two, or all of LC CDR1, LC CDR2, and LC CDR3 of any amino acid sequences as provided in Table 12, incorporated herein by reference; and one, two or all of HC CDR1, HC CDR2, and HC CDR3 of any amino acid sequences as provided in Table 12. 
     In one embodiment, the BCMA antigen binding domain comprises:
         (v) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 814, a LC CDR2 amino acid sequence of SEQ ID NO: 854, and a LC CDR3 amino acid sequence of SEQ ID NO: 894; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 694, a HC CDR2 amino acid sequence of SEQ ID NO: 734, and a HC CDR3 amino acid sequence of SEQ ID NO: 774   (vi) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 804, a LC CDR2 amino acid sequence of SEQ ID NO: 844, and a LC CDR3 amino acid sequence of SEQ ID NO: 884; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 684, a HC CDR2 amino acid sequence of SEQ ID NO: 724, and a HC CDR3 amino acid sequence of SEQ ID NO: 764   (vii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 805, a LC CDR2 amino acid sequence of SEQ ID NO: 845, and a LC CDR3 amino acid sequence of SEQ ID NO: 885; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 685, a HC CDR2 amino acid sequence of SEQ ID NO: 725, and a HC CDR3 amino acid sequence of SEQ ID NO: 765   (viii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 806, a LC CDR2 amino acid sequence of SEQ ID NO: 846, and a LC CDR3 amino acid sequence of SEQ ID NO: 886; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 686, a HC CDR2 amino acid sequence of SEQ ID NO: 726, and a HC CDR3 amino acid sequence of SEQ ID NO: 766   (ix) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 807, a LC CDR2 amino acid sequence of SEQ ID NO: 847, and a LC CDR3 amino acid sequence of SEQ ID NO: 887; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 687, a HC CDR2 amino acid sequence of SEQ ID NO: 727, and a HC CDR3 amino acid sequence of SEQ ID NO: 767   (x) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 808, a LC CDR2 amino acid sequence of SEQ ID NO: 848, and a LC CDR3 amino acid sequence of SEQ ID NO: 888; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 688, a HC CDR2 amino acid sequence of SEQ ID NO: 728, and a HC CDR3 amino acid sequence of SEQ ID NO: 768   (xi) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 809, a LC CDR2 amino acid sequence of SEQ ID NO: 849, and a LC CDR3 amino acid sequence of SEQ ID NO: 889; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 689, a HC CDR2 amino acid sequence of SEQ ID NO: 729, and a HC CDR3 amino acid sequence of SEQ ID NO: 769   (xii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 810, a LC CDR2 amino acid sequence of SEQ ID NO: 850, and a LC CDR3 amino acid sequence of SEQ ID NO: 890; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 690, a HC CDR2 amino acid sequence of SEQ ID NO: 730, and a HC CDR3 amino acid sequence of SEQ ID NO: 770   (xiii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 811, a LC CDR2 amino acid sequence of SEQ ID NO: 851, and a LC CDR3 amino acid sequence of SEQ ID NO: 891; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 691, a HC CDR2 amino acid sequence of SEQ ID NO: 731, and a HC CDR3 amino acid sequence of SEQ ID NO: 771   (xiv) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 812, a LC CDR2 amino acid sequence of SEQ ID NO: 852, and a LC CDR3 amino acid sequence of SEQ ID NO: 892; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 692, a HC CDR2 amino acid sequence of SEQ ID NO: 732, and a HC CDR3 amino acid sequence of SEQ ID NO: 772   (xv) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 813, a LC CDR2 amino acid sequence of SEQ ID NO: 853, and a LC CDR3 amino acid sequence of SEQ ID NO: 893; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 693, a HC CDR2 amino acid sequence of SEQ ID NO: 733, and a HC CDR3 amino acid sequence of SEQ ID NO: 773   (xvi) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 815, a LC CDR2 amino acid sequence of SEQ ID NO: 855, and a LC CDR3 amino acid sequence of SEQ ID NO: 895; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 695, a HC CDR2 amino acid sequence of SEQ ID NO: 735, and a HC CDR3 amino acid sequence of SEQ ID NO: 775   (xvii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 816, a LC CDR2 amino acid sequence of SEQ ID NO: 856, and a LC CDR3 amino acid sequence of SEQ ID NO: 896; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 696, a HC CDR2 amino acid sequence of SEQ ID NO: 736, and a HC CDR3 amino acid sequence of SEQ ID NO: 776   (xviii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 817, a LC CDR2 amino acid sequence of SEQ ID NO: 857, and a LC CDR3 amino acid sequence of SEQ ID NO: 897; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 697, a HC CDR2 amino acid sequence of SEQ ID NO: 737, and a HC CDR3 amino acid sequence of SEQ ID NO: 777   (xix) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 818, a LC CDR2 amino acid sequence of SEQ ID NO: 858, and a LC CDR3 amino acid sequence of SEQ ID NO: 898; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 698, a HC CDR2 amino acid sequence of SEQ ID NO: 738, and a HC CDR3 amino acid sequence of SEQ ID NO: 778   (xx) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 819, a LC CDR2 amino acid sequence of SEQ ID NO: 859, and a LC CDR3 amino acid sequence of SEQ ID NO: 899; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 699, a HC CDR2 amino acid sequence of SEQ ID NO: 739, and a HC CDR3 amino acid sequence of SEQ ID NO: 779   (xxi) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 820, a LC CDR2 amino acid sequence of SEQ ID NO: 860, and a LC CDR3 amino acid sequence of SEQ ID NO: 900; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 700, a HC CDR2 amino acid sequence of SEQ ID NO: 740, and a HC CDR3 amino acid sequence of SEQ ID NO: 780   (xxii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 821, a LC CDR2 amino acid sequence of SEQ ID NO: 861, and a LC CDR3 amino acid sequence of SEQ ID NO: 901; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 701, a HC CDR2 amino acid sequence of SEQ ID NO: 741, and a HC CDR3 amino acid sequence of SEQ ID NO: 781   (xxiii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 822, a LC CDR2 amino acid sequence of SEQ ID NO: 862, and a LC CDR3 amino acid sequence of SEQ ID NO: 902; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 702, a HC CDR2 amino acid sequence of SEQ ID NO: 742, and a HC CDR3 amino acid sequence of SEQ ID NO: 782   (xxiv) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 823, a LC CDR2 amino acid sequence of SEQ ID NO: 863, and a LC CDR3 amino acid sequence of SEQ ID NO: 903; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 703, a HC CDR2 amino acid sequence of SEQ ID NO: 743, and a HC CDR3 amino acid sequence of SEQ ID NO: 783   (xxv) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 824, a LC CDR2 amino acid sequence of SEQ ID NO: 864, and a LC CDR3 amino acid sequence of SEQ ID NO: 904; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 704, a HC CDR2 amino acid sequence of SEQ ID NO: 744, and a HC CDR3 amino acid sequence of SEQ ID NO: 784   (xxvi) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 825, a LC CDR2 amino acid sequence of SEQ ID NO: 865, and a LC CDR3 amino acid sequence of SEQ ID NO: 905; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 705, a HC CDR2 amino acid sequence of SEQ ID NO: 745, and a HC CDR3 amino acid sequence of SEQ ID NO: 785 or   (xxvii) (a) a LC CDR1 amino acid sequence of SEQ ID NO: 826, a LC CDR2 amino acid sequence of SEQ ID NO: 866, and a LC CDR3 amino acid sequence of SEQ ID NO: 906; and   (b) a HC CDR1 amino acid sequence of SEQ ID NO: 706, a HC CDR2 amino acid sequence of SEQ ID NO: 746, and a HC CDR3 amino acid sequence of SEQ ID NO: 786.       

     In one embodiment, the BCMA binding domain comprises a light chain variable region described herein (e.g., in Table 12 or 13) and/or a heavy chain variable region described herein (e.g., in Table 12 or 13). In one embodiment, the BCMA binding domain is a scFv comprising a light chain and a heavy chain of an amino acid sequence listed in Table 12 or 13. In an embodiment, the 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 12 or 13, or a sequence with 95-99% identity with an amino acid sequence provided in Table 12 or 13, 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 12 or 13, or a sequence with 95-99% identity to an amino acid sequence provided in Table 12 or 13. 
     In one embodiment, the BCMA binding domain comprises an amino acid sequence selected from a group consisting of SEQ ID NO: 349; SEQ ID NO: 339, SEQ ID NO: 340; SEQ ID NO: 341; SEQ ID NO: 342; SEQ ID NO: 343; SEQ ID NO: 344, SEQ ID NO: 345, SEQ ID NO: 346, SEQ ID NO: 347, SEQ ID NO: 348, SEQ ID NO: 350, SEQ ID NO: 351, SEQ ID NO: 352, SEQ ID NO: 353, SEQ ID NO: 429, SEQ ID NO: 430, SEQ ID NO: 431, SEQ ID NO: 432, SEQ ID NO: 433, SEQ ID NO: 434, SEQ ID NO: 435, SEQ ID NO: 436, SEQ ID NO: 437, SEQ ID NO: 438, SEQ ID NO: 439, SEQ ID NO: 440, SEQ ID NO: 441, SEQ ID NO: 442, SEQ ID NO: 443, SEQ ID NO: 444, SEQ ID NO: 445, SEQ ID NO: 446, SEQ ID NO: 447, SEQ ID NO: 448, SEQ ID NO: 449, SEQ ID NO: 563, SEQ ID NO: 564, SEQ ID NO: 565 and SEQ ID NO: 566; or 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) to any of the aforesaid sequences; or a sequence with 95-99% identity to any of the aforesaid sequences. In one embodiment, the BCMA binding domain is a scFv, and a light chain variable region comprising an amino acid sequence described herein, e.g., in Table 12 or 13, is attached to a heavy chain variable region comprising an amino acid sequence described herein, e.g., in Table 12 or 13, via a linker, e.g., a linker described herein. In one embodiment, the BCMA binding domain includes a (Gly4-Ser)n linker, wherein n is 1, 2, 3, 4, 5, or 6, preferably 4 (SEQ ID NO: 80). 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. 
     Any known BCMA CAR, e.g., the BMCA antigen binding domain of any known BCMA CAR, in the art can be used in accordance with the instant invention to construct a BCA CAR For example, those described herein. As another example, the BCMA CAR comprises an anti-BCMA binding domain or portion thereof, e.g., CDRs, of a CAR or antigen binding domain described in, e.g., WO2016/094304, WO2016/014789, or U.S. Pat. No. 9,034,324 (e.g., C11D5 of U.S. Pat. No. 9,034,324), the contents of each of which are hereby incorporated by reference in their entirety. 
     In one embodiment, an antigen binding domain against ROR1 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Hudecek et al., Clin Cancer Res 19(12):3153-3164 (2013); WO 2011159847; and US20130101607. 
     In one embodiment, an antigen binding domain against CD22 is an antigen binding portion, e.g., CDRs, of an antibody described in, e.g., Haso et al., Blood, 121(7): 1165-1174 (2013); Wayne et al., Clin Cancer Res 16(6): 1894-1903 (2010); Kato et al., Leuk Res 37(1):83-88 (2013); Creative BioMart (creativebiomart.net): MOM-18047-S(P). In an aspect, an antigen binding domain against CD22 is an antigen binding portion, e.g., CDRs, VL and VH, or scFV, of an antigen binding domain or CAR described in, e.g., WO2016/164731 (e.g., as described in Table 6A of WO2016/164731), the contents of which is hereby incorporated by reference in its entirety. 
     In one embodiment, an antigen binding domain against CD20 is an antigen binding portion, e.g., CDRs, of the antibody Rituximab, Ofatumumab, Ocrelizumab, Veltuzumab, or GA101, or derivatives thereof. In an aspect, an antigen binding domain against CD20 is an antigen binding portion, e.g., CDRs, VL and VH, or scFV, of an antigen binding domain or CAR described in, e.g., WO2016/164731 (e.g., as described in Table 11A or 11B of WO2016/164731), the contents of which is hereby incorporated 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 listed above, and/or one, two, three (e.g., all three) light chain CDRs, LC CDR1, LC CDR2 and LC CDR3, from an antibody that binds a tumor antigen or a B cell antigen 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 that binds a tumor antigen or a B cell antigen listed above. 
     In one embodiment, the antigen binding domain of a CAR, e.g., a TA CAR and/or a BCA CAR, described herein 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 efficacy, as the IgG antibody from which it is derived. In other embodiments, the antibody fragment has a lower binding affinity, e.g., it binds the same antigen with a lower binding affinity than the antibody from which it is derived, but is functional in that it provides a biological response described herein. In one embodiment, the CAR molecule comprises an antibody fragment that has a binding affinity K D  of 10 −4  M to 10 −8  M, e.g., 10 −5  M to 10 −7  M, e.g., 10 −6  M or 10 −7  M, for the target antigen. In one embodiment, the antibody fragment has a binding affinity that is at least five-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold or 1,000-fold less than a reference antibody, e.g., an antibody described herein. 
     In one embodiment, the antigen binding domain comprises a non-human antibody or antibody fragment, e.g., a mouse antibody or antibody fragment. 
     In another embodiment, the antigen binding domain comprises a humanized antibody or an antibody fragment. 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 aspect, the antigen binding domain is humanized compared to the murine sequence of the antibody or antibody fragment, e.g., scFv, from which it is derived. 
     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. Often, framework residues in the framework regions will be substituted with the corresponding residue from the CDR donor antibody to alter, for example improve, antigen binding. These framework substitutions are identified by methods well-known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions. (See, e.g., Queen et al., U.S. Pat. No. 5,585,089; and Riechmann et al., 1988, Nature, 332:323, which are incorporated herein by reference in their entireties.) 
     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. 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. 
     In some aspects, the portion of a CAR of the invention, e.g., a TA CAR and/or a BCA CAR described herein, 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 disclosure, the ability to bind human a tumor antigen as described herein. In some embodiments, a humanized antibody or antibody fragment may have improved affinity and/or specificity of binding to a tumor antigen as described herein or a B cell antigen as described herein. In some embodiments, a humanized antibody or antibody fragment may have lower affinity and/or specificity of a tumor antigen as described herein or a B cell antigen as described herein. 
     In one aspect, the antigen binding domain of the invention is characterized by particular functional features or properties of an antibody or antibody fragment. For example, in one aspect, the portion of a CAR of the invention that comprises an antigen binding domain specifically binds a tumor antigen as described herein or a B cell antigen as described herein. 
     In one aspect, the antigen binding domain is a fragment, e.g., a single chain variable fragment (scFv). In one aspect, the anti-tumor antigen as described herein 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 tumor antigen as described herein 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:22). In one embodiment, the linker can be (Gly 4 Ser) 4  (SEQ ID NO:29) or (Gly 4 Ser) 3 (SEQ ID NO:30). Variation in the linker length may retain or enhance activity, giving rise to superior efficacy in activity studies. 
     In another aspect, the antigen binding domain is a T cell receptor (“TCR”), an engineered TCR, or a fragment thereof, for example, a single chain TCR (scTCR). Methods to make such TCRs are known in the art. See, e.g., Willemsen R A et al, Gene Therapy 7: 1369-1377 (2000); Zhang T et al, Cancer Gene Ther 11: 487-496 (2004); Aggen et al, Gene Ther. 19(4):365-74 (2012) (references are incorporated herein by its entirety). For example, scTCR can be engineered that contains the Vα and Vβ genes from a T cell clone linked by a linker (e.g., a flexible peptide). This approach is very useful to cancer associated target that itself is intracellular, however, a fragment of such antigen (peptide) is presented on the surface of the cancer cells by MHC. 
     In one aspect, the antigen binding domain of the CAR comprises an amino acid sequence that is homologous to an antigen binding domain amino acid sequence described herein, and the antigen binding domain retains the desired functional properties of the antigen binding domain described herein. 
     In one specific aspect, the CAR composition of the invention comprises an antibody fragment. In a further aspect, the antibody fragment comprises a scFv. In a further aspect, the antibody fragment comprises a variable heavy chain (VH) only. 
     In various aspects, the antigen binding domain of the CAR is engineered by modifying one or more amino acids within one or both variable regions (e.g., VH and/or VL), for example within one or more CDR regions and/or within one or more framework regions. In one specific aspect, the CAR composition of the invention comprises an antibody fragment. In a further aspect, the antibody fragment comprises an scFv. 
     It will be understood by one of ordinary skill in the art that the antibody or antibody fragment of the invention may further be modified such that they vary in amino acid sequence (e.g., from wild-type), but not in desired activity. For example, additional nucleotide substitutions leading to amino acid substitutions at “non-essential” amino acid residues may be made to the protein. For example, a nonessential amino acid residue in a molecule may be replaced with another amino acid residue from the same side chain family. In another embodiment, a string of amino acids can be replaced with a structurally similar string that differs in order and/or composition of side chain family members, e.g., a conservative substitution, in which an amino acid residue is replaced with an amino acid residue having a similar side chain, may be made. 
     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., 600/o 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 more preferably 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 disclosure 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 to—a tumor antigen described herein, 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 to the tumor antigen described herein, e.g., scFv. The present disclosure 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 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 sulfhydryl 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-CHI regions of two antibodies (two Fab fragments) linked through a polypeptide spacer between the CHI 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 bispecifc, 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, US2005100543 A1, US2005136049A1, US2005136051 A1, 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, WO006605A2, 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 (VH 1 ) upstream of its VL (VL 1 ) 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 (VL 1 ) upstream of its VH (VH 1 ) 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, preferably 4 (SEQ ID NO: 80). 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 one aspect, the invention provides a chimeric antigen receptor comprising a bispecific antigen binding domain, a transmembrane domain (e.g., as described herein), and an intracellular signaling domain (e.g., as described herein). In embodiments, the bispecific antigen binding domain comprises a first immunoglobulin variable domain sequence, e.g., an scFv (or comprises the light chain CDRs and/or heavy chain CDRs from a scFv described herein), which binds a B-cell antigen, e.g., as described herein, e.g., (a CD19 binding domain or BCMA binding domain described herein, e.g., in Table 6 or Table 12), and a second immunoglobulin variable domain sequence, e.g., a scFv (or comprises the light chain CDRs and/or heavy chain CDRs from a scFv described herein), which has binding specificity for one or more tumor antigens described herein, e.g., a solid tumor antigen, e.g., comprises a scFv as described herein, e.g., comprising a mesothelin binding domain or EGFRvIII binding domain (e.g., as described in Table 2 or Table 5). In embodiments, the bispecific antigen binding domain comprises a CD19 binding domain described herein and a mesothelin binding domain described herein. In embodiments, the bispecific antigen binding domain comprises a BCMA binding domain described herein and a mesothelin binding domain described herein. In embodiments, the bispecific antigen binding domain comprises a CD19 binding domain described herein and a EGFRvIII binding domain described herein. In embodiments, the bispecific antigen binding domain comprises a BCMA binding domain described herein and a EGFRvII binding domain described herein. In another aspect, the invention provides a cell (e.g., a population of cells), e.g., an immune effector cell, e.g., a T cell or NK cell, e.g., as described herein, which is engineered to express (e.g., comprises) a bispecific CAR as described herein, e.g., a bispecific CAR comprising a B-cell antigen binding domain described herein and a tumor antigen (e.g., a solid tumor antigen) described herein. Without being bound by any theory, it is believed that cells expressing such bispecific CARs (e.g., comprising a B-cell antigen binding domain, e.g., as described herein, and a tumor antigen binding domain, e.g., as described herein) are useful in the methods and compositions described herein. 
     Chimeric TCR 
     In one aspect, the antigen binding domains described herein, e.g., the antibodies and antibody fragments, e.g., provided in the Tables herein, 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 specificity to a tumor antigen or B cell antigendescribed herein. Without being bound by theory, it is believed that chimeric TCRs will signal through the TCR complex upon antigen binding. For example, a mesothelin or CD19 scFv or a fragment there of, e.g., a VL domain, or VH domain, 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, the CDRs of an antibody or antibody fragment, e.g., the CDRs of anyantibody or antibody fragment as described in Tables provided herein may be grafted into a TCR alpha and/or beta chain to create a chimeric TCR that binds specifically to a tumor antigen or a B cell antigen described herein. For example, the LCDRs disclosed herein may be grafted into the variable domain of a TCR alpha chain and the HCDRs disclosed herein may be grafted to the variable domain of a TCR beta chain, or vice versa. Such chimeric TCRs may be produced by methods known in the art (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 Apr.; 19(4):365-74). 
     Transmembrane Domain 
     With respect to the transmembrane domain, in various embodiments, a CAR, e.g., a TA CAR and/or a BCA CAR, can be designed to comprise a transmembrane domain that is attached to the extracellular domain of the CAR, e.g., the antigen binding domain. 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, for example, the transmembrane domain is from the same protein as the intracellular signalling domain, e.g., the costimulatory domain. 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, CD27, 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, VLA, 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. 
     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, or a CD8a hinge. In one embodiment, the hinge or spacer comprises (e.g., consists of) the amino acid sequence of SEQ ID NO:4. In one aspect, the transmembrane domain comprises (e.g., consists of) a transmembrane domain of SEQ ID NO: 12. 
     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: 6. 
     In some embodiments, the hinge or spacer comprises a hinge encoded by a nucleotide sequence of SEQ ID NO: 7. 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: 8. In some embodiments, the hinge or spacer comprises a hinge encoded by a nucleotide sequence of SEQ ID NO: 9. 
     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: 10). In some embodiments, the linker is encoded by a nucleotide sequence of GGTGGCGGAGGTCTGGAGGTGGAGGTTCC (SEQ ID NO: 11). 
     In one aspect, the hinge or spacer comprises a KIR2DS2 hinge. 
     Cytoplasmic Domain 
     The cytoplasmic domain or region of the CAR, e.g., the TA CAR and/or the BCA 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. 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. Thus the term “intracellular signaling domain” refers to the portion of a protein which transduces the effector function signal and directs the cell to perform a specialized function. While usually 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. 
     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 TCR zeta, FcR gamma, FcR beta, CD3 gamma, CD3 delta, CD3 epsilon, CD5, CD22, 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, e.g., a CD3-zeta sequence described herein. 
     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. 
     The intracellular signaling 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. A costimulatory molecule is 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, PD-1, 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 an MHC class I molecule, a TNF receptor protein, an Immunoglobulin-like protein, a cytokine receptor, an integrin, a signaling lymphocytic activation molecule (SLAM protein), an activating NK cell receptor, 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 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: 14. In one aspect, the signaling domain of CD3-zeta is a signaling domain of SEQ ID NO: 18. 
     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: 16. In one aspect, the signalling domain of CD27 is encoded by a nucleic acid sequence of SEQ ID NO: 17. 
     In one aspect, the intracellular is designed to comprise the signaling domain of CD3-zeta and the signaling domain of CD28. In one aspect, the signaling domain of CD28 comprises an amino acid sequence of SEQ ID NO: 44. In one aspect, the signaling domain of CD28 is encoded by a nucleic acid sequence of SEQ ID NO: 45. 
     In one aspect, the intracellular is designed to comprise the signaling domain of CD3-zeta and the signaling domain of ICOS. In one aspect, the signaling domain of ICOS comprises an amino acid sequence of SEQ ID NO: 42. In one aspect, the signaling domain of ICOS is encoded by a nucleic acid sequence of SEQ ID NO: 43. 
     In one aspect, the cell of the invention, e.g., described herein, e.g., a cell expressing both a TA CAR and a BCA CAR, includes a TA CAR that includes an antigen binding domain that binds a target tumor antigen described herein, a transmembrane domain, a primary signaling domain, and a costimulatory signaling domain, and a BCA CAR that includes an antigen binding domain that binds a target B-Cell antigen described herein, a transmembrane domain, a primary signaling domain, and a costimulatory signaling domain. In other aspects, the cell of the invention, e.g., described herein, e.g., a cell expressing both a TA CAR and a BCA CAR, includes a TA CAR that includes an antigen binding domain that binds a target tumor antigen described herein, a transmembrane domain, a primary signaling domain, and a costimulatory signaling domain, and a BCA CAR that includes an antigen binding domain that binds a target B-Cell antigen described herein, a transmembrane domain, and a costimulatory signaling domain, but does not include a primary signaling domain. Without being bound by theory, it is believed that providing a BCA CAR comprising a costimulatory signaling domain, but not a primary signaling domain, may allow the cell of the invention to persist and or proliferate in response to circulating B cells, but may minimize the cytotoxicity against said B cells. 
     In one aspect, the CAR-expressing cell described herein, e.g. a cell expressing both a TA CAR and a BCA CAR can further comprise another TA CAR, e.g., another TA CAR that includes a different antigen binding domain, e.g., to the same target or a different target (e.g., a target other than a tumor antigen described herein or a different tumor antigen described herein). For example, in an embodiment where the cell of the invention expresses a second TA CAR, the second TA CAR includes an antigen binding domain to a target expressed the same cancer cell type as the tumor antigen targeted by the first TA CAR. In one embodiment, the CAR-expressing cell comprises a first TA CAR that targets a first tumor antigen and includes an intracellular signaling domain having a costimulatory signaling domain but not a primary signaling domain, and a second TA CAR that targets a second, different, tumor 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 TA CAR, and the primary signaling domain, e.g., CD3 zeta, on the second TA CAR can limit the CAR activity to cells where both targets are expressed. In one embodiment, the cell of the invention comprises a first tumor antigen (TA) CAR that includes an antigen binding domain that binds a target antigen described herein, a transmembrane domain and a costimulatory domain and a second TA CAR that targets a different target antigen (e.g., an antigen expressed on that same cancer cell type as the first target antigen) and includes an antigen binding domain, a transmembrane domain and a primary signaling domain. In another embodiment, the cell of the invention comprises (i.e., is genetically engineered to express) a first TA CAR that includes an antigen binding domain that binds a target antigen described herein, a transmembrane domain and a primary signaling domain and a second TA CAR that targets a tumor antigen other than the first target antigen (e.g., an antigen expressed on the same cancer cell type as the first target antigen) and includes an antigen binding domain to the antigen, a transmembrane domain and a costimulatory signaling domain. In another embodiment, the cell of the invention comprises (i.e., is genetically engineered to express) a first TA CAR that includes an antigen binding domain that binds a target antigen described herein, a transmembrane domain, a costimulatory signaling domain and a primary signaling domain, and a second TA CAR that targets a tumor antigen other than the first target antigen (e.g., an antigen expressed on the same cancer cell type as the first target antigen) and includes an antigen binding domain to the antigen, a transmembrane domain, a costimulatory signaling domain and a primary signaling domain. In embodiments where both the first and second TA CAR include a costimulatory signaling domain, the costimulatory signaling domain of the first TA CAR and the second TA CAR may be derived from the same protein, e.g., from a costimulatory protein described herein, e.g., 4-1BB, CD28, or ICOS. In other embodiments, the costimulatory signaling domain of the first TA CAR and the second TA CAR may be derived from the different proteins, e.g., the first TA CAR includes a costimulatory signaling domain described herein, e.g., of 4-1BB, and the second TA CAR includes a different costimulatory signaling domain described herein, e.g., of CD28. 
     In one embodiment, the CAR-expressing cell comprises a TA CAR described herein, a BCA 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 the tumor antigen targeted by the TA CAR 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 of PD1, PD-L1, CTLA4, TIM3, 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 one embodiment, the antigen binding domains of the different CARs (e.g., of the TA CAR and of the BCA CAR) 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. 
     In some embodiments, the antigen binding domain comprises a single domain antigen binding (SDAB) molecules include molecules whose complementary determining regions are part of a single domain polypeptide. Examples include, but are not limited to, heavy chain variable domains, binding molecules naturally devoid of light chains, single domains derived from conventional 4-chain antibodies, engineered domains and single domain scaffolds other than those derived from antibodies. SDAB molecules may be any of the art, or any future single domain molecules. SDAB molecules may be derived from any species including, but not limited to mouse, human, camel, llama, lamprey, fish, shark, goat, rabbit, and bovine. This term also includes naturally occurring single domain antibody molecules from species other than Camelidae and sharks. 
     In one aspect, an SDAB molecule can be derived from a variable region of the immunoglobulin found in fish, such as, for example, that which is derived from the immunoglobulin isotype known as Novel Antigen Receptor (NAR) found in the serum of shark. Methods of producing single domain molecules derived from a variable region of NAR (“IgNARs”) are described in WO 03/014161 and Streltsov (2005) Protein Sci. 14:2901-2909. 
     According to another aspect, an SDAB molecule is a naturally occurring single domain antigen binding molecule known as heavy chain devoid of light chains. Such single domain molecules are disclosed in WO 9404678 and Hamers-Casterman, C. et al. (1993) Nature 363:446-448, for example. For clarity reasons, this variable domain derived from a heavy chain molecule naturally devoid of light chain is known herein as a VHH or nanobody to distinguish it from the conventional VH of four chain immunoglobulins. Such a VHH molecule can be derived from Camelidae species, for example in camel, llama, dromedary, alpaca and guanaco. Other species besides Camelidae may produce heavy chain molecules naturally devoid of light chain; such VHHs are within the scope of the invention. 
     The SDAB molecules can be recombinant, CDR-grafted, humanized, camelized, de-immunized and/or in vitro generated (e.g., selected by phage display). 
     It has also been discovered, that cells having a plurality of chimeric membrane embedded receptors comprising an antigen binding domain that interactions between the antigen binding domain of the receptors can be undesirable, e.g., because it inhibits the ability of one or more of the antigen binding domains to bind its cognate antigen. Accordingly, disclosed herein are cells having a first and a second non-naturally occurring chimeric membrane embedded receptor comprising antigen binding domains that minimize such interactions. Also disclosed herein are nucleic acids encoding a first and a second non-naturally occurring chimeric membrane embedded receptor comprising a antigen binding domains that minimize such interactions, as well as methods of making and using such cells and nucleic acids. In an embodiment the antigen binding domain of one of said first said second non-naturally occurring chimeric membrane embedded receptor, comprises an scFv, and the other comprises a single VH domain, e.g., a camelid, shark, or lamprey single VH domain, or a single VH domain derived from a human or mouse sequence. 
     In some embodiments, the claimed invention comprises a first and second CAR (e.g., a TA CAR and a BCA CAR), wherein the antigen binding domain of one of the first CAR and the second CAR does not comprise a variable light domain and a variable heavy domain. In some embodiments, the antigen binding domain of one of the first CAR and the second CAR is an scFv, and the other is not an scFv. In some embodiments, the antigen binding domain of one of the first CAR and the second CAR comprises a single VH domain, e.g., a camelid, shark, or lamprey single VH domain, or a single VH domain derived from a human or mouse sequence. In some embodiments, the antigen binding domain of one of the first CAR and the second CAR comprises a nanobody. In some embodiments, the antigen binding domain of one of the first CAR and the second CAR comprises a camelid VHH domain. 
     In some embodiments, the antigen binding domain of one of the first CAR and the second CAR comprises an scFv, and the other comprises a single VH domain, e.g., a camelid, shark, or lamprey single VH domain, or a single VH domain derived from a human or mouse sequence. In some embodiments, the antigen binding domain of one of the first CAR and the second CAR comprises an scFv, and the other comprises a nanobody. In some embodiments, the antigen binding domain of one of the first CAR and the second CAR comprises an scFv, and the other comprises a camelid VHH domain. 
     In some embodiments, when present on the surface of a cell, binding of the antigen binding domain of the first CAR to its cognate antigen is not substantially reduced by the presence of the second CAR. In some embodiments, binding of the antigen binding domain of the first CAR to its cognate antigen in the presence of the second CAR is 85%, 90%, 95%, 96%, 97%, 98% or 99% of binding of the antigen binding domain of the first CAR to its cognate antigen in the absence of the second CAR. 
     In some embodiments, when present on the surface of a cell, the antigen binding domains of the first CAR and the second CAR, associate with one another less than if both were scFv antigen binding domains. In some embodiments, the antigen binding domains of said first CAR said second CAR, associate with one another 85%, 90%, 95%, 96%, 97%, 98% or 99% less than if both were scFv antigen binding domains. 
     In another aspect, the CAR-expressing cell described herein can further express another agent, e.g., 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. 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, 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 one embodiment, the agent which inhibits an inhibitory molecule, e.g., is a molecule described herein, e.g., an agent that 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, 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, 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 PD 1), 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), 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 incombinations with a XCAR 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: 26. In one embodiment, the PD1 CAR comprises the amino acid sequence of SEQ ID NO:26. In one embodiment, the PD1 CAR comprises the amino acid sequence of SEQ ID NO:39). 
     In one embodiment, the agent comprises a nucleic acid sequence encoding the PD 1 CAR, e.g., the PD1 CAR described herein. In one embodiment, the nucleic acid sequence for the PD1 CAR is shown as SEQ ID NO: 27 in Table 1, with the sequence for PD1 ECD underlined. 
     In another aspect, the present disclosure provides a population of CAR-expressing cells. 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, 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. 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. 
     In another aspect, the present disclosure 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. For example, 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, 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 one embodiment, the agent which inhibits an inhibitory molecule, e.g., is a molecule described herein, e.g., an agent that 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 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, and 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). 
     In one aspect, the present disclosure provides methods comprising administering a population of CAR-expressing cells, e.g., a mixture of cells expressing different CARs, in combination with another agent, e.g., a kinase inhibitor, such as a kinase inhibitor described herein. In another aspect, the present disclosure provides methods comprising administering a population of cells wherein at least one cell in the population expresses a CAR having an antigen binding domain of 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, in combination with another agent, e.g., a kinase inhibitor, such as a kinase inhibitor described herein. 
     Exemplary CAR Molecules 
     In one aspect, the BCA CAR comprises a CAR molecule comprising an antigen binding domain that binds to a B cell antigen. In one embodiment, the BCA CAR comprises a CAR molecule comprising a CD19 antigen binding domain (e.g., a murine, human 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). 
     Exemplary CAR molecules of a BCA CAR described herein are provided in Table 10. The CAR molecules in Table 10 comprise a CD19 antigen binding domain, e.g., an amino acid sequence of any CD19 antigen binding domain provided in Table 6. 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Exemplary CD19 CAR molecules 
               
            
           
           
               
               
               
               
            
               
                 B cell 
                   
                   
                 SEQ 
               
               
                 antigen 
                 Name 
                 Amino Acid Sequence 
                 ID NO: 
               
               
                   
               
               
                 CD19 
                 CTL019 
                 MALPVTALLLPLALLLHAARPDIQMTQTTSSLSASLGDRVTISCRASQDISKYL 
                 281 
               
               
                   
                   
                 NWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYF 
                   
               
               
                   
                   
                 CQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQESGPGLVAPSQSLS 
                   
               
               
                   
                   
                 VTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDN 
                   
               
               
                   
                   
                 SKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSTTTPAPR 
                   
               
               
                   
                   
                 PPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLL 
                   
               
               
                   
                   
                 SLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKF 
                   
               
               
                   
                   
                 SRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGL 
                   
               
               
                   
                   
                 YNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
                   
               
               
                   
               
               
                 CD19 
                 CAR 1 
                 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYL 
                 269 
               
               
                   
                   
                 NWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYF 
                   
               
               
                   
                   
                 CQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPLGVKPSETLS 
                   
               
               
                   
                   
                 LTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDN 
                   
               
               
                   
                   
                 SKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPR 
                   
               
               
                   
                   
                 PPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLL 
                   
               
               
                   
                   
                 SLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKF 
                   
               
               
                   
                   
                 SRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGL 
                   
               
               
                   
                   
                 YNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
                   
               
               
                   
               
               
                 CD19 
                 CAR 2 
                 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYL 
                 270 
               
               
                   
                   
                 NWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYF 
                   
               
               
                   
                   
                 CQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLS 
                   
               
               
                   
                   
                 LTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDN 
                   
               
               
                   
                   
                 SKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPR 
                   
               
               
                   
                   
                 PPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLL 
                   
               
               
                   
                   
                 SLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKF 
                   
               
               
                   
                   
                 SRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGL 
                   
               
               
                   
                   
                 YNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
                   
               
               
                   
               
               
                 CD19 
                 CAR 3 
                 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYG 
                 271 
               
               
                   
                   
                 VSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTA 
                   
               
               
                   
                   
                 ADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQ 
                   
               
               
                   
                   
                 SPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPA 
                   
               
               
                   
                   
                 RFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTTTPAPR 
                   
               
               
                   
                   
                 PPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIQAPLAGTCGVLLL 
                   
               
               
                   
                   
                 SLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKF 
                   
               
               
                   
                   
                 SRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGL 
                   
               
               
                   
                   
                 YNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
                   
               
               
                   
               
               
                 CD19 
                 CAR 4 
                 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYG 
                 272 
               
               
                   
                   
                 VSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTA 
                   
               
               
                   
                   
                 ADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQ 
                   
               
               
                   
                   
                 SPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHYSRLHSGIPA 
                   
               
               
                   
                   
                 RFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTTTPAPR 
                   
               
               
                   
                   
                 PPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLL 
                   
               
               
                   
                   
                 SLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKF 
                   
               
               
                   
                   
                 SRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGL 
                   
               
               
                   
                   
                 YNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
                   
               
               
                   
               
               
                 CD19 
                 CAR 5 
                 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYL 
                 273 
               
               
                   
                   
                 NWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYF 
                   
               
               
                   
                   
                 CQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKP 
                   
               
               
                   
                   
                 SETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVT 
                   
               
               
                   
                   
                 ISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTT 
                   
               
               
                   
                   
                 TPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTC 
                   
               
               
                   
                   
                 GVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCE 
                   
               
               
                   
                   
                 LRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKN 
                   
               
               
                   
                   
                 PQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQ 
                   
               
               
                   
                   
                 ALPPR 
                   
               
               
                   
               
               
                 CD19 
                 CAR 6 
                 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYL 
                 274 
               
               
                   
                   
                 NWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYF 
                   
               
               
                   
                   
                 CQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKP 
                   
               
               
                   
                   
                 SETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVT 
                   
               
               
                   
                   
                 ISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTT 
                   
               
               
                   
                   
                 TPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTC 
                   
               
               
                   
                   
                 GVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCE 
                   
               
               
                   
                   
                 LRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKN 
                   
               
               
                   
                   
                 PQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQ 
                   
               
               
                   
                   
                 ALPPR 
                   
               
               
                   
               
               
                 CD19 
                 CAR 7 
                 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYG 
                 275 
               
               
                   
                   
                 VSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTA 
                   
               
               
                   
                   
                 ADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSE 
                   
               
               
                   
                   
                 IVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLH 
                   
               
               
                   
                   
                 SGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTT 
                   
               
               
                   
                   
                 TPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTC 
                   
               
               
                   
                   
                 GVLLLSLCITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCE 
                   
               
               
                   
                   
                 LRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVDLKRRGRDPEMGGKPRRKN 
                   
               
               
                   
                   
                 PQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQ 
                   
               
               
                   
                   
                 ALPPR 
                   
               
               
                   
               
               
                 CD19 
                 CAR 8 
                 MALPVTALLLPLALLLHAARPQVQLQESGPGLKVPSETLSLTCTVSGVSLPDYG 
                 276 
               
               
                   
                   
                 VSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTA 
                   
               
               
                   
                   
                 ADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSE 
                   
               
               
                   
                   
                 IVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLH 
                   
               
               
                   
                   
                 SGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTT 
                   
               
               
                   
                   
                 TPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTC 
                   
               
               
                   
                   
                 GVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCE 
                   
               
               
                   
                   
                 LRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKN 
                   
               
               
                   
                   
                 PQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQ 
                   
               
               
                   
                   
                 ALPPR 
                   
               
               
                   
               
               
                 CD19 
                 CAR 9 
                 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYL 
                 277 
               
               
                   
                   
                 NWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYF 
                   
               
               
                   
                   
                 CQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKP 
                   
               
               
                   
                   
                 SETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVT 
                   
               
               
                   
                   
                 ISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTT 
                   
               
               
                   
                   
                 TPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTC 
                   
               
               
                   
                   
                 GVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCE 
                   
               
               
                   
                   
                 LRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKN 
                   
               
               
                   
                   
                 PQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQ 
                   
               
               
                   
                   
                 ALPPR 
                   
               
               
                   
               
               
                 CD19 
                 CAR 10 
                 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYL 
                 278 
               
               
                   
                   
                 NWYQQKPGQAPRLLIHYTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYF 
                   
               
               
                   
                   
                 CQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKP 
                   
               
               
                   
                   
                 SETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVT 
                   
               
               
                   
                   
                 ISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTT 
                   
               
               
                   
                   
                 TPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTC 
                   
               
               
                   
                   
                 GVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCE 
                   
               
               
                   
                   
                 LRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKN 
                   
               
               
                   
                   
                 PQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQ 
                   
               
               
                   
                   
                 ALPPR 
                   
               
               
                   
               
               
                 CD19 
                 CAR 11 
                 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYG 
                 279 
               
               
                   
                   
                 VSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTA 
                   
               
               
                   
                   
                 ADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSE 
                   
               
               
                   
                   
                 IVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIHYTSRLH 
                   
               
               
                   
                   
                 SGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTT 
                   
               
               
                   
                   
                 TPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTC 
                   
               
               
                   
                   
                 GVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCE 
                   
               
               
                   
                   
                 LRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKN 
                   
               
               
                   
                   
                 PQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQ 
                   
               
               
                   
                   
                 ALPPR 
                   
               
               
                   
               
               
                 CD19 
                 CAR 12 
                 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYL 
                 280 
               
               
                   
                   
                 NWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYF 
                   
               
               
                   
                   
                 CQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLS 
                   
               
               
                   
                   
                 LTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDN 
                   
               
               
                   
                   
                 SKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPR 
                   
               
               
                   
                   
                 PPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLL 
                   
               
               
                   
                   
                 SLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKF 
                   
               
               
                   
                   
                 SRSADAPAYKQGQGQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGL 
                   
               
               
                   
                   
                 YNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                   
               
            
           
         
       
     
     In one embodiment, the CAR molecule of the BCA CAR comprises (e.g., consists of) an amino acid sequence as provided in Table 10, or in Table 3 of International Publication No. WO2014/153270, filed Mar. 15, 2014; incorporated herein by reference. In one embodiment, the CAR molecule of the BCA CAR comprises (e.g., consists of) an amino acid sequence of SEQ ID NO: 269, SEQ ID NO: 270, SEQ ID NO: 271, SEQ ID NO: 272, SEQ ID NO: 273, SEQ ID NO: 274, SEQ ID NO: 275, SEQ ID NO: 276, SEQ ID NO: 277, SEQ ID NO: 278, SEQ ID NO: 279, SEQ ID NO: 280, or SEQ ID NO: 281; or an amino acid sequence having at least one, two, three, four, five, 10, 15, 20 or 30 modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 60, 50, or 40 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of SEQ ID NO: 269, SEQ ID NO: 270, SEQ ID NO: 271, SEQ ID NO: 272, SEQ ID NO: 273, SEQ ID NO: 274, SEQ ID NO: 275, SEQ ID NO: 276, SEQ ID NO: 277, SEQ ID NO: 278, SEQ ID NO: 279, SEQ ID NO: 280, or SEQ ID NO: 281; or an amino acid sequence having 85%, 90°/%, 95%, 96%, 97%, 98%, 99% identity to an amino acid sequence of SEQ ID NO: 269, SEQ ID NO: 270, SEQ ID NO: 271, SEQ ID NO: 272, SEQ ID NO: 273, SEQ ID NO: 274, SEQ ID NO: 275, SEQ ID NO: 276, SEQ ID NO: 277, SEQ ID NO: 278, SEQ ID NO: 279, SEQ ID NO: 280, or SEQ ID NO: 281. 
     In one aspect, the BCA CAR comprises a CAR molecule comprising an antigen binding domain that binds to a B cell antigen. In one embodiment, the BCA CAR comprises a CAR molecule comprising a BCMA antigen binding domain (e.g., a murine, human or humanized antibody or antibody fragment that specifically binds to BCMA, e.g., human BCMA), a transmembrane domain, and an intracellular signaling domain (e.g., an intracellular signaling domain comprising a costimulatory domain and/or a primary signaling domain). 
     Exemplary CAR molecules of a BCA CAR described herein are provided in Table 16, or Table 1 of WO2016/014565, or as otherwise described herein. The CAR molecules in Table 16 comprise a BCMA antigen binding domain, e.g., an amino acid sequence of any BCMA antigen binding domain provided in Table 12 or 13. 
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 Exemplary BCMA CAR molecules. 
               
               
                 Sequences are provided with a leader sequence. 
               
            
           
           
               
               
               
            
               
                 Name/ 
                   
                   
               
               
                 Description 
                 SEQ ID NO: 
                 Sequence 
               
               
                   
               
            
           
           
               
            
               
                 139109 
               
            
           
           
               
               
               
            
               
                 139109-aa 
                  959 
                 MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAVSGFALS 
               
               
                 Full CAR 
                   
                 NHGMSWVRRAPGKGLEWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQ 
               
               
                   
                   
                 MNSLRPEDTAIYYCSAHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGS 
               
               
                   
                   
                 DIQLTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAA 
               
               
                   
                   
                 SSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPYTFGQGT 
               
               
                   
                   
                 KVEIKTTTPAPRPPTPAPTIASQPSLSRPEACRPAAGGAVHTRGLDFACDI 
               
               
                   
                   
                 YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLIYFKQPFMRPVQTTQEEDGC 
               
               
                   
                   
                 SCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDK 
               
               
                   
                   
                 RRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDG 
               
               
                   
                   
                 LYQGLSTATKDTYDALHMQALPPR 
               
               
                 139109-nt 
                  974 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCGAAGTGCAATTGGTGGAATCAGGGGGAGGACTTGTGCAG 
               
               
                   
                   
                 CCTGGAGGATCGCTGAGACTGTCATGTGCCGTGTCCGGCTTTGCCCTGTCC 
               
               
                   
                   
                 AACCACGGGATGTCCTGGGTCCGCCGCGCGCCTGGAAAGGGCCTCGAATGG 
               
               
                   
                   
                 GTGTCGGGTATTGTGTACAGCGGTAGCACCTACTATGCCGCATCCGTGAAG 
               
               
                   
                   
                 GGGAGATTCACCATCAGCCGGGACAACTCCAGGAACACTCTGTACCTCCAA 
               
               
                   
                   
                 ATGAATTCGCTGAGGCCAGAGGACACTGCCATCTACTACTGCTCCGCGCAT 
               
               
                   
                   
                 GGCGGAGAGTCCGACGTCTGGGGACAGGGGACCACCGTGACCGTGTCTAGC 
               
               
                   
                   
                 GCGTCCGGCGGAGGCGGCAGCGGGGGTCGGGCATCAGGGGGCGGCGGATCG 
               
               
                   
                   
                 GACATCCAGCTCACCCAGTCCCCGAGCTCGCTGTCCGCCTCCGTGGGAGAT 
               
               
                   
                   
                 CGGGTCACCATCACGTGCCGCGCCAGCCAGTCGATTTCCTCCTACCTGAAC 
               
               
                   
                   
                 TGGTACCAACAGAAGCCCGGAAAAGCCCCGAAGCTTCTCATCTACGCCGCC 
               
               
                   
                   
                 TCGAGCCTGCAGTCAGGAGTGCCCTCACGGTTCTCCGGCTCCGGTTCCGGT 
               
               
                   
                   
                 ACTGATTTCACCCTGACCATTTCCTCCCTGCAACCGGAGGACTTCGCTACT 
               
               
                   
                   
                 TACTACTGCCAGCAGTCGTACTCCACCCCCTACACTTTCGGACAAGGCACC 
               
               
                   
                   
                 AAGGTCGAAATCAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCT 
               
               
                   
                   
                 CCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCC 
               
               
                   
                   
                 GCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATC 
               
               
                   
                   
                 TACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTC 
               
               
                   
                   
                 GTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTT 
               
               
                   
                   
                 AAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGT 
               
               
                   
                   
                 TCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAA 
               
               
                   
                   
                 TTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTC 
               
               
                   
                   
                 TACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAG 
               
               
                   
                   
                 CGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCC 
               
               
                   
                   
                 CAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTAT 
               
               
                   
                   
                 AGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGA 
               
               
                   
                   
                 CTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCAC 
               
               
                   
                   
                 ATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139103 
               
            
           
           
               
               
               
            
               
                 139103-aa 
                  949 
                 MALPVTALLLPLALLLHAARPQVQLVESGGGLVQPGRSLRLSCAASGFTFS 
               
               
                 Full CAR 
                   
                 NYAMSWVRQAPGKGLGWVSGISRSGENTYYADSVKGRFTISRDNSKNTLYL 
               
               
                   
                   
                 QMNSLRDEDTAVYYCARSPAHYYGGMDVWGQGTTVTVSSASGGGGSGGRAS 
               
               
                   
                   
                 GGGGSDIVLTQSPGTLSLSPGERATLSCRASQSISSSFLAWYQQKPGQPAR 
               
               
                   
                   
                 LLIYGASRRATGIPDRFSGSGSGTDFTLTISRLEPEDSAVYYCQQYHSSPS 
               
               
                   
                   
                 WTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRG 
               
               
                   
                   
                 LDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLKYIFKQPFMRPVQT 
               
               
                   
                   
                 TQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRRE 
               
               
                   
                   
                 EYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERR 
               
               
                   
                   
                 RGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 139103-nt 
                  964 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCCAAGTGCAACTCGTGGAATCTGGTGGAGGACTCGTGCAA 
               
               
                   
                   
                 CCCGGAAGATCGCTTAGACTGTCGTGTGCCGCCAGCGGGTTCACTTTCTCG 
               
               
                   
                   
                 AACTACGCGATGTCCTGGGTCCGCCAGGCACCCGGAAAGGGACTCGGTTGG 
               
               
                   
                   
                 GTGTCCGGCATTTCCCGGTCCGGCGAAAATACCTACTACGCCGACTCCGTG 
               
               
                   
                   
                 AAGGGCCGCTTCACCATCTCAAGGGACAACAGCAAAAACACCCTGTACTTG 
               
               
                   
                   
                 CAAATGAACTCCCTGCGGGATGAAGATACAGCCGTGTACTATTGCGCCCGG 
               
               
                   
                   
                 TCGCCTGCCCATTACTACGGCGGAATGGACGTCTGGGGACAGGGAACCACT 
               
               
                   
                   
                 GTGACTGTCAGCAGCGCGTCGGGTGGCGGCGGCTCAGGGGGTCGGGCCTCC 
               
               
                   
                   
                 GGGGGGGGAGGGTCCGACATCGTGCTGACCCAGTCCCCGGGAACCCTGAGC 
               
               
                   
                   
                 CTGAGCCCGGGAGAGCGCGCGACCCTGTCATGCCGGGCATCCCAGAGCATT 
               
               
                   
                   
                 AGCTCCTCCTTTCTCGCCTGGTATCAGCAGAAGCCCGGACAGGCCCCGAGG 
               
               
                   
                   
                 CTGCTGATCTACGGCGCTAGCAGAAGGGCTACCGGAATCCCAGACCGGTTC 
               
               
                   
                   
                 TCCGGCTCCGGTTCCGGGACCGATTTCACCCTTACTATCTCGCGCCTGGAA 
               
               
                   
                   
                 CCTGAGGACTCCGCCGTCTACTACTGCCAGCAGTACCACTCATCCCCGTCG 
               
               
                   
                   
                 TGGACGTTCGGACAGGGCACCAAGCTGGAGATTAAGACCACTACCCCAGCA 
               
               
                   
                   
                 CCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTG 
               
               
                   
                   
                 CGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGT 
               
               
                   
                   
                 CTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGC 
               
               
                   
                   
                 GGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGG 
               
               
                   
                   
                 AAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACT 
               
               
                   
                   
                 ACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGC 
               
               
                   
                   
                 GGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTAC 
               
               
                   
                   
                 AAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAG 
               
               
                   
                   
                 GAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGG 
               
               
                   
                   
                 AAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAG 
               
               
                   
                   
                 GATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGA 
               
               
                   
                   
                 AGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAG 
               
               
                   
                   
                 GACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139105 
               
            
           
           
               
               
               
            
               
                 139105-aa 
                  950 
                 MALPVTALLLPLALLLHAARPQVQLVESGGGLVQPGRSLRLSCAASGFTFD 
               
               
                 Full CAR 
                   
                 DYAMHWVRQAPGKGLEWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYL 
               
               
                   
                   
                 QMNSLRAEDTALYYCSVHSFLAYWGQGTLVTVSSASGGGGSGGRASGGGGS 
               
               
                   
                   
                 DIVMTQTPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQL 
               
               
                   
                   
                 LIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPYT 
               
               
                   
                   
                 FGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLD 
               
               
                   
                   
                 FACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQ 
               
               
                   
                   
                 EEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEY 
               
               
                   
                   
                 DVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRG 
               
               
                   
                   
                 KGHDGLYQGLSTATDKTYDALHMQALPPR 
               
               
                 193015-nt 
                  965 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCCAAGTGCAACTCGTCGAATCCGGTGGAGGTCTGGTCCAA 
               
               
                   
                   
                 CCTGGTAGAAGCCTGAGACTGTCGTGTGCGGCCAGCGGATTCACCTTTGAT 
               
               
                   
                   
                 GACTATGCTATGCACTGGGTGCGGCAGGCCCCAGGAAAGGGCCTGGAATGG 
               
               
                   
                   
                 GTGTCGGGAATTAGCTGGAACTCCGGGTCCATTGGCTACGCCGACTCCGTG 
               
               
                   
                   
                 AAGGGCCGCTTCACCATCTCCCGCGACAACGCAAAGAACTCCCTGTACTTG 
               
               
                   
                   
                 CAAATGAACTCGCTCAGGGCTGAGGATACCGCGCTGTACTACTGCTCCGTG 
               
               
                   
                   
                 CATTCCTTCCTGGCCTACTGGGGACAGGGAACTCTGGTCACCGTGTCGAGC 
               
               
                   
                   
                 GCCTCCGGCGGCGGGGGCTCGGGTGGACGGGCCTCGGGCGGAGGGGGGTCC 
               
               
                   
                   
                 GACATCGTGATGACCCAGACCCCGCTGAGCTTGCCCGTGACTCCCGGAGAG 
               
               
                   
                   
                 CCTGCATCCATCTCCTGCCGGTCATCCCAGTCCCTTCTCCACTCCAACGGA 
               
               
                   
                   
                 TACAACTACCTCGACTGGTACCTCCAGAAGCCGGGACAGAGCCCTCAGCTT 
               
               
                   
                   
                 CTGATCTACCTGGGGTCAAATAGAGCCTCAGGAGTGCCGGATCGGTTCAGC 
               
               
                   
                   
                 GGATCTGGTTCGGGAACTGATTTCACTCTGAAGATTTCCCGCGTGGAAGCC 
               
               
                   
                   
                 GAGGACGTGGGCGTCTACTACTGTATGCAGGCGCTGCAGACCCCCTATACC 
               
               
                   
                   
                 TTCGGCCAAGGGACGAAAGTGGAGATCAAGACCACTACCCCAGCACCGAGG 
               
               
                   
                   
                 CCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCG 
               
               
                   
                   
                 GAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGAC 
               
               
                   
                   
                 TTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTC 
               
               
                   
                   
                 CTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAG 
               
               
                   
                   
                 CTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAA 
               
               
                   
                   
                 GAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGC 
               
               
                   
                   
                 GAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAG 
               
               
                   
                   
                 GGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTAC 
               
               
                   
                   
                 GACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCG 
               
               
                   
                   
                 CGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAG 
               
               
                   
                   
                 ATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGC 
               
               
                   
                   
                 AAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACC 
               
               
                   
                   
                 TATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139111 
               
            
           
           
               
               
               
            
               
                 139111-aa 
                  951 
                 MALPVTALLLPLALLLHAARPEVQLLESGGGLVQPGGSLRLSCAVSGFALS 
               
               
                 Full CAR 
                   
                 NHGMSEVRRAPGKGLEWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQ 
               
               
                   
                   
                 MNSLRPEDTAIYYCSAHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGS 
               
               
                   
                   
                 DIVMTQTPLSLSVTPGQPASISCKSSQSLLRNDGKTPLYWYLQKAGQPPQL 
               
               
                   
                   
                 LIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGAYYCMQNIQFPSF 
               
               
                   
                   
                 GGGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDF 
               
               
                   
                   
                 ACDIYIWAPLAGTCGVLLLSVLITLYCKRGRKKLLYIFKQPFMRPVQTTQE 
               
               
                   
                   
                 EDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYD 
               
               
                   
                   
                 VLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGK 
               
               
                   
                   
                 GHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 139111-nt 
                  966 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCGAAGTGCAATTGTTGGAATCTGGAGGAGGACTTGTGCAG 
               
               
                   
                   
                 CCTGGAGGATCACTGAGACTTTCGTGTGCGGTGTCAGGCTTCGCCCTGAGC 
               
               
                   
                   
                 AACCACGGCATGAGCTGGGTGCGGAGAGCCCCGGGGAAGGGTCTGGAATGG 
               
               
                   
                   
                 GTGTCCGGGATCGTCTACTCCGGTTCAACTTACTACGCCGCAAGCGTGAAG 
               
               
                   
                   
                 GGTCGCTTCACCATTTCCCGCGATAACTCCCGGAACACCCTGTACCTCCAA 
               
               
                   
                   
                 ATGAACTCCCTGCGGCCCGAGGACACCGCCATCTACTACTGTTCCGCGCAT 
               
               
                   
                   
                 GGAGGAGAGTCCGATGTCTGGGGACAGGGCACTACCGTGACCGTGTCGAGC 
               
               
                   
                   
                 GCCTCGGGGGGAGGAGGCTCCGGCGGTCGCGCCTCCGGGGGGGGTGGCAGC 
               
               
                   
                   
                 GACATTGTGATGACGCAGACTCCACTCTCGCTGTCCGTGACCCCGGGACAG 
               
               
                   
                   
                 CCCGCGTCCATCTCGTGCAAGAGCTCCCAGAGCCTGCTGAGGAACGACGGA 
               
               
                   
                   
                 AAGACTCCTCTGTATTGGTACCTCCAGAAGGCTGGACAGCCCCCGCAACTG 
               
               
                   
                   
                 CTCATCTACGAAGTGTCAAATCGCTTCTCCGGGGTGCCGGATCGGTTTTCC 
               
               
                   
                   
                 GGCTCGGGATCGGGCACCGACTTCACCCTGAAAATCTCCAGGGTCGAGGCC 
               
               
                   
                   
                 GAGGACGTGGGAGCCTACTACTGCATGCAAAACATCCAGTTCCCTTCCTTC 
               
               
                   
                   
                 GGCGGCGGCACAAAGCTGGAGATTAAGACCACTACCCCAGCACCGAGGCCA 
               
               
                   
                   
                 CCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAG 
               
               
                   
                   
                 GCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTC 
               
               
                   
                   
                 GCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTG 
               
               
                   
                   
                 CTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTG 
               
               
                   
                   
                 CTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAG 
               
               
                   
                   
                 GAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAA 
               
               
                   
                   
                 CTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGG 
               
               
                   
                   
                 CAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGAC 
               
               
                   
                   
                 GTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGC 
               
               
                   
                   
                 AGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATG 
               
               
                   
                   
                 GCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAA 
               
               
                   
                   
                 GGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTAT 
               
               
                   
                   
                 GACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139100 
               
            
           
           
               
               
               
            
               
                 139100-aa 
                  952 
                 MALPVTALLLPLALLLHAARPQVQLVQSGAEVRKTGASVKVSCKASGYIFD 
               
               
                 Full CAR 
                   
                 NFGINWVRQAPGQGLEWMGWINPKNNNTNYAQKFQGRVTITADESTNTAYM 
               
               
                   
                   
                 EVSSLRSEDTAVYYCARGPYYYQSYMDVWGQGTMVTVSSASGGGGSGGRAS 
               
               
                   
                   
                 GGGGSDIVMTQTPLSLPVTGPEPASISVRSSQSLLHSNGYNYLNWYLQKPG 
               
               
                   
                   
                 QSPQLLIYLGSKRASGVPDRFSGSGSGTDFTLHITRVGAEDVGVYYCMQAL 
               
               
                   
                   
                 QTPYTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVH 
               
               
                   
                   
                 TRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRP 
               
               
                   
                   
                 VQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLG 
               
               
                   
                   
                 RREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKG 
               
               
                   
                   
                 ERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 139100-aa 
                  967 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCCAAGTCCAACTCGTCCAGTCCGGCGCAGAAGTCAGAAAA 
               
               
                   
                   
                 ACCGGTGCTAGCGTGAAAGTGTCCTGCAAGGCCTCCGGCTACATTTTCGAT 
               
               
                   
                   
                 AACTTCGGAATCAACTGGGTCAGACAGGCCCCGGGCCAGGGGCTGGAATGG 
               
               
                   
                   
                 ATGGGATGGATCAACCCCAAGAACAACAACACCAACTACGCACAGAAGTTC 
               
               
                   
                   
                 CAGGGCCGCGTGACTATCACCGCCGATGAATCGACCAATACCGCCTACATG 
               
               
                   
                   
                 GAGGTGTCCTCCCTGCGGTCGGAGGACACTGCCGTGTATTACTGCGCGAGG 
               
               
                   
                   
                 GGCCCATACTACTACCAAAGCTACATGGACGTCTGGGGACAGGGAACCATG 
               
               
                   
                   
                 GTGACCGTGTCATCCGCCTCCGGTGGTGGAGGCTCCGGGGGGCGGGCTTCA 
               
               
                   
                   
                 GGAGGCGGAGGAAGCGATATTGTGATGACCCAGACTCCGCTTAGCCTGCCC 
               
               
                   
                   
                 GTGACTCCTGGAGAACCGGCCTCCATTTCCTGCCGGTCCTCGCAATCACTC 
               
               
                   
                   
                 CTGCATTCCAACGGTTACAACTACCTGAATTGGTACCTCCAGAAGCCTGGC 
               
               
                   
                   
                 CAGTCGCCCCAGTTGCTGATCTATCTGGGCTCGAAGCGCGCCTCCGGGGTG 
               
               
                   
                   
                 CCTGACCGGTTTAGCGGATCTGGGAGCGGCACGGACTTCACTCTCCACATC 
               
               
                   
                   
                 ACCCGCGTGGGAGCGGAGGACGTGGGAGTGTACTACTGTATGCAGGCGCTG 
               
               
                   
                   
                 CAGACTCCGTACACATTCGGACAGGGCACCAAGCTGGAGATCAAGACCACT 
               
               
                   
                   
                 ACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCT 
               
               
                   
                   
                 CTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCAT 
               
               
                   
                   
                 ACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCT 
               
               
                   
                   
                 GGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAG 
               
               
                   
                   
                 CGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCT 
               
               
                   
                   
                 GTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAG 
               
               
                   
                   
                 GAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCT 
               
               
                   
                   
                 CCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGT 
               
               
                   
                   
                 CGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAA 
               
               
                   
                   
                 ATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAG 
               
               
                   
                   
                 CTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGG 
               
               
                   
                   
                 GAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACC 
               
               
                   
                   
                 GCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139101 
               
            
           
           
               
               
               
            
               
                 139101-aa 
                  953 
                 MALPVTALLLPLALLLHAARPQVQLQESGGGLVQPGGSLRLSCAASGFTFS 
               
               
                 Full CAR 
                   
                 SDAMTWVRQAPGKGLEWVSVISGSGGTTYYADSVKGRFTISRDNSKNTLYL 
               
               
                   
                   
                 QMNSLRAEDTAVYYCAKLDSSGYYYARGPRYWGQGTLVTVSSASGGGGSGG 
               
               
                   
                   
                 RASGGGGSDIQLTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKA 
               
               
                   
                   
                 PKLLIYGASTLASGVPARFSGSGSGTHFTLTINSLQSEDSATYYCQQSYKR 
               
               
                   
                   
                 ASFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRG 
               
               
                   
                   
                 LDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQT 
               
               
                   
                   
                 TQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRRE 
               
               
                   
                   
                 EYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERR 
               
               
                   
                   
                 RGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 139101-nt 
                  968 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCCAAGTGCAACTTCAAGAATCAGGCGGAGGACTCGTGCAG 
               
               
                   
                   
                 CCCGGAGGATCATTGCGGCTCTCGTGCGCCGCCTCGGGCTTCACCTTCTCG 
               
               
                   
                   
                 AGCGACGCCATGACCTGGGTCCGCCAGGCCCCGGGGAAGGGGCTGGAATGG 
               
               
                   
                   
                 GTGTCTGTGATTTCCGGCTCCGGGGGAACTACGTACTACGCCGATTCCGTG 
               
               
                   
                   
                 AAAGGTCGCTTCACTATCTCCCGGGACAACAGCAAGAACACCCTTTATCTG 
               
               
                   
                   
                 CAAATGAATTCCCTCCGCGCCGAGGACACCGCCGTGTACTACTGCGCCAAG 
               
               
                   
                   
                 CTGGACTCCTCGGGCTACTACTATGCCCGGGGTCCGAGATACTGGGGACAG 
               
               
                   
                   
                 GGAACCCTCGTGACCGTGTCCTCCGCGTCCGGCGGAGGAGGGTCGGGAGGG 
               
               
                   
                   
                 CGGGCCTCCGGCGGCGGCGGTTCGGACATCCAGCTGACCCAGTCCCCATCC 
               
               
                   
                   
                 TCACTGAGCGCAAGCGTGGGCGACAGAGTCACCATTACATGCAGGGCGTCC 
               
               
                   
                   
                 CAGAGCATCAGCTCCTACCTGAACTGGTACCAACAGAAGCCTGGAAAGGCT 
               
               
                   
                   
                 CCTAAGCTGTTGATCTACGGGGCTTCGACCCTGGCATCCGGGGTGCCCGCG 
               
               
                   
                   
                 AGGTTTAGCGGAAGCGGTAGCGGCACTCACTTCACTCTGACCATTAACAGC 
               
               
                   
                   
                 CTCCAGTCCGAGGATTCAGCCACTTACTACTGTCAGCAGTCCTACAAGCGG 
               
               
                   
                   
                 GCCAGCTTCGGACAGGGCACTAAGGTCGAGATCAAGACCACTACCCCAGCA 
               
               
                   
                   
                 CCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTG 
               
               
                   
                   
                 CGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGT 
               
               
                   
                   
                 CTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGC 
               
               
                   
                   
                 GGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGG 
               
               
                   
                   
                 AAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACT 
               
               
                   
                   
                 ACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGC 
               
               
                   
                   
                 GGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTAC 
               
               
                   
                   
                 AAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAG 
               
               
                   
                   
                 GAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGG 
               
               
                   
                   
                 AAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAG 
               
               
                   
                   
                 GATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGA 
               
               
                   
                   
                 AGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAG 
               
               
                   
                   
                 GACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139102 
               
            
           
           
               
               
               
            
               
                 139102-aa 
                  954 
                 MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGASVKVSCKASGYTFS 
               
               
                 Full CAR 
                   
                 NYGITWVRQAPGQGLEWMGWISAYNGNTNYAQKFQGRVTMTRNTSISTAYM 
               
               
                   
                   
                 ELSSLRSEDTAVYYCARGPYYYYMDVWGKGTMVTVSSASGGGGSGGRASGG 
               
               
                   
                   
                 GGSEIVMTQSPLSLPVTPGEPASISVRSSQSLLYSNGYNYVDWYLQKPGQS 
               
               
                   
                   
                 PQLLIYLGSNRASGVPDRFSGSGSGTDFKLQISRVEAEDVGIYYCMQGRQF 
               
               
                   
                   
                 PYSFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTR 
               
               
                   
                   
                 GLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQ 
               
               
                   
                   
                 TTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRR 
               
               
                   
                   
                 EEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGER 
               
               
                   
                   
                 RRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 139201-nt 
                  969 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCCAAGTCCAACTGGTCCAGAGCGGTGCAGAAGTGAAGAAG 
               
               
                   
                   
                 CCCGGAGCGAGCGTGAAAGTGTCCTGCAAGGCTTCCGGGTACACCTTCTCC 
               
               
                   
                   
                 AACTACGGCATCACTTGGGTGCGCCAGGCCCCGGGACAGGGCCTGGAATGG 
               
               
                   
                   
                 ATGGGGTGGATTTCCGCGTACAACGGCAATACGAACTACGCTCAGAAGTTC 
               
               
                   
                   
                 CAGGGTAGAGTGACCATGACTAGGAACACCTCCATTTCCACCGCCTACATG 
               
               
                   
                   
                 GAACTGTCCTCCCTGCGGAGCGAGCACACCGCCGTGTACTATTGCGCCCGG 
               
               
                   
                   
                 GGACCATACTACTACTACATGGATGTCTGGGGGAAGGGGACTATGGTCACC 
               
               
                   
                   
                 GTGTCATCCGCCTCGGGAGGCGGCGGATCAGGAGGACGCGCCTCTGGTGGT 
               
               
                   
                   
                 GGAGGATCGGAGATCGTGATGACCCAGAGCCCTCTCTCCTTGCCCGTGACT 
               
               
                   
                   
                 CCTGGGGAGCCCGCATCCATTTCATGCCGGAGCTCCCAGTCACTTCTCTAC 
               
               
                   
                   
                 TCCAACGGCTATAACTACGTGGATTGGTACCTCCAAAAGCCGGGCCAGAGC 
               
               
                   
                   
                 CCGCAGCTGCTGATCTACCTGGGCTCGAACAGGGCCAGCGGAGTGCCTGAC 
               
               
                   
                   
                 CGGTTCTCCGGGTCGGGAAGCGGGACCGACTTCAAGCTGCAAATCTCGAGA 
               
               
                   
                   
                 GTGGAGGCCGAGGACGTGGGAATCTACTACTGTATGCAGGGCCGCCAGTTT 
               
               
                   
                   
                 CCGTACTCGTTCGGACAGGGCACCAAAGTGGAAATCAAGACCACTACCCCA 
               
               
                   
                   
                 GCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCC 
               
               
                   
                   
                 CTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGG 
               
               
                   
                   
                 GGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACT 
               
               
                   
                   
                 TGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGT 
               
               
                   
                   
                 CGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAG 
               
               
                   
                   
                 ACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAA 
               
               
                   
                   
                 GGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCC 
               
               
                   
                   
                 TACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGA 
               
               
                   
                   
                 GAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGC 
               
               
                   
                   
                 GGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAA 
               
               
                   
                   
                 AAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGC 
               
               
                   
                   
                 AGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACC 
               
               
                   
                   
                 AAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139104 
               
            
           
           
               
               
               
            
               
                 139104-aa 
                  955 
                 MALPVTALLLPLALLLHAARPEVQLLETGGGLVQPGGSLRLSCAVSGFALS 
               
               
                 Full CAR 
                   
                 NHGMSWVRRAPGKGLEWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQ 
               
               
                   
                   
                 MNSLRPEDTAIYYCSAHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGS 
               
               
                   
                   
                 EIVLTQSPATLSVSPGESATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGA 
               
               
                   
                   
                 STRASGIPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYGSSLTFGGGTK 
               
               
                   
                   
                 VEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY 
               
               
                   
                   
                 IWAPLAGTCGVLLLSVLITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCS 
               
               
                   
                   
                 CRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKR 
               
               
                   
                   
                 RGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL 
               
               
                   
                   
                 YQGLSTATKDTYDALHMQALPPR 
               
               
                 139104-nt 
                  970 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCGAAGTGCAATTGCTCGAAACTGGAGGAGGTCTGGTGCAA 
               
               
                   
                   
                 CCTGGAGGATCACTTCGCCTGTCCTGCGCCGTGTCGGGCTTTGCCCTGTCC 
               
               
                   
                   
                 AACCATGGAATGAGCTGGGTCCGCCGCGCGCCGGGGAAGGGCCTCGAATGG 
               
               
                   
                   
                 GTGTCCGGCATCGTCTACTCCGGCTCCACCTACTACGCCGCGTCCGTGAAG 
               
               
                   
                   
                 GGCCGGTTCACGATTTCACGGGACAACTCGCGGAACACCCTGTACCTCCAA 
               
               
                   
                   
                 ATGAATTCCCTTCGGCCGGAGGATACTGCCATCTACTACTGCTCCGCCCAC 
               
               
                   
                   
                 GGTGGCGAATCCGACGTCTGGGGCCAGGGAACCACCGTGACCGTGTCCAGC 
               
               
                   
                   
                 GCGTCCGGGGGAGGAGGAAGCGGGGGTAGAGCATCGGGTGGAGGCGGATCA 
               
               
                   
                   
                 GAGATCGTGCTGACCCAGTCCCCCGCCACCTTGAGCGTGTCACCAGGAGAG 
               
               
                   
                   
                 TCCGCCACCCTGTCATGCCGCGCCAGCCAGTCCGTGTCCTCCAACCTGGCT 
               
               
                   
                   
                 TGGTACCAGCAGAAGCCGGGGCAGGCCCCTAGACTCCTGATCTATGGGGCG 
               
               
                   
                   
                 TCGACCCGGGCATCTGGAATTCCCGATAGGTTCAGCGGATCGGGCTCGGGC 
               
               
                   
                   
                 ACTGACTTCACTCTGACCATCTCCTCGCTGCAAGCCGAGGACGTGGCTGTG 
               
               
                   
                   
                 TACTACTGTCAGCAGTACGGAAGCTCCCTGACTTTCGGTGGCGGGACCAAA 
               
               
                   
                   
                 GTCGAGATTAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCT 
               
               
                   
                   
                 ACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCA 
               
               
                   
                   
                 GCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTAC 
               
               
                   
                   
                 ATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTG 
               
               
                   
                   
                 ATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAG 
               
               
                   
                   
                 CAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCA 
               
               
                   
                   
                 TGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTC 
               
               
                   
                   
                 AGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTAC 
               
               
                   
                   
                 AACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGG 
               
               
                   
                   
                 AGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAA 
               
               
                   
                   
                 GAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGC 
               
               
                   
                   
                 GAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTG 
               
               
                   
                   
                 TACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATG 
               
               
                   
                   
                 CAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139106 
               
            
           
           
               
               
               
            
               
                 139106-aa 
                  956 
                 MALPVTALLLPLALLLHAARPEVQLVETGGGLVQPGGSLRLSCAVSGFALS 
               
               
                 Full CAR 
                   
                 NHGMSWVRRAPGKGLEWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQ 
               
               
                   
                   
                 MNSLRPEDTAIYYCSAHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGS 
               
               
                   
                   
                 EIVMTQSPATLSVSPGERATLSCRASQSVSSKLAWYQQKPGQAPRLLMYGA 
               
               
                   
                   
                 SIRATGIPDRFSGSGSGTEFTLTISSLEPEDFAVYYCQQYGSSSWTFGQGT 
               
               
                   
                   
                 KVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI 
               
               
                   
                   
                 YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGC 
               
               
                   
                   
                 SCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDK 
               
               
                   
                   
                 RRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDG 
               
               
                   
                   
                 LYQGLSTATKDTYDALHMQALPPR 
               
               
                 139106-nt 
                  971 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCGAAGTGCAATTGGTGGAAACTGGAGGAGGACTTGTGCAA 
               
               
                   
                   
                 CCTGGAGGATCATTGAGACTGAGCTGCGCAGTGTCGGGATTCGCCCTGAGC 
               
               
                   
                   
                 AACCATGGAATGTCCTGGGTCAGAAGGGCCCCTGGAAAAGGCCTCGAATGG 
               
               
                   
                   
                 GTGTCAGGGATCGTGTACTCCGGTTCCACTTACTACGCCGCCTCCGTGAAG 
               
               
                   
                   
                 GGGCGCTTCACTATCTCACGGGATAACTCCCGCAATACCCTGTACCTCCAA 
               
               
                   
                   
                 ATGAACAGCCTGCGGCCGGAGGATACCGCCATCTACTACTGTTCCGCCCAC 
               
               
                   
                   
                 GGTGGAGAGTCTGACGTCTGGGGCCAGGGAACTACCGTGACCGTGTCCTCC 
               
               
                   
                   
                 GCGTCCGGCGGTGGAGGGAGCGGCGGCCGCGCCAGCGGCGGCGGAGGCTCC 
               
               
                   
                   
                 GAGATCGTGATGACCCAGAGCCCCGCTACTCTGTCGGTGTCGCCCGGAGAA 
               
               
                   
                   
                 AGGGCGACCCTGTCCTGCCGGGCGTCGCAGTCCGTGAGCAGCAAGCTGGCT 
               
               
                   
                   
                 TGGTACCAGCAGAAGCCGGGCCAGGCACCACGCCTGCTTATGTACGGTGCC 
               
               
                   
                   
                 TCCATTCGGGCCACCGGAATCCCGGACCGGTTCTCGGGGTCGGGGTCCGGT 
               
               
                   
                   
                 ACCGAGTTCACACTGACCATTTCCTCGCTCGAGCCCGAGGACTTTGCCGTC 
               
               
                   
                   
                 TATTACTGCCAGCAGTACGGCTCCTCCTCATGGACGTTCGGCCAGGGGACC 
               
               
                   
                   
                 AAGGTCGAAATCAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCT 
               
               
                   
                   
                 CCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCC 
               
               
                   
                   
                 GCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATC 
               
               
                   
                   
                 TACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTC 
               
               
                   
                   
                 GTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTT 
               
               
                   
                   
                 AAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGT 
               
               
                   
                   
                 TCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAA 
               
               
                   
                   
                 TTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTC 
               
               
                   
                   
                 TACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAG 
               
               
                   
                   
                 CGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCC 
               
               
                   
                   
                 CAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTAT 
               
               
                   
                   
                 AGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGA 
               
               
                   
                   
                 CTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCAC 
               
               
                   
                   
                 ATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139107 
               
            
           
           
               
               
               
            
               
                 139107-aa 
                  957 
                 MALPVTALLLPLALLLHAARPEVQLVETGGGVVQPGGSLRLSCAVSGFALS 
               
               
                 Full CAR 
                   
                 NHGMSWVRRAPGKGLEWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQ 
               
               
                   
                   
                 MNSLRPEDTAIYYCSAHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGS 
               
               
                   
                   
                 EIVLTQSPGTLSLSPGERATLSCRASQSVGSTNLAWYQQKPGQAPRLLIYD 
               
               
                   
                   
                 ASNRATGIPDRFSGGGSGTDFTLTISRLEPEDFAVYYCQQYGSSPPWTFGQ 
               
               
                   
                   
                 GTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFAC 
               
               
                   
                   
                 DIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEED 
               
               
                   
                   
                 GCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVL 
               
               
                   
                   
                 DKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGH 
               
               
                   
                   
                 DGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 139107-nt 
                  972 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCGAAGTGCAATTGGTGGAGACTGGAGGAGGAGTGGTGCAA 
               
               
                   
                   
                 CCTGGAGGAAGCCTGAGACTGTCATGCGCGGTGTCGGGCTTCGCCCTCTCC 
               
               
                   
                   
                 AACCACGGAATGTCCTGGGTCCGCCGGGCCCCTGGGAAAGGACTTGAATGG 
               
               
                   
                   
                 GTGTCCGGCATCGTGTACTCGGGTTCCACCTACTACGCGGCCTCAGTGAAG 
               
               
                   
                   
                 GGCCGGTTTACTATTAGCCGCGACAACTCCAGAAACACACTGTACCTCCAA 
               
               
                   
                   
                 ATGAACTCGCTGCGGCCGGAAGATACCGCTATCTACTACTGCTCCGCCCAT 
               
               
                   
                   
                 GGGGGAGAGTCGGACGTCTGGGGACAGGGCACCACTGTCACTGTGTCCAGC 
               
               
                   
                   
                 GCTTCCGGCGGTGGTGGAAGCGGGGGACGGGCCTCAGGAGGCGGTGGCAGC 
               
               
                   
                   
                 GAGATTGTGCTGACCCAGTCCCCCGGGACCCTGAGCCTGTCCCCGGGAGAA 
               
               
                   
                   
                 AGGGCCACCCTCTCCTGTCGGGCATCCCAGTCCGTGGGGTCTACTAACCTT 
               
               
                   
                   
                 GCATGGTACCAGCAGAAGCCCGGCCAGGCCCCTCGCCTGCTGATCTACGAC 
               
               
                   
                   
                 GCGTCCAATAGAGCCACCGGCATCCCGGATCGCTTCAGCGGAGGCGGATCG 
               
               
                   
                   
                 GGCACCGACTTCACCCTCACCATTTCAAGGCTGGAACCGGAGGACTTCGCC 
               
               
                   
                   
                 GTGTACTACTGCCAGCAGTATGGTTCGTCCCCACCCTGGACGTTCGGCCAG 
               
               
                   
                   
                 GGGACTAAGGTCGAGATCAAGACCACTACCCCAGCACCGAGGCCACCCACC 
               
               
                   
                   
                 CCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGT 
               
               
                   
                   
                 AGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGC 
               
               
                   
                   
                 GATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTT 
               
               
                   
                   
                 TCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTAC 
               
               
                   
                   
                 ATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGAC 
               
               
                   
                   
                 GGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGC 
               
               
                   
                   
                 GTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAAC 
               
               
                   
                   
                 CAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTG 
               
               
                   
                   
                 GACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAG 
               
               
                   
                   
                 AATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAA 
               
               
                   
                   
                 GCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCAC 
               
               
                   
                   
                 GACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCT 
               
               
                   
                   
                 CTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139108 
               
            
           
           
               
               
               
            
               
                 139108-aa 
                  958 
                 MALPVTALLLPLALLLHAARPQVQLVESGGGLVKPGGSLRLSCAASGFTFS 
               
               
                 Full CAR 
                   
                 DYYMSWIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYL 
               
               
                   
                   
                 QMNSLRAEDTAVYYCARESGDGMDVWGQGTTVTVSSASGGGGSGGRASGGG 
               
               
                   
                   
                 GSDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIY 
               
               
                   
                   
                 AASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTLAFGQGT 
               
               
                   
                   
                 KVDIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI 
               
               
                   
                   
                 YIWAPLAGTCGVLLLSVLITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGC 
               
               
                   
                   
                 SCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDK 
               
               
                   
                   
                 RRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSIEGMKGERRRGHGHDG 
               
               
                   
                   
                 LYQGLSTATDKTYDALHMQALPPR 
               
               
                 139108-nt 
                  973 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCCAAGTGCAACTCGTGGAATCTGGTGGAGGACTCGTGAAA 
               
               
                   
                   
                 CCTGGAGGATCATTGAGACTGTCATGCGCGGCCTCGGGATTCACGTTCTCC 
               
               
                   
                   
                 GATTACTACATGAGCTGGATTCGCCAGGCTCCGGGGAAGGGACTGGAATGG 
               
               
                   
                   
                 GTGTCCTACATTTCCTCATCCGGCTCCACCATCTACTACGCGGACTCCGTG 
               
               
                   
                   
                 AAGGGGAGATTCACCATTAGCCGCGATAACGCCAAGAACAGCCTGTACCTT 
               
               
                   
                   
                 CAGATGAACTCCCTGCGGGCTGAAGATACTGCCGTCTACTACTGCGCAAGG 
               
               
                   
                   
                 GAGAGCGGAGATGGGATGGACGTCTGGGGACAGGGTACCACTGTGACCGTG 
               
               
                   
                   
                 TCGTCGGCCTCCGGCGGAGGGGGTTCGGGTGGAAGGGCCAGCGGCGGCGGA 
               
               
                   
                   
                 GGCAGCGACATCCAGATGACCCAGTCCCCCTCATCGCTGTCCGCCTCCGTG 
               
               
                   
                   
                 GGCGACCGCGTCACCATCACATGCCGGGCCTCACAGTCGATCTCCTCCTAC 
               
               
                   
                   
                 CTCAATTGGTATCAGCAGAAGCCCGGAAAGGCCCCTAAGCTTCTGATCTAC 
               
               
                   
                   
                 GCAGCGTCCTCCCTGCAATCCGGGGTCCCATCTCGGTTCTCCGGCTCGGGC 
               
               
                   
                   
                 AGCGGTACCGACTTCACTCTGACCATCTCGAGCCTGCAGCCGGAGGACTTC 
               
               
                   
                   
                 GCCACTTACTACTGTCAGCAAAGCTACACCCTCGCGTTTGGCCAGGGCACC 
               
               
                   
                   
                 AAAGTGGACATCAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCT 
               
               
                   
                   
                 CCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCC 
               
               
                   
                   
                 GCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATC 
               
               
                   
                   
                 TACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTC 
               
               
                   
                   
                 GTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTT 
               
               
                   
                   
                 AAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGT 
               
               
                   
                   
                 TCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAA 
               
               
                   
                   
                 TTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTC 
               
               
                   
                   
                 TACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAG 
               
               
                   
                   
                 CGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCC 
               
               
                   
                   
                 CAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTAT 
               
               
                   
                   
                 AGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGA 
               
               
                   
                   
                 CTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCAC 
               
               
                   
                   
                 ATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139110 
               
            
           
           
               
               
               
            
               
                 139110-aa 
                  960 
                 MALPVTALLLPLALLLHAARPQVQLVQSGGGLVKPGGSLRLSCAASGFTFS 
               
               
                 Full CAR 
                   
                 DYYMSWIRQPAGKGLEWVSYISSSGNTIYYADSVKGRFTISRDNAKNSLYL 
               
               
                   
                   
                 QMNSLRAEDTAVYYCARSTMVREDYWGQGTLVTVSSASGGGGSGGRASGGG 
               
               
                   
                   
                 GSDIVLTQSPLSLPVTLGQPASISCKSSESLVHNSGKTYLNWFHQRPGQSP 
               
               
                   
                   
                 RRLIYEVSNRDSGVPDRFTGSGSGTDFTLKISRVEAEDVGVYYCMQGTHWP 
               
               
                   
                   
                 GTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRG 
               
               
                   
                   
                 LDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQT 
               
               
                   
                   
                 TQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRRE 
               
               
                   
                   
                 EYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERR 
               
               
                   
                   
                 AGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 139110-nt 
                  975 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCCAAGTGCAACTGGTGCAAAGCGGAGGAGGATTGGTCAAA 
               
               
                   
                   
                 CCCGGAGGAAGCCTGAGACTGTCATGCGCGGCCTCTGGATTCACCTTCTCC 
               
               
                   
                   
                 GATTACTACATGTCATGGATCAGACAGGCCCCGGGGAAGGGCCTCGAATGG 
               
               
                   
                   
                 GTGTCCTACATCTCGTCCTCCGGGAACACCATCTACTACGCCGACAGCGTG 
               
               
                   
                   
                 AAGGGCCGCTTTACCATTTCCCGCGACAACGCAAAGAACTCGCTGTACCTT 
               
               
                   
                   
                 CAGATGAATTCCCTGCGGGCTGAAGATACCGCGGTGTACTATTGCGCCCGG 
               
               
                   
                   
                 TCCACTATGGTCCGGGAGGACTACTGGGGACAGGGCACACTCGTGACCGTG 
               
               
                   
                   
                 TCCAGCGCGAGCGGGGGTGGAGGCAGCGGTGGACGCGCCTCCGGCGGCGGC 
               
               
                   
                   
                 GGTTCAGACATCGTGCTGACTCAGTCGCCCCTGTCGCTGCCGGTCACCCTG 
               
               
                   
                   
                 GGCCAACCGGCCTCAATTAGCTGCAAGTCCTCGGAGAGCCTGGTGCACAAC 
               
               
                   
                   
                 TCAGGAAAGACTTACCTGAACTGGTTCCATCAGCGGCCTGGACAGTCCCCA 
               
               
                   
                   
                 CGGAGGCTCATCTATGAAGTGTCCAACAGGGATTCGGGGGTGCCCGACCGC 
               
               
                   
                   
                 TTCACTGGCTCCGGGTCCGGCACCGACTTCACCTTGAAAATCTCCAGAGTG 
               
               
                   
                   
                 GAAGCCGAGGACGTGGGCGTGTACTACTGTATGCAGGGTACCCACTGGCCT 
               
               
                   
                   
                 GGAACCTTTGGACAAGGAACTAAGCTCGAGATTAAGACCACTACCCCAGCA 
               
               
                   
                   
                 CCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTG 
               
               
                   
                   
                 CGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGT 
               
               
                   
                   
                 CTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGC 
               
               
                   
                   
                 GGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGG 
               
               
                   
                   
                 AAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACT 
               
               
                   
                   
                 ACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGC 
               
               
                   
                   
                 GGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTAC 
               
               
                   
                   
                 AAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAG 
               
               
                   
                   
                 GAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGG 
               
               
                   
                   
                 AAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAG 
               
               
                   
                   
                 GATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGA 
               
               
                   
                   
                 AGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAG 
               
               
                   
                   
                 GACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139112 
               
            
           
           
               
               
               
            
               
                 139112-aa 
                  961 
                 MALPVTALLLPLALLLHAARPQVQLVESGGGLVQPGGSLRLSCAVSGFALS 
               
               
                 Full CAR 
                   
                 NHGMSWVRRAPGKGLEWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQ 
               
               
                   
                   
                 MNSLRPEDTAIYYCSAHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGS 
               
               
                   
                   
                 DIRLTQSPSPLSASVGDRVTITCQASEDINKFLNWYHQTPGKAPKLLIYDA 
               
               
                   
                   
                 STLQTGVPSRFSGSGSGTDFTLTINSLQPEDIGTYYCQQYESLPLTFGGGT 
               
               
                   
                   
                 KVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI 
               
               
                   
                   
                 YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGC 
               
               
                   
                   
                 SCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDK 
               
               
                   
                   
                 RRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDG 
               
               
                   
                   
                 LYQGLSTATKDTYDALHMQALPPR 
               
               
                 139112-nt 
                  976 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCCAAGTGCAACTCGTGGAATCTGGTGGAGGACTCGTGCAA 
               
               
                   
                   
                 CCCGGTGGAAGCCTTAGGCTGTCGTGCGCCGTCAGCGGGTTTGCTCTGAGC 
               
               
                   
                   
                 AACCATGGAATGTCCTGGGTCCGCCGGGCACCGGGAAAAGGGCTGGAATGG 
               
               
                   
                   
                 GTGTCCGGCATCGTGTACAGCGGGTCAACCTATTACGCCGCGTCCGTGAAG 
               
               
                   
                   
                 GGCAGATTCACTATCTCAAGAGACAACAGCCGGAACACCCTGTACTTGCAA 
               
               
                   
                   
                 ATGAATTCCCTGCGCCCCGAGGACACCGCCATCTACTACTGCTCCGCCCAC 
               
               
                   
                   
                 GGAGGAGAGTCGGACGTGTGGGGCCAGGGAACGACTGTGACTGTGTCCAGC 
               
               
                   
                   
                 GCATCAGGAGGGGGTGGTTCGGGCGGCCGGGCCTCGGGGGGAGGAGGTTCC 
               
               
                   
                   
                 GACATTCGGCTGACCCAGTCCCCGTCCCCACTGTCGGCCTCCGTCGGCGAC 
               
               
                   
                   
                 CGCGTGACCATCACTTGTCAGGCGTCCGAGGACATTAACAAGTTCCTGAAC 
               
               
                   
                   
                 TGGTACCACCAGACCCCTGGAAAGGCCCCCAAGCTGCTGATCTACGATGCC 
               
               
                   
                   
                 TCGACCCTTCAAACTGGAGTGCCTAGCCGGTTCTCCGGGTCCGGCTCCGGC 
               
               
                   
                   
                 ACTGATTTCACTCTGACCATCAACTCATTGCAGCCGGAAGATATCGGGACC 
               
               
                   
                   
                 TACTATTGCCAGCAGTACGAATCCCTCCCGCTCACATTCGGCGGGGGAACC 
               
               
                   
                   
                 AAGGTCGAGATTAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCT 
               
               
                   
                   
                 CCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCC 
               
               
                   
                   
                 GCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATC 
               
               
                   
                   
                 TACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTC 
               
               
                   
                   
                 GTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTT 
               
               
                   
                   
                 AAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGT 
               
               
                   
                   
                 TCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAA 
               
               
                   
                   
                 TTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTC 
               
               
                   
                   
                 TACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAG 
               
               
                   
                   
                 CGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCC 
               
               
                   
                   
                 CAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTAT 
               
               
                   
                   
                 AGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGA 
               
               
                   
                   
                 CTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCAC 
               
               
                   
                   
                 ATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139113 
               
            
           
           
               
               
               
            
               
                 139113-aa 
                  962 
                 MALPVTALLLPLALLLHAARPEVQLVETGGGLVQPGGSLRLSCAVSGFALS 
               
               
                 Full CAR 
                   
                 NHGMSWVRRAPGKGLEWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQ 
               
               
                   
                   
                 MNSLRPEDTAIYYCSAHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGS 
               
               
                   
                   
                 ETTLTQSPATLSVSPGERATLSCRASQSVGSNLAWYQQKPGQGPRLLIYGA 
               
               
                   
                   
                 STRATGIPARFSGSGSGTEFTLTISSLQPEDFAVYYCQQYNDWLPVTFGQG 
               
               
                   
                   
                 TKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD 
               
               
                   
                   
                 IYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDG 
               
               
                   
                   
                 CSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLD 
               
               
                   
                   
                 KRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRKGGHD 
               
               
                   
                   
                 GLYQGLSTATKDTYDALHMQALPPR 
               
               
                 139113-nt 
                  977 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCGAAGTGCAATTGGTGGAAACTGGAGGAGGACTTGTGCAA 
               
               
                   
                   
                 CCTGGAGGATCATTGCGGCTCTCATGCGCTGTCTCCGGCTTCGCCCTGTCA 
               
               
                   
                   
                 AATCACGGGATGTCGTGGGTCAGACGGGCCCCGGGAAAGGGTCTGGAATGG 
               
               
                   
                   
                 GTGTCGGGGATTGTGTACAGCGGCTCCACCTACTACGCCGCTTCGGTCAAG 
               
               
                   
                   
                 GGCCGCTTCACTATTTCACGGGACAACAGCCGCAACACCCTCTATCTGCAA 
               
               
                   
                   
                 ATGAACTCTCTCCGCCCGGAGGATACCGCCATCTACTACTGCTCCGCACAC 
               
               
                   
                   
                 GGCGGCGAATCCGACGTGTGGGGACAGGGAACCACTGTCACCGTGTCGTCC 
               
               
                   
                   
                 GCATCCGGTGGCGGAGGATCGGGTGGCCGGGCCTCCGGGGGCGGCGGCAGC 
               
               
                   
                   
                 GAGACTACCCTGACCCAGTCCCCTGCCACTCTGTCCGTGAGCCCGGGAGAG 
               
               
                   
                   
                 AGAGCCACCCTTAGCTGCCGGGCCAGCCAGAGCGTGGGCTCCAACCTGGCC 
               
               
                   
                   
                 TGGTACCAGCAGAAGCCAGGACAGGGTCCCAGCCTGCTGATCTACGGAGCC 
               
               
                   
                   
                 TCCACTCGCGCGACCGGCATCCCCGCGAGGTTCTCCGGGTCGGGTTCCGGG 
               
               
                   
                   
                 ACCGAGTTCACCCTGACCATCTCCTCCCTCCAACCGGAGGACTTCGCGGTG 
               
               
                   
                   
                 TACTACTGTCAGCAGTACAACGATTGGCTGCCCGTGACATTTGGACAGGGG 
               
               
                   
                   
                 ACGAAGGTGGAAATCAAAACCACTACCCCAGCACCGAGGCCACCCACCCCG 
               
               
                   
                   
                 GCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGA 
               
               
                   
                   
                 CCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGAT 
               
               
                   
                   
                 ATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCA 
               
               
                   
                   
                 CTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATC 
               
               
                   
                   
                 TTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGC 
               
               
                   
                   
                 TGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTG 
               
               
                   
                   
                 AAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAG 
               
               
                   
                   
                 CTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGAC 
               
               
                   
                   
                 AAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAAT 
               
               
                   
                   
                 CCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCC 
               
               
                   
                   
                 TATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGAC 
               
               
                   
                   
                 GGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTT 
               
               
                   
                   
                 CACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 139114 
               
            
           
           
               
               
               
            
               
                 139114-aa 
                  963 
                 MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAVSGFALS 
               
               
                 Full CAR 
                   
                 NHGMSWVRRAPGKGLEWVSGIVYSGSTYYAASVKGRFTISRDNSRNTLYLQ 
               
               
                   
                   
                 MNSLRPEDTAIYYCSAHGGESDVWGQGTTVTVSSASGGGGSGGRASGGGGS 
               
               
                   
                   
                 EIVLTQSPGTLSLSPGERATLSCRASQSIGSSSLAWYQQKPGQAPRLLMYG 
               
               
                   
                   
                 ASSRASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYAGSPPFTFGQ 
               
               
                   
                   
                 GTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFAC 
               
               
                   
                   
                 DIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEED 
               
               
                   
                   
                 GCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVL 
               
               
                   
                   
                 DKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGH 
               
               
                   
                   
                 DGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 139114-nt 
                  978 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCGAAGTGCAATTGGTGGAATCTGGTGGAGGACTTGTGCAA 
               
               
                   
                   
                 CCTGGAGGATCACTGAGACTGTCATGCGCGGTGTCCGGTTTTGCCCTGAGC 
               
               
                   
                   
                 AATCATGGGATGTCGTGGGTCCGGCGCGCCCCCGGAAAGGGTCTGGAATGG 
               
               
                   
                   
                 GTGTCGGGTATCGTCTACTCCGGGAGCACTTACTACGCCGCGAGCGTGAAG 
               
               
                   
                   
                 GGCCGCTTCACCATTTCCCGCGATAACTCCCGCAACACCCTGTACTTGCAA 
               
               
                   
                   
                 ATGAACTCGCTCCGGCCTGAGGACACTGCCATCTACTACTGCTCCGCACAC 
               
               
                   
                   
                 GGAGGAGAATCCGACGTGTGGGGCCAGGGAACTACCGTGACCGTCAGCAGC 
               
               
                   
                   
                 GCCTCCGGCGGCGGGGGCTCAGGCGGACGGGCTAGCGGCGGCGGTGGCTCC 
               
               
                   
                   
                 GAGATCGTGCTGACCCAGTCGCCTGGCACTCTCTCGCTGAGCCCCGGGGAA 
               
               
                   
                   
                 AGGGCAACCCTGTCCTGTCGGGCCAGCCAGTCCATTGGATCATCCTCCCTC 
               
               
                   
                   
                 GCCTGGTATCAGCAGAAACCGGGACAGGCTCCGCGGCTGCTTATGTATGGG 
               
               
                   
                   
                 GCCAGCTCAAGAGCCTCCGGCATTCCCGACCGGTTCTCCGGGTCCGGTTCC 
               
               
                   
                   
                 GGCACCGATTTCACCCTGACTATCTCGAGGCTGGAGCCAGAGGACTTCGCC 
               
               
                   
                   
                 GTGTACTACTGCCAGCAGTACGCGGGGTCCCCGCCGTTCACGTTCGGACAG 
               
               
                   
                   
                 GGAACCAAGGTCGAGATCAAGACCACTACCCCAGCACCGAGGCCACCCACC 
               
               
                   
                   
                 CCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGT 
               
               
                   
                   
                 AGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGC 
               
               
                   
                   
                 GATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTT 
               
               
                   
                   
                 TCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTAC 
               
               
                   
                   
                 ATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGAC 
               
               
                   
                   
                 GGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGC 
               
               
                   
                   
                 GTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAAC 
               
               
                   
                   
                 CAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTG 
               
               
                   
                   
                 GACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAG 
               
               
                   
                   
                 AATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAA 
               
               
                   
                   
                 GCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCAC 
               
               
                   
                   
                 GACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCT 
               
               
                   
                   
                 CTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 149362 
               
            
           
           
               
               
               
            
               
                 149362-aa 
                  979 
                 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGGSIS 
               
               
                 Full CAR 
                   
                 SSYYYWGQIRQPPGKGLEWIGSIYYSGSAYYNPSLKSRVTISVDTSKNQFS 
               
               
                   
                   
                 LRLSSVTAADTAVYYCARHWQEWPDAFDIWGQGTMVTVSSGGGGSGGGGSG 
               
               
                   
                   
                 GGGSETTLTQSPAFMSATPGDKVIISCKASQDIDDAMNWYQQKPGEAPLFI 
               
               
                   
                   
                 IQSATSPVPGIPPRFSGSGFGTDFSLTINNIESEDAAYYFCLQHDNFPLTF 
               
               
                   
                   
                 GQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDF 
               
               
                   
                   
                 ACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQE 
               
               
                   
                   
                 EDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYD 
               
               
                   
                   
                 VLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGK 
               
               
                   
                   
                 GHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 149362-nt 
                 1001 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCCAAGTGCAGCTTCAGGAAAGCGGACCGGGCCTGGTCAAG 
               
               
                   
                   
                 CCATCCGAAACTCTCTCCCTGACTTGCACTGTGTCTGGCGGTTCCATCTCA 
               
               
                   
                   
                 TCGTCGTACTACTACTGGGGCTGGATTAGGCAGCCGCCCGGAAAGGGACTG 
               
               
                   
                   
                 GAGTGGATCGGAAGCATCTACTATTCCGGCTCGGCGTACTACAACCCTAGC 
               
               
                   
                   
                 CTCAAGTCGAGAGTGCACCATCTCCGTGGATACCTCCAAGAACCAGTTTCC 
               
               
                   
                   
                 CTGCGCCTGAGCTCCGTGACCGCCGCTGACACCGCCGTGTACTACTGTGCT 
               
               
                   
                   
                 CGGCATTGGCAGGAATGGCCCGATGCCTTCGACATTTGGGGCCAGGGCACT 
               
               
                   
                   
                 ATGGTCACTGTGTCATCCGGGGGTGGAGGCAGCGGGGGAGGAGGGTCCGGG 
               
               
                   
                   
                 GGGGGAGGTTCAGAGACAACCTTGACCCAGTCACCCGCATTCATGTCCGCC 
               
               
                   
                   
                 ACTCCGGGAGACAAGGTCATCATCTCGTGCAAAGCGTCCCAGGATATCGAC 
               
               
                   
                   
                 GATGCCATGAATTGGTACCAGCAGAAGCCTGGCGAAGCGCCGCTGTTCATT 
               
               
                   
                   
                 ATCCAATCCGCAACCTCGCCCGTGCCTGGAATCCCACCGCGGTTCAGCGGC 
               
               
                   
                   
                 AGCGGTTTCGGAACCGACTTTTCCCTGACCATTAACAACATTGAGTCCGAG 
               
               
                   
                   
                 GACGCCGCCTACTACTTCTGCCTGCAACACGACAACTTCCCTCTCACGTTC 
               
               
                   
                   
                 GGCCAGGGAACCAAGCTGGAAATCAAGACCACTACCCCAGCACCGAGGCCA 
               
               
                   
                   
                 CCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAG 
               
               
                   
                   
                 GCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTC 
               
               
                   
                   
                 GCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTG 
               
               
                   
                   
                 CTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTG 
               
               
                   
                   
                 CTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAG 
               
               
                   
                   
                 GAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAA 
               
               
                   
                   
                 CTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGG 
               
               
                   
                   
                 CAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGAC 
               
               
                   
                   
                 GTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGC 
               
               
                   
                   
                 AGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATG 
               
               
                   
                   
                 GCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAA 
               
               
                   
                   
                 GGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTAT 
               
               
                   
                   
                 GACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 149363 
               
            
           
           
               
               
               
            
               
                 149363-aa 
                  980 
                 MALPVTALLLPLALLLHAARPQVNLRESGPALVKPTQTLTLTCTFSGFSLR 
               
               
                 Full CAR 
                   
                 TSGMCVSWIRQPPGKALEWLARIDWDEDKFYSTSLKTRLTISKDTSDVQVV 
               
               
                   
                   
                 LRMTNMDPADTATYYCARSGAGGTSATAFDIWGPGTMVTVSSGGGGSGGGG 
               
               
                   
                   
                 SGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIYNNLAWFQLKPGSAPR 
               
               
                   
                   
                 SLMYAANKSQSGVPSRFSGSASGTDFTLTISSLQPEDFATYYCQHYYRFPY 
               
               
                   
                   
                 SFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGL 
               
               
                   
                   
                 DFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTT 
               
               
                   
                   
                 QEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREE 
               
               
                   
                   
                 YDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRR 
               
               
                   
                   
                 GKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 149363-nt 
                 1002 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCCAAGTCAATCTGCGCGAATCCGGCCCCGCCTTGGTCAAG 
               
               
                   
                   
                 CCTACCCAGACCCTCACTCTGACCTGTACTTTCTCCGGCTTCTCCCTGCGG 
               
               
                   
                   
                 ACTTCCGGGATGTGCGTGTCCTGGATCAGACAGCCTCCGGGAAAGGCCCTG 
               
               
                   
                   
                 GAGTGGCTCGCTCGCATTGACTGGGATGAGGACAAGTTCTACTCCACCTCA 
               
               
                   
                   
                 CTCAAGACCAGGCTGACCATCAGCAAAGATACCTCTGACAACCAAGTGGTG 
               
               
                   
                   
                 CTCCGCATGACCAACATGGACCCAGCCGACACTGCCACTTACTACTGCGCG 
               
               
                   
                   
                 AGGAGCGGAGCGGGCGGAACCTCCGCCACCGCCTTCGATATTTGGGGCCCG 
               
               
                   
                   
                 GGTACCATGGTCACCGTGTCAAGCGGAGGAGGGGGGTCCGGGGGCGGCGGT 
               
               
                   
                   
                 TCCGGGGGAGGCGGATCGGACATTCAGATGACTCAGTCACCATCGTCCCTG 
               
               
                   
                   
                 AGCGCTAGCGTGGGCGACAGAGTGACAATCACTTGCCGGGCATCCCAGGAC 
               
               
                   
                   
                 ATCTATAACAACCTTGCGTGGTTCCAGCTGAAGCCTGGTTCCGCACCGCGG 
               
               
                   
                   
                 TCACTTATGTACGCCGCCAACAAGAGCCAGTCGGGAGTGCCGTGCCCGGTT 
               
               
                   
                   
                 TCCGGTTCGGCCTCGGGAACTGACTTCACCCTGACGATCTCCAGCCTGCAA 
               
               
                   
                   
                 CCCGAGGATTTCGCCACCTACTACTGCCAGCACTACTACCGCTTTCCCTAC 
               
               
                   
                   
                 TCGTTCGGACAGGGAACCAAGCTGGAAATCAAGACCACTACCCCAGCACCG 
               
               
                   
                   
                 AGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGT 
               
               
                   
                   
                 CCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTT 
               
               
                   
                   
                 GACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGG 
               
               
                   
                   
                 GTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAG 
               
               
                   
                   
                 AAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACT 
               
               
                   
                   
                 CAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGC 
               
               
                   
                   
                 TGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAG 
               
               
                   
                   
                 CAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAG 
               
               
                   
                   
                 TACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAG 
               
               
                   
                   
                 CCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGAT 
               
               
                   
                   
                 AAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGA 
               
               
                   
                   
                 GGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGAC 
               
               
                   
                   
                 ACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 149364 
               
            
           
           
               
               
               
            
               
                 149364-aa 
                  981 
                 MALPVTALLLPLALLLHAARPEVQLVESGGGLVKPGGSLRLSCAASGFTFS 
               
               
                 Full CAR 
                   
                 SYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRFTISRDNAKNSLYL 
               
               
                   
                   
                 QMNSLRAEDTAVYYCAKTIAAVYAFDIWGQGTTVTVSSGGGGSGGGGSGGG 
               
               
                   
                   
                 GSEIVLTQSPLSLPVTPEEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSP 
               
               
                   
                   
                 QLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTP 
               
               
                   
                   
                 YTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRG 
               
               
                   
                   
                 LDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQT 
               
               
                   
                   
                 TQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRRE 
               
               
                   
                   
                 EYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERR 
               
               
                   
                   
                 RGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 149364-nt 
                 1003 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCGAAGTGCAGCTTGTCGAATCCGGGGGGGGACTGGTCAAG 
               
               
                   
                   
                 CCGGGCGGATCACTGAGACTGTCCTGCGCCGCGAGCGGCTTCACGTTCTCC 
               
               
                   
                   
                 TCCTACTCCATGAACTGGGTCCGCCAAGCCCCCGGGAAGGGACTGGAATGG 
               
               
                   
                   
                 GTGTCCTCTATCTCCTCGTCGTCGTCCTACATCTACTACGCCGACTCCGTG 
               
               
                   
                   
                 AAGGGAAGATTCACCATTTCCCGCGACAACGCAAAGAACTCACTGTACTTG 
               
               
                   
                   
                 CAAATGAACTCACTCCGGGCCGAAGATACTGCTGTGTACTATTGCGCCAAG 
               
               
                   
                   
                 ACTATTGCCGCCGTCTACGCTTTCGACATCTGGGGCCAGGGAACCACCGTG 
               
               
                   
                   
                 ACTGTGTCGTCCGGTGGTGGTGGCTCGGGCGGAGGAGGAAGCGGCGGCGGG 
               
               
                   
                   
                 GGGTCCGAGATTGTGCTGACCCAGTCGCCACTGAGCCTCCCTGTGACCCCC 
               
               
                   
                   
                 GAGGAACCCGCCAGCATCAGCTGCCGGTCCAGCCAGTCCCTGCTCCACTCC 
               
               
                   
                   
                 AACGGATACAATTACCTCGATTGGTACCTTCAGAAGCCTGGACAAAGCCCG 
               
               
                   
                   
                 CAGCTGCTCATCTACTTGGGATCAAACCGCGCGTCAGGAGTGCCTGACCGG 
               
               
                   
                   
                 TTCTCCGGCTCGGGCAGCGGTACCGATTTCACCCTGAAAATCTCCAGGGTG 
               
               
                   
                   
                 GAGGCAGAGGACGTGGGAGTGTATTACTGTATGCAGGCGCTGCAGACTCCG 
               
               
                   
                   
                 TACACATTTGGGCAGGGCACCAAGCTGGAGATCAAGACCACTACCCCAGCA 
               
               
                   
                   
                 CCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTG 
               
               
                   
                   
                 CGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGT 
               
               
                   
                   
                 CTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGC 
               
               
                   
                   
                 GGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGG 
               
               
                   
                   
                 AAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACT 
               
               
                   
                   
                 ACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGC 
               
               
                   
                   
                 GGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTAC 
               
               
                   
                   
                 AAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAG 
               
               
                   
                   
                 GAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGG 
               
               
                   
                   
                 AAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAG 
               
               
                   
                   
                 GATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGA 
               
               
                   
                   
                 AGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAG 
               
               
                   
                   
                 GACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 149365 
               
            
           
           
               
               
               
            
               
                 149365-aa 
                  982 
                 MALPVTALLLPLALLLHAARPEVQLVESGGGLVKPGGSLRLSCAASGFTFS 
               
               
                 Full CAR 
                   
                 DYYMSWIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYL 
               
               
                   
                   
                 QMNSLRAEDTAVYYCARDLRGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGS 
               
               
                   
                   
                 SYVLTQSPSVSAAPGYTATISCGGNNIGTKSVHWYQQKPGQAPLLVIRDDS 
               
               
                   
                   
                 VRPSKIPGRFSGSNSGNMATLTISGVQAGDEADFYCQVWDSDSEHVVFGGG 
               
               
                   
                   
                 TKLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD 
               
               
                   
                   
                 IYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDG 
               
               
                   
                   
                 CSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNLENLGRREEYDVLD 
               
               
                   
                   
                 KRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHD 
               
               
                   
                   
                 GLYGGLSTATKDTYDALHMQALPPR 
               
               
                 149365-nt 
                 1004 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCGAAGTCCAGCTCGTGGAGTCCGGCGGAGGCCTTGTGAAG 
               
               
                   
                   
                 CCTGGAGGTTCGCTGAGACTGTCCTGCGCCGCCTCCGGCTTCACCTTCTCC 
               
               
                   
                   
                 GACTACTACATGTCCTGGATCAGACAGGCCCCGGGAAAGGGCCTGGAATGG 
               
               
                   
                   
                 GTGTCCTACATCTCGTCATCGGGCAGCACTATCTACTACGCGGACTCAGTG 
               
               
                   
                   
                 AAGGGGCGGTTCACCATTTCCCGGGATAACGCGAAGAACTCGCTGTATCTG 
               
               
                   
                   
                 CAAATGAACTCACTGAGGGCCGAGGACACCGCCGTGTACTACTGCGCCCGC 
               
               
                   
                   
                 GATCTCCGCGGGGCATTTGACATCTGGGGACAGGGAACCATGGTCACAGTG 
               
               
                   
                   
                 TCCAGCGGAGGGGGAGGATCGGGTGGCGGAGGTTCCGGGGGTGGAGGCTCC 
               
               
                   
                   
                 TCCTACGTGCTGACTCAGAGCCCAAGCGTCAGCGCTGCGCCCGGTTACACG 
               
               
                   
                   
                 GCAACCATCTCCTGTGGCGGAAACAACATTGGGACCAAGTCTGTGCACTGG 
               
               
                   
                   
                 TATCAGCAGAAGCCGGGCCAAGCTCCCCTGTTGGTGATCCGCGATGACTCC 
               
               
                   
                   
                 GTGCGGCCTAGCAAAATTCCGGGACGGTTCTCCGGCTCCAACAGCGGCAAT 
               
               
                   
                   
                 ATGGCCACTCTCACCATCTCGGGAGTGCAGGCCGGAGATGAAGCCGACTTC 
               
               
                   
                   
                 TACTGCCAAGTCTGGGACTCAGACTCCGAGCATGTGGTGTTCGGGGGCGGA 
               
               
                   
                   
                 ACCAAGCTGACTGTGCTCACCACTACCCCAGCACCGAGGCCACCCACCCCG 
               
               
                   
                   
                 GCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGA 
               
               
                   
                   
                 CCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGAT 
               
               
                   
                   
                 ATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCA 
               
               
                   
                   
                 CTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATC 
               
               
                   
                   
                 TTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGC 
               
               
                   
                   
                 TGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTG 
               
               
                   
                   
                 AAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAG 
               
               
                   
                   
                 CTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGAC 
               
               
                   
                   
                 AAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAAT 
               
               
                   
                   
                 CCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCC 
               
               
                   
                   
                 TATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGAC 
               
               
                   
                   
                 GGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTT 
               
               
                   
                   
                 CACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 149366 
               
            
           
           
               
               
               
            
               
                 149366-aa 
                  983 
                 MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGASVKVSCKPSGYTVT 
               
               
                 Full CAR 
                   
                 SHYIHWVRRAPGQGLEWMGMINPSGGVTAYSQTLQGRVTMTSDTSSSTVYM 
               
               
                   
                   
                 ELSSLRSEDTAMYYCAREGSGSGWYFDFWGRGTLVTVSSGGGGSGGGGSGG 
               
               
                   
                   
                 GGSSYVLTQPPSVSVSPGQTASITCSGDGLSKKYVSWYQQKAGQSPVVLIS 
               
               
                   
                   
                 RDKERPSGIPDRFSGSNSADTATLTISGTQAMDEADYYCQAWDDTTVVFGG 
               
               
                   
                   
                 GTKLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFAC 
               
               
                   
                   
                 DIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEED 
               
               
                   
                   
                 GCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVL 
               
               
                   
                   
                 DKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGH 
               
               
                   
                   
                 DGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 149366-nt 
                 1005 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCCAAGTGCAGCTGGTGCAGAGCGGGGCCGAAGTCAAGAAG 
               
               
                   
                   
                 CCGGGAGCCTCCGTGAAAGTGTCCTGCAAGCCTTCGGGATACACCGTGACC 
               
               
                   
                   
                 TCCCACTACATTCATTGGGTCCGCCGCGCCCCCGGCCAAGGACTCGAGTGG 
               
               
                   
                   
                 ATGGGCATGATCAACCCTAGCGGCGGAGTGACCGCGTACAGCCAGACGCTG 
               
               
                   
                   
                 CAGGGACGCGTGACTATGACCTCGGATACCTCCTCCTCCACCGTCTATATG 
               
               
                   
                   
                 GAACTGTCCAGCCTGCGGTCCGAGGATACCGCCATGTACTACTGCGCCCGG 
               
               
                   
                   
                 GAAGGATCAGGCTCCGGGTGGTATTTCGACTTCTGGGGAAGAGGCACCCTC 
               
               
                   
                   
                 GTGACTGTGTCATCTGGGGGAGGGGGTTCCGGTGGTGGCGGATCGGGAGGA 
               
               
                   
                   
                 GGCGGTTCATCCTACGTGCTGACCCAGCCACCCTCCGTGTCCGTGAGCCCC 
               
               
                   
                   
                 GGCCAGACTGCATCGATTACATGTAGCGGCGACGGCCTCTCCAAGAAATAC 
               
               
                   
                   
                 GTGTCGTGGTACCAGCAGAAGGCCGGACAGAGCCCGGTGGTGCTGATCTCA 
               
               
                   
                   
                 AGAGATAAGGAGCGGCCTAGCGGAATCCCGGACAGGTTCTCGGGTTCCAAC 
               
               
                   
                   
                 TCCGCGGACACTGCTACTCTGACCATCTCGGGGACCCAGGCTATGGACGAA 
               
               
                   
                   
                 GCCGATTACTACTGCCAAGCCTGGGACGACACTACTGTCGTGTTTGGAGGG 
               
               
                   
                   
                 GGCACCAAGTTGACCGTCCTTACCACTACCCCAGCACCGAGGCCACCCACC 
               
               
                   
                   
                 CCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGT 
               
               
                   
                   
                 AGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGC 
               
               
                   
                   
                 GATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTT 
               
               
                   
                   
                 TCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTAC 
               
               
                   
                   
                 ATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGAC 
               
               
                   
                   
                 GGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGC 
               
               
                   
                   
                 GTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAAC 
               
               
                   
                   
                 CAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTG 
               
               
                   
                   
                 GACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAG 
               
               
                   
                   
                 AATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAA 
               
               
                   
                   
                 GCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCAC 
               
               
                   
                   
                 GACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCT 
               
               
                   
                   
                 CTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 149367 
               
            
           
           
               
               
               
            
               
                 149367-aa 
                  984 
                 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSQTLSLTCTVSGGSIS 
               
               
                 Full CAR 
                   
                 SGGYYWSWIRQHPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFS 
               
               
                   
                   
                 LKLSSVTAADTAVYYCARAGIAARLRGAFDIWGQGTMVTVSSGGGGSGGGG 
               
               
                   
                   
                 SGGGGSDIVMTQSPSSVSASVGDRVIITCRASQGIRNWLAWYQQKPGKAPN 
               
               
                   
                   
                 LLIYAASNLQSGVPSRFSGSGSGADFTLTISSLQPEDVATYYCQKYNSAPF 
               
               
                   
                   
                 TFGPGTKVDIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGL 
               
               
                   
                   
                 DFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTT 
               
               
                   
                   
                 QEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREE 
               
               
                   
                   
                 YDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRR 
               
               
                   
                   
                 GKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 149367-nt 
                 1006 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCCAAGTGCAGCTTCAGGAGAGCGGCCCGGGACTCGTGAAG 
               
               
                   
                   
                 CCGTCCCAGACCCTGTCCCTGACTTGCACCGTGTCGGGAGGAAGCATCTCG 
               
               
                   
                   
                 AGCGGAGGCTACTATTGGTCGTGGATTCGGCAGCACCCTGGAAAGGGCCTG 
               
               
                   
                   
                 GAATGGATCGGCTACATCTACTACTCCGGCTCGACCTACTACAACCCATCG 
               
               
                   
                   
                 CTGAAGTCCAGAGTGACAATCTCAGTGGACACGTCCAAGAATCAGTTCAGC 
               
               
                   
                   
                 CTGAAGCTCTCTTCCGTGACTGCGGCCGACACCGCCGTGTACTACTGCGCA 
               
               
                   
                   
                 CGCGCTGGAATTGCCGCCCGGCTGAGGGGTGCCTTCGACATTTGGGGACAG 
               
               
                   
                   
                 GGCACCATGGTCACCGTGTCCTCCGGCGGCGGAGGTTCCGGGGGTGGAGGC 
               
               
                   
                   
                 TCAGGAGGAGGGGGGTCCGACATCGTCATGACTCAGTCGCCCTCAAGCGTC 
               
               
                   
                   
                 AGCGCGTCCGTCGGGGACAGAGTGATCATCACCTGTCGGGCGTCCCAGGGA 
               
               
                   
                   
                 ATTCGCAACTGGCTGGCCTGGTATCAGCAGAAGCCCGGAAAGGCCCCCAAC 
               
               
                   
                   
                 CTGTTGATCTACGCCGCCTCAAACCTCCAATCCGGGGTGCCGAGCCGCTTC 
               
               
                   
                   
                 AGCGGCTCCGGTTCGGGTGCCGATTTCACTCTGACCATCTCCTCCCTGCAA 
               
               
                   
                   
                 CCTGAAGATGTGGCTACCTACTACTGCCAAAAGTACAACTCCGCACCTTTT 
               
               
                   
                   
                 ACTTTCGGACCGGGGACCAAAGTGGACATTAAGACCACTACCCCAGCACCG 
               
               
                   
                   
                 AGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGT 
               
               
                   
                   
                 CCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTT 
               
               
                   
                   
                 GACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGG 
               
               
                   
                   
                 GTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAG 
               
               
                   
                   
                 AAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACT 
               
               
                   
                   
                 CAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGC 
               
               
                   
                   
                 TGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAG 
               
               
                   
                   
                 CAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAG 
               
               
                   
                   
                 TACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAG 
               
               
                   
                   
                 CCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGAT 
               
               
                   
                   
                 AAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGA 
               
               
                   
                   
                 GGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGAC 
               
               
                   
                   
                 ACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 149368 
               
            
           
           
               
               
               
            
               
                 149368-aa 
                  985 
                 MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGSSVKVSCKASGGTFS 
               
               
                 Full CAR 
                   
                 SYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYM 
               
               
                   
                   
                 ELSSLRSEDTAVYYCARRGGYQLLRWDVGLLRSAFDIWGQGTMVTVSSGGG 
               
               
                   
                   
                 GSGGGGSGGGGSSYVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKP 
               
               
                   
                   
                 GQAPVLVLYGKNNRPSGVPDRFSGSRSGTTASLTITGAQAEDEADYYCSSR 
               
               
                   
                   
                 DSSGDHLRVFGTGTKVTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAG 
               
               
                   
                   
                 GAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQP 
               
               
                   
                   
                 FMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNE 
               
               
                   
                   
                 LNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEI 
               
               
                   
                   
                 GMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 149368-nt 
                 1007 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCCAAGTGCAGCTGGTCCAGTCGGGCGCCGAGGTCAAGAAG 
               
               
                   
                   
                 CCCGGGAGCTCTGTGAAAGTGTCCTGCAAGGCCTCCGGGGGCACCTTTAGC 
               
               
                   
                   
                 TCCTACGCCATCTCCTGGGTCCGCCAAGCACCGGGTCAAGGCCTGGAGTGG 
               
               
                   
                   
                 ATGGGGGGAATTATCCCTATCTTCGGCACTGCCAACTACGCCCAGAAGTTC 
               
               
                   
                   
                 CAGGGACGCGTGACCATTACCGCGGACGAATCCACCTCCACCGCTTATATG 
               
               
                   
                   
                 GAGCTGTCCAGCTTGCGCTCGGAAGATACCGCCGTGTACTACTGCGCCCGG 
               
               
                   
                   
                 AGGGGTGGATACCAGCTGCTGAGATGGGACGTGGGCCTCCTGCGGTCGGCG 
               
               
                   
                   
                 TTCGACATCTGGGGCCAGGGCACTATGGTCACTGTGTCCAGCGGAGGAGGC 
               
               
                   
                   
                 GGATCGGGAGGCGGCGGATCAGGGGGAGGCGGTTCCAGCTACGTGCTTACT 
               
               
                   
                   
                 CAACCCCCTTCGGTGTCCGTGGCCCCGGGACAGACCGCCAGAATCACTTGC 
               
               
                   
                   
                 GGAGGAAACAACATTGGGTCCAAGAGCGTGCATTGGTACCAGCAGAAGCCA 
               
               
                   
                   
                 GGACAGGCCCCTGTGCTGGTGCTCTACGGGAAGAACAATCGGCCCAGCGGA 
               
               
                   
                   
                 GTGCCGGACAGGTTCTCGGGTTCACGCTCCGGTACAACCGCTTCACTGACT 
               
               
                   
                   
                 ATCACCGGGGCCCAGGCAGAGGATGAAGCGGACTACTACTGTTCCTCCCGG 
               
               
                   
                   
                 GATTCATCCGGCGACCACCTCCGGGTGTTCGGAACCGGAACGAAGGTCACC 
               
               
                   
                   
                 GTGCTGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATC 
               
               
                   
                   
                 GCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGT 
               
               
                   
                   
                 GGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGG 
               
               
                   
                   
                 GCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACT 
               
               
                   
                   
                 CTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCC 
               
               
                   
                   
                 TTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGG 
               
               
                   
                   
                 TTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGC 
               
               
                   
                   
                 AGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAA 
               
               
                   
                   
                 CTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGA 
               
               
                   
                   
                 CGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGC 
               
               
                   
                   
                 CTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATT 
               
               
                   
                   
                 GGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAG 
               
               
                   
                   
                 GGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCC 
               
               
                   
                   
                 CTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 149369 
               
            
           
           
               
               
               
            
               
                 149369-aa 
                  986 
                 MALPVTALLLPLALLLHAARPEVQLQQSGPGLVKPSQTLSLTCAISGDSVS 
               
               
                 Full CAR 
                   
                 SNSAAWNWIRQSPSRGLEWLGRTYYRSKWYSFYAISLKSRIIINPDTSKNQ 
               
               
                   
                   
                 FSLQLKSVTPEDTAVYYCARSSPEGLFLYWFDPWGQGTLVTVSSGGDGSGG 
               
               
                   
                   
                 GGSGGGGSSSELTQDPAVSVALGQTIRITCQGDSLGNYYATWYQQKPGQAP 
               
               
                   
                   
                 VLVIYGTNNRPSGIPDRFSASSSGNTASLTITGAQAEDEADYYCNSRDSSG 
               
               
                   
                   
                 HHLLFGTGTKVTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHT 
               
               
                   
                   
                 RGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPV 
               
               
                   
                   
                 QTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGR 
               
               
                   
                   
                 REEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGE 
               
               
                   
                   
                 RRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 149369-nt 
                 1008 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 Full CAR 
                   
                 GCCGCTCGGCCCGAAGTGCAGCTCCAACAGTCAGGACCGGGGCTCGTGAAG 
               
               
                   
                   
                 CCATCCCAGACCCTGTCCCTGACTTGTGCCATCTCGGGAGATAGCGTGTCA 
               
               
                   
                   
                 TCGAACTCCGCCGCCTGGAACTGGATTCGGCAGAGCCCGTCCCGCGGACTG 
               
               
                   
                   
                 GAGTGGCTTGGAAGGACCTACTACCGGTCCAAGTGGTACTCTTTCTACGCG 
               
               
                   
                   
                 ATCTCGCTGAAGTCCCGCATTATCATTAACCCTGATACCTCCAAGAATCAG 
               
               
                   
                   
                 TTCTCCCTCCAACTGAAATCCGTCACCCCCGAGGACACAGCAGTGTATTAC 
               
               
                   
                   
                 TGCGCACGGAGCAGCCCCGAAGGACTGTTCCTGTATTGGTTTGACCCCTGG 
               
               
                   
                   
                 GGCCAGGGGACTCTTGTGACCGTGTCGAGCGGCGGAGATGGGTCCGGTGGC 
               
               
                   
                   
                 GGTGGTTCGGGGGGCGGCGGATCATCATCCGAACTGACCCAGGACCCGGCT 
               
               
                   
                   
                 GTGTCCGTGGCGCTGGGACAAACCATCCGCATTACGTGCCAGGGAGACTCC 
               
               
                   
                   
                 CTGGGCAACTACTACGCCACTTGGTACCAGCAGAAGCCGGGCCAAGCCCCT 
               
               
                   
                   
                 GTGTTGGTCATCTACGGGACCAACAACAGACCTTCCGGCATCCCCGACCGG 
               
               
                   
                   
                 TTCAGCGCTTCGTCCTCCGGCAACACTGCCAGCCTGACCATCACTGGAGCG 
               
               
                   
                   
                 CAGGCCGAAGATGAGGCCGACTACTACTGCAACAGCAGAGACTCCTCGGGT 
               
               
                   
                   
                 CATCACCTCTTGTTCGGAACTGGAACCAAGGTCACCGTGCTGACCACTACC 
               
               
                   
                   
                 CCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTG 
               
               
                   
                   
                 TCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACC 
               
               
                   
                   
                 CGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGT 
               
               
                   
                   
                 ACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGC 
               
               
                   
                   
                 GGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTG 
               
               
                   
                   
                 CAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAG 
               
               
                   
                   
                 GAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCA 
               
               
                   
                   
                 GCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCATTCTTGGTCGG 
               
               
                   
                   
                 AGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATG 
               
               
                   
                   
                 GGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTC 
               
               
                   
                   
                 CAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAA 
               
               
                   
                   
                 CGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCC 
               
               
                   
                   
                 ACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-A4 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                  987 
                 MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGFTFS 
               
               
                 C1978-A4-aa 
                   
                 SYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYL 
               
               
                 Full CART 
                   
                 QMNSLRAEDTAVYYCAKVEGSGSLDYWGQGTLVTVSSGGGGSGGGGSGGGG 
               
               
                   
                   
                 SEIVMTQSPGTLSLSPGERATLSCRASQSVSSAYLAWYQQKPGQPPRLLIS 
               
               
                   
                   
                 GASTRATGIPDRFGGSGSGTDFTLTISRLEPEDFAVYYCQHYGSSFNGSSL 
               
               
                   
                   
                 FTFGQGTRLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRG 
               
               
                   
                   
                 LDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQT 
               
               
                   
                   
                 TQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRRE 
               
               
                   
                   
                 EYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERR 
               
               
                   
                   
                 RGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 BCMA_EBB- 
                 1009 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 C1978-A4-nt 
                   
                 GCCGCTCGGCCCGAAGTGCAGCTCGTGGAGTCAGGAGGCGGCCTGGTCCAG 
               
               
                 Full CART 
                   
                 CCGGGAGGGTCCCTTAGACTGTCATGCGCCGCAAGCGGATTCACTTTCTCC 
               
               
                   
                   
                 TCCTATGCCATGAGCTGGGTCCGCCAAGCCCCCGGAAAGGGACTGGAATGG 
               
               
                   
                   
                 GTGTCCGCCATCTCGGGGTCTGGAGGCTCAACTTACTACGCTGACTCCGTG 
               
               
                   
                   
                 AAGGGACGGTTCACCATTAGCCGCGACAACTCCAAGAACACCCTCTACCTC 
               
               
                   
                   
                 CAAATGAACTCCCTGCGGGCCGAGGATACCGCCGTCTACTACTGCGCCAAA 
               
               
                   
                   
                 GTGGAAGGTTCAGGATCGCTGGACTACTGGGGACAGGGTACTCTCGTGACC 
               
               
                   
                   
                 GTGTCATCGGGCGGAGGAGGTTCCGGCGGTGGCGGCTCCGGCGGCGGAGGG 
               
               
                   
                   
                 TCGGAGATCGTGATGACCCAGAGCCCTGGTACTCTGAGCCTTTCGCCGGGA 
               
               
                   
                   
                 GAAAGGGCCACCCTGTCCTGCCGCGCTTCCCAATCCGTGTCCTCCGCGTAC 
               
               
                   
                   
                 TTGGCGTGGTACCAGCAGAAGCCGGGACAGCCCCCTCGGCTGCTGATCAGC 
               
               
                   
                   
                 GGGGCCAGCACCCGGGCAACCGGAATCCCAGACAGATTCGGGGGTTCCGGC 
               
               
                   
                   
                 AGCGGCACAGATTTCACCCTGACTATTTCGAGGTTGGAGCCCGAGGACTTT 
               
               
                   
                   
                 GCGGTGTATTACTGTCAGCACTACGGGTCGTCCTTTAATGGCTCCAGCCTG 
               
               
                   
                   
                 TTCACGTTCGGACAGGGGACCCGCCTGGAAATCAAGACCACTACCCCAGCA 
               
               
                   
                   
                 CCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTG 
               
               
                   
                   
                 CGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGT 
               
               
                   
                   
                 CTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGC 
               
               
                   
                   
                 GGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGG 
               
               
                   
                   
                 AAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACT 
               
               
                   
                   
                 ACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGC 
               
               
                   
                   
                 GGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTAC 
               
               
                   
                   
                 AAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAG 
               
               
                   
                   
                 GAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGG 
               
               
                   
                   
                 AAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAG 
               
               
                   
                   
                 GATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGA 
               
               
                   
                   
                 AGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAG 
               
               
                   
                   
                 GACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-G1 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                  988 
                 MALPVTALLLPLALLLHAARPEVQLVETGGGLVQPGGSLRLSCAASGITFS 
               
               
                 C1978-G1-aa 
                   
                 RYPMSWVRQAPGKGLEWVSGISDSGVSTYYADSAKGRFTISRDNSKNTLFL 
               
               
                 Full CART 
                   
                 QMSSLRDEDTAVYYCVTRAGSEASDIWGQGTMVTVSSGGGGSGGGGSGGGG 
               
               
                   
                   
                 SEIVLTQSPATLSLSPGERATLSCRASQSVSNSLAWYQQKPGQAPRLLIYD 
               
               
                   
                   
                 ASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAIYYCQQFGTSSGLTFGG 
               
               
                   
                   
                 GTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFAC 
               
               
                   
                   
                 DIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEED 
               
               
                   
                   
                 GCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVL 
               
               
                   
                   
                 DKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGH 
               
               
                   
                   
                 DGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 BCMA_EBB- 
                 1010 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 C1978-G1-nt 
                   
                 GCCGCTCGGCCCGAAGTGCAACTGGTGGAAACCGGTGGCGGCCTGGTGCAG 
               
               
                 Full CART 
                   
                 CCTGGAGGATCATTGAGGCTGTCATGCGCGGCCAGCGGTATTACCTTCTCC 
               
               
                   
                   
                 CGGTACCCCATGTCCTGGGTCAGACAGGCCCCGGGGAAAGGGCTTGAATGG 
               
               
                   
                   
                 GTGTCCGGGATCTCGGACTCCGGTGTCAGCACTTACTACGCCGACTCCGCC 
               
               
                   
                   
                 AAGGGACGCTTCACCATTTCCCGGGACAACTCGAAGAACACCCTGTTCCTC 
               
               
                   
                   
                 CAAATGAGCTCCCTCCGGGACGAGGATACTGCAGTGTACTACTGCGTGACC 
               
               
                   
                   
                 CGCGCCGGGTCCGAGGCGTCTGACATTTGGGGACAGGGCACTATGGTCACC 
               
               
                   
                   
                 GTGTCGTCCGGCGGAGGGGGCTCGGGAGGCGGTGGCAGCGGAGGAGGAGGG 
               
               
                   
                   
                 TCCGAGATCGTGCTGACCCAATCCCCGGCCACCCTCTCGCTGAGCCCTGGA 
               
               
                   
                   
                 GAAAGGGCAACCTTGTCCTGTCGCGCGAGCCAGTCCGTGAGCAACTCCCTG 
               
               
                   
                   
                 GCCTGGTACCAGCAGAAGCCCGGACAGGCTCCGAGACTTCTGATCTACGAC 
               
               
                   
                   
                 GCTTCGAGCCGGGCCACTGGAATCCCCGACCGCTTTTCGGGGTCCGGCTCA 
               
               
                   
                   
                 GGAACCGATTTCACCCTGACAATCTCACGGCTGGAGCCAGAGGATTTCGCC 
               
               
                   
                   
                 ATCTATTACTGCCAGCAGTTCGGTACTTCCTCCGGCCTGACTTTCGGAGGC 
               
               
                   
                   
                 GGCACGAAGCTCGAAATCAAGACCACTACCCCAGCACCGAGGCCACCCACC 
               
               
                   
                   
                 CCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGT 
               
               
                   
                   
                 AGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGC 
               
               
                   
                   
                 GATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTT 
               
               
                   
                   
                 TCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTAC 
               
               
                   
                   
                 ATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGAC 
               
               
                   
                   
                 GGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGC 
               
               
                   
                   
                 GTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAAC 
               
               
                   
                   
                 CAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTG 
               
               
                   
                   
                 GACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAG 
               
               
                   
                   
                 AATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAA 
               
               
                   
                   
                 GCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCAC 
               
               
                   
                   
                 GACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCT 
               
               
                   
                   
                 CTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-1979-C1 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                  989 
                 MALPVTALLLPLALLLHAARPQVQLVESGGGLVQPGGSLRLSCAASGFTFS 
               
               
                 C1979-C1-aa 
                   
                 SYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNAKNSLYL 
               
               
                 Full CART 
                   
                 QMNSLRAEDTAIYYCARATYKRELRYYYGMDVWGQGTMVTVSSGGGGSGGG 
               
               
                   
                   
                 GSGGGGSEIVMTQSPGTVSLSPGERATLSCRASQSVSSSFLAWYQQKPGQA 
               
               
                   
                   
                 PRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDSAVYYCQQYHSS 
               
               
                   
                   
                 PSWTFGQGTRLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHT 
               
               
                   
                   
                 RGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPV 
               
               
                   
                   
                 QTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGR 
               
               
                   
                   
                 REEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGE 
               
               
                   
                   
                 RRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 BCMA_EBB- 
                 1011 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 C1979-C1-nt 
                   
                 GCCGCTCGGCCCCAAGTGCAGCTCGTGGAATCGGGTGGCGGACTGGTGCAG 
               
               
                 Full CART 
                   
                 CCGGGGGGCTCACTTAGACTGTCCTGCGCGGCCAGCGGATTCACTTTCTCC 
               
               
                   
                   
                 TCCTACGCCATGTCCTGGGTCAGACAGGCCCCTGGAAAGGGCCTGGAATGG 
               
               
                   
                   
                 GTGTCCGCAATCAGCGGCAGCGGCGGCTCGACCTATTACGCGGATTCAGTG 
               
               
                   
                   
                 AAGGGCAGATTCACCATTTCCCGGGACAACGCCAAGAACTCCTTGTACCTT 
               
               
                   
                   
                 CAAATGAACTCCCTCCGCGCGGAAGATACCGCAATCTACTACTGCGCTCGG 
               
               
                   
                   
                 GCCACTTACAAGAGGGAACTGCGCTACTACTACGGGATGGACGTCTGGGGC 
               
               
                   
                   
                 CAGGGAACCATGGTCACCGTGTCCAGCGGAGGAGGAGGATCGGGAGGAGGC 
               
               
                   
                   
                 GGTAGCGGGGGTGGAGGGTCGGAGATCGTGATGACCCAGTCCCCCGGCACT 
               
               
                   
                   
                 GTGTCGCTGTCCCCCGGCGAACGGGCCACCCTGTCATGTCGGGCCAGCCAG 
               
               
                   
                   
                 TCAGTGTCGTCAAGCTTCCTCGCCTGGTACCAGCAGAAACCGGGACAAGCT 
               
               
                   
                   
                 CCCCGCCTGCTGATCTACGGAGCCAGCAGCCGGGCCACCGGTATTCCTGAC 
               
               
                   
                   
                 CGGTTCTCCGGTTCGGGGTCCGGGACCGACTTTACTCTGACTATCTCTCGC 
               
               
                   
                   
                 CTCGAGCCAGAGGACTCCGCCGTGTATTACTGCCAGCAGTACCACTCCTCC 
               
               
                   
                   
                 CCGTCCTGGACGTTCGGACAGGGCACAAGGCTGGAGATTAAGACCACTACC 
               
               
                   
                   
                 CCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTG 
               
               
                   
                   
                 TCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACC 
               
               
                   
                   
                 CGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGT 
               
               
                   
                   
                 ACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGC 
               
               
                   
                   
                 GGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTG 
               
               
                   
                   
                 CAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAG 
               
               
                   
                   
                 GAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCA 
               
               
                   
                   
                 GCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGG 
               
               
                   
                   
                 AGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATG 
               
               
                   
                   
                 GGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTC 
               
               
                   
                   
                 CAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAA 
               
               
                   
                   
                 CGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCC 
               
               
                   
                   
                 ACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-1978-C7 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                  990 
                 MALPVTALLLPLALLLHAARPEVQLVETGGGLVQPGGSLRLSCAASGFTFS 
               
               
                 C1978-C7-aa 
                   
                 SYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYL 
               
               
                 Full CART 
                   
                 QMNTLKAEDTAVYYCARATYKRELRYYYGMDVWGQGTTVTVSSGGGGSGGG 
               
               
                   
                   
                 GSGGGGSEIVLTQSPSTLSLSPGESATLSCRASQSVSTTFLAWYQQKPGQA 
               
               
                   
                   
                 PRLLIYGSSNRATGIPDRFSGSGSGTDFTLTIRRLEPEDFAVYYCQQYHSS 
               
               
                   
                   
                 PSWTFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHT 
               
               
                   
                   
                 RGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPV 
               
               
                   
                   
                 QTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGR 
               
               
                   
                   
                 REEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGE 
               
               
                   
                   
                 RRRGHGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 BCMA_EBB- 
                 1012 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 C1978-C7-nt 
                   
                 GCCGCTCGGCCCGAGGTGCAGCTTGTGGAAACCGGTGGCGGACTGGTGCAG 
               
               
                 Full CART 
                   
                 CCCGGAGGAAGCCTCAGGCTGTCCTGCGCCGCGTCCGGCTTCACCTTCTCC 
               
               
                   
                   
                 TCGTACGCCATGTCCTGGGTCCGCCAGGCCCCCGGAAAGGGCCTGGAATGG 
               
               
                   
                   
                 GTGTCCGCCATCTCTGGAAGCGGAGGTTCCACGTACTACGCGGACAGCGTC 
               
               
                   
                   
                 AAGGGAAGGTTCACAATCTCCCGCGATAATTCGAAGAACACTCTGTACCTT 
               
               
                   
                   
                 CAAATGAACACCCTGAAGGCCGAGGACACTGCTGTGTACTACTGCGCACGG 
               
               
                   
                   
                 GCCACCTACAAGAGAGAGCTCCGGTACTACTACGGAATGGACGTCTGGGGC 
               
               
                   
                   
                 CAGGGAACTACTGTGACCGTGTCCTCGGGAGGGGGTGGCTCCGGGGGGGGC 
               
               
                   
                   
                 GGCTCCGGCGGAGGCGGTTCCGAGATTGTGCTGACCCAGTCACCTTCAACT 
               
               
                   
                   
                 CTGTCGCTGTCCCCGGGAGAGAGCGCTACTCTGAGCTGCCGGGCCAGCCAG 
               
               
                   
                   
                 TCCGTGTCCACCACCTTCCTCGCCTGGTATCAGCAGAAGCCGGGGCAGGCA 
               
               
                   
                   
                 CCACGGCTCTTGATCTACGGGTCAAGCAACAGAGCGACCGGAATTCCTGAC 
               
               
                   
                   
                 CGCTTCTCGGGGAGCGGTTCAGGCACCGACTTCACCCTGACTATCCGGCGC 
               
               
                   
                   
                 CTGGAACCCGAAGATTTCGCCGTGTATTACTGTCAACAGTACCACTCCTCG 
               
               
                   
                   
                 CCGTCCTGGACCTTTGGCCAAGGAACCAAAGTGGAAATCAAGACCACTACC 
               
               
                   
                   
                 CCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTG 
               
               
                   
                   
                 TCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACC 
               
               
                   
                   
                 CGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGT 
               
               
                   
                   
                 ACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGC 
               
               
                   
                   
                 GGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTG 
               
               
                   
                   
                 CAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAG 
               
               
                   
                   
                 GAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCA 
               
               
                   
                   
                 GCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGG 
               
               
                   
                   
                 AGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATG 
               
               
                   
                   
                 GGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTC 
               
               
                   
                   
                 CAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAA 
               
               
                   
                   
                 CGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCC 
               
               
                   
                   
                 ACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-D10 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                  991 
                 MALPVTALLLPLALLLHAARPEVQLVETGGGLVQPGRSLRLSCAASGFTFD 
               
               
                 C1978-D10-aa 
                   
                 DYAMHWVRQAPGKGLEWVSGISWNSGSIGYADSVKGRFTISRDNAKNSLYL 
               
               
                 Full CART 
                   
                 QMNSLRDEDTAVYYCARVGKAVPDVWGQGTTVTVSSGGGGSGGGGSGGGGS 
               
               
                   
                   
                 DIVMTQTPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAA 
               
               
                   
                   
                 SSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPYSFGQGT 
               
               
                   
                   
                 RLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGDLFACDI 
               
               
                   
                   
                 YIWAPLAGTCGVLLLSVLITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGC 
               
               
                   
                   
                 SCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNLELNGRREEYDVLDK 
               
               
                   
                   
                 RRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDG 
               
               
                   
                   
                 LYQGLSTATKDTYDALHMQALPPR 
               
               
                 BCMA_EBB- 
                 1013 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 C1978-D10-nt 
                   
                 GCCGCTCGGCCCGAAGTGCAGCTCGTGGAAACTGGAGGTGGACTCGTGCAG 
               
               
                 Full CART 
                   
                 CCTGGACGGTCGCTGCGGCTGAGCTGCGCTGCATCCGGCTTCACCTTCGAC 
               
               
                   
                   
                 GATTATGCCATGCACTGGGTCAGACAGGCGCCAGGGAAGGGACTTGAGTGG 
               
               
                   
                   
                 GTGTCCGGTATCAGCTGGAATAGCGGCTCAATCGGATACGCGGACTCCGTG 
               
               
                   
                   
                 AAGGGAAGGTTCACCATTTCCCGCGACAACGCCAAGAACTCCCTGTACTTG 
               
               
                   
                   
                 CAAATGAACAGCCTCCGGGATGAGGACACTGCCGTGTACTACTGCGCCCGC 
               
               
                   
                   
                 GTCGGAAAAGCTGTGCCCGACGTCTGGGGCCAGGGAACCACTGTGACCGTG 
               
               
                   
                   
                 TCCAGCGGCGGGGGTGGATCGGGCGGTGGAGGGTCCGGTGGAGGGGGCTCA 
               
               
                   
                   
                 GATATTGTGATGACCCAGACCCCCTCGTCCCTGTCCGCCTCGGTCGGCGAC 
               
               
                   
                   
                 CGCGTGACTATCACATGTAGAGCCTCGCAGAGCATCTCCAGCTACCTGAAC 
               
               
                   
                   
                 TGGTATCAGCAGAAGCCGGGGAAGGCCCCGAAGCTCCTGATCTACGCGGCA 
               
               
                   
                   
                 TCATCACTGCAATCGGGAGTGCCGAGCCGGTTTTCCGGGTCCGGCTCCGGC 
               
               
                   
                   
                 ACCGACTTCACGCTGACCATTTCTTCCCTGCAACCCGAGGACTTCGCCACT 
               
               
                   
                   
                 TACTACTGCCAGCAGTCCTACTCCACCCCTTACTCCTTCGGCCAAGGAACC 
               
               
                   
                   
                 AGGCTGGAAATCAAGACCACTACCCCAGCACCGAGGCCACCCACCCCGGCT 
               
               
                   
                   
                 CCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCC 
               
               
                   
                   
                 GCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGCGATATC 
               
               
                   
                   
                 TACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTC 
               
               
                   
                   
                 GTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTT 
               
               
                   
                   
                 AAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGT 
               
               
                   
                   
                 TCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAA 
               
               
                   
                   
                 TTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTC 
               
               
                   
                   
                 TACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAG 
               
               
                   
                   
                 CGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCC 
               
               
                   
                   
                 CAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTAT 
               
               
                   
                   
                 AGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGA 
               
               
                   
                   
                 CTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCAC 
               
               
                   
                   
                 ATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1979-C12 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                  992 
                 MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFD 
               
               
                 C1979-C12- 
                   
                 DYAMHWVRQRPGKGLEWVASINWKGNSLAYGDSVKGRFAISRDNAKNTVFL 
               
               
                 aa 
                   
                 QMNSLRTEDTAVYYCASHQGVAYYNYAMDVWGRGTLVTVSSGGGGSGGGGS 
               
               
                 Full CART 
                   
                 GGGGSEIVLTQSPGTLSLSPGERATLSCRATQSIGSSFLAWYQQRPGQAPR 
               
               
                   
                   
                 LLIYGASQRATFIPDRFSGRGSGTDFTLTISRVEPEDSAVYYCQHYESSPS 
               
               
                   
                   
                 WTFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRG 
               
               
                   
                   
                 LDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQT 
               
               
                   
                   
                 TQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRRE 
               
               
                   
                   
                 EYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERR 
               
               
                   
                   
                 RGHGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 BCMA_EBB- 
                 1014 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 C1979-C12- 
                   
                 GCCGCTCGGCCCGAAGTGCAGCTCGTGGAGAGCGGGGGAGGATTGGTGCAG 
               
               
                 nt 
                   
                 CCCGGAAGGTCCCTGCGGCTCTCCTGCACTGCGTCTGGCTTCACCTTCGAC 
               
               
                 Full CART 
                   
                 GACTACGCGATGCACTGGGTCAGACAGCGCCCGGGAAAGGGCCTGGAATGG 
               
               
                   
                   
                 GTCGCCTCAATCAACTGGAAGGGAAACTCCCTGGCCTATGGCGACAGCGTG 
               
               
                   
                   
                 AAGGGCCGCTTCGCCATTTCGCGCGACAACGCCAAGAACACCGTGTTTCTG 
               
               
                   
                   
                 CAAATGAATTCCCTGCGGACCGAGGATACCGCTGTGTACTACTGCGCCAGC 
               
               
                   
                   
                 CACCAGGGCGTGGCATACTATAACTACGCCATGGACGTGTGGGGAAGAGGG 
               
               
                   
                   
                 ACGCTCGTCACCGTGTCCTCCGGGGGCGGTGGATCGGGTGGAGGAGGAAGC 
               
               
                   
                   
                 GGTGGCGGGGGCAGCGAAATCGTGCTGACTCAGAGCCCGGGAACTCTTTCA 
               
               
                   
                   
                 CTGTCCCCGGGAGAACGGGCCACTCTCTCGTGCCGGGCCACCCAGTCCATC 
               
               
                   
                   
                 GGCTCCTCCTTCCTTGCCTGGTACCAGCAGAGGCCAGGACAGGCGCCCCGC 
               
               
                   
                   
                 CTGCTGATCTACGGTGCTTCCCAACGCGCCACTGGCATTCCTGACCGGTTC 
               
               
                   
                   
                 AGCGGCAGAGGGTCGGGAACCGATTTCACACTGACCATTTCCCGGGTGGAG 
               
               
                   
                   
                 CCCGAAGATTCGGCAGTCTACTACTGTCAGCATTACGAGTCCTCCCCTTCA 
               
               
                   
                   
                 TGGACCTTCGGTCAAGGGACCAAAGTGGAGATCAAGACCACTACCCCAGCA 
               
               
                   
                   
                 CCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTG 
               
               
                   
                   
                 CGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGT 
               
               
                   
                   
                 CTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGC 
               
               
                   
                   
                 GGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGG 
               
               
                   
                   
                 AAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACT 
               
               
                   
                   
                 ACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGC 
               
               
                   
                   
                 GGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTAC 
               
               
                   
                   
                 AAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAG 
               
               
                   
                   
                 GAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGG 
               
               
                   
                   
                 AAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAG 
               
               
                   
                   
                 GATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGA 
               
               
                   
                   
                 AGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAG 
               
               
                   
                   
                 GACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1980-G4 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                  993 
                 MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGFTFS 
               
               
                 C1980-G4-aa 
                   
                 SYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYL 
               
               
                 Full CART 
                   
                 QMNSLRAEDTAVYYCAKVVRDGMDVWGQGTTVTVSSGGGGSGGGGSGGGGS 
               
               
                   
                   
                 EIVLTQSPATLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYG 
               
               
                   
                   
                 ASSRATGIPDRFSGNGSGTDFTLTISRLEPEDFAVYYCQQYGSPPRFTFGP 
               
               
                   
                   
                 GTKVDIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFAC 
               
               
                   
                   
                 DIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEED 
               
               
                   
                   
                 GCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVL 
               
               
                   
                   
                 DKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGH 
               
               
                   
                   
                 DGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 BCMA_EBB- 
                 1015 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 C1980-G4-nt 
                   
                 GCCGCTCGGCCCGAGGTGCAGTTGGTCGAAAGCGGGGGCGGGCTTGTGCAG 
               
               
                 Full CART 
                   
                 CCTGGCGGATCACTGCGGCTGTCCTGCGCGGCATCAGGCTTCACGTTTTCT 
               
               
                   
                   
                 TCCTACGCCATGTCCTGGGTGCGCCAGGCCCCTGGAAAGGGACTGGAATGG 
               
               
                   
                   
                 GTGTCCGCGATTTCGGGGTCCGGCGGGAGCACCTACTACGCCGATTCCGTG 
               
               
                   
                   
                 AAGGGCCGCTTCACTATCTCGCGGGACAACTCCAAGAACACCCTCTACCTC 
               
               
                   
                   
                 CAAATGAATAGCCTGCGGGCCGAGGATACCGCCGTCTACTATTGCGCTAAG 
               
               
                   
                   
                 GTCGTGCGCGACGGAATGGACGTGTGGGGACAGGGTACCACCGTGACAGTG 
               
               
                   
                   
                 TCCTCGGGGGGAGGCGGTAGCGGCGGAGGAGGAAGCGGTGGTGGAGGTTCC 
               
               
                   
                   
                 GAGATTGTGCTGACTCAATCACCCGCGACCCTGAGCCTGTCCCCCGGCGAA 
               
               
                   
                   
                 AGGGCCACTCTGTCCTGTCGGGCCAGCCAATCAGTCTCCTCCTCGTACCTG 
               
               
                   
                   
                 GCCTGGTACCAGCAGAAGCCAGGACAGGCTCCGAGACTCCTTATCTATGGC 
               
               
                   
                   
                 GCATCCTCCCGCGCCACCGGAATCCCGGATAGGTTCTCGGGAAACGGATCG 
               
               
                   
                   
                 GGGACCGACTTCACTCTCACCATCTCCCGGCTGGAACCGGAGGACTTCGCC 
               
               
                   
                   
                 GTGTACTACTGCCAGCAGTACGGCAGCCCGCCTAGATTCACTTTCGGCCCC 
               
               
                   
                   
                 GGCACCAAAGTGGACATCAAGACCACTACCCCAGCACCGAGGCCACCCACC 
               
               
                   
                   
                 CCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCATGT 
               
               
                   
                   
                 AGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCCTGC 
               
               
                   
                   
                 GATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTT 
               
               
                   
                   
                 TCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTGTAC 
               
               
                   
                   
                 ATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGAC 
               
               
                   
                   
                 GGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTGCGC 
               
               
                   
                   
                 GTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAAC 
               
               
                   
                   
                 CAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTG 
               
               
                   
                   
                 GACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAG 
               
               
                   
                   
                 AATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAA 
               
               
                   
                   
                 GCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCAC 
               
               
                   
                   
                 GACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCT 
               
               
                   
                   
                 CTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1980-D2 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                  994 
                 MALPVTALLLPLALLLHAARPEVQLLESGGGLVQPGGSLRLSCAASGFTFS 
               
               
                 C1980-D2-aa 
                   
                 SYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYL 
               
               
                 Full CART 
                   
                 QMNSLRAEDTAVYYCAKIPQTGTFDYWGQGTLVTVSSGGGGSGGGGSGGGG 
               
               
                   
                   
                 SEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQRPGQAPRLLIY 
               
               
                   
                   
                 GASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFACYYCQHYGSSPSWTFG 
               
               
                   
                   
                 QGTRLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFA 
               
               
                   
                   
                 CDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEE 
               
               
                   
                   
                 DGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDV 
               
               
                   
                   
                 LDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKG 
               
               
                   
                   
                 HDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 BCMA_EBB- 
                 1016 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 C1980-D2-nt 
                   
                 GCCGCTCGGCCCGAAGTGCAGCTGCTGGAGTCCGGCGGTGGATTGGTGCAA 
               
               
                 Full CART 
                   
                 CCGGGGGGATCGCTCAGACTGTCCTGTGCGGCGTCAGGCTTCACCTTCTCG 
               
               
                   
                   
                 AGCTACGCCATGTCATGGGTCAGACAGGCCCCTGGAAAGGGTCTGGAATGG 
               
               
                   
                   
                 GTGTCCGCCATTTCCGGGAGCGGGGGATCTACATACTACGCCGATAGCGTG 
               
               
                   
                   
                 AAGGGCCGCTTCACCATTTCCCGGGACAACTCCAAGAACACTCTCTATCTG 
               
               
                   
                   
                 CAAATGAACTCCCTCCGCGCTGAGGACACTGCCGTGTACTACTGCGCCAAA 
               
               
                   
                   
                 ATCCCTCAGACCGGCACCTTCGACTACTGGGGACAGGGGACTCTGGTCACC 
               
               
                   
                   
                 GTCAGCAGCGGTGGCGGAGGTTCGGGGGGAGGAGGAAGCGGCGGCGGAGGG 
               
               
                   
                   
                 TCCGAGATTGTGCTGACCCAGTCACCCGGCACTTTGTCCCTGTCGCCTGGA 
               
               
                   
                   
                 GAAAGGGCCACCCTTTCCTGCCGGGCATCCCAATCCGTGTCCTCCTCGTAC 
               
               
                   
                   
                 CTGGCCTGGTACCAGCAGAGGCCCGGACAGGCCCCACGGCTTCTGATCTAC 
               
               
                   
                   
                 GGAGCAAGCAGCCGCGCGACCGGTATCCCGGACCGGTTTTCGGGCTCGGGC 
               
               
                   
                   
                 TCAGGAACTGACTTCACCCTCACCATCTCCCGCCTGGAACCCGAAGATTTC 
               
               
                   
                   
                 GCTGTGTATTACTGCCAGCACTACGGCAGCTCCCCGTCCTGGACGTTCGGC 
               
               
                   
                   
                 CAGGGAACTCGGCTGGAGATCAAGACCACTACCCCAGCACCGAGGCCACCC 
               
               
                   
                   
                 ACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCGGAGGCA 
               
               
                   
                   
                 TGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGACTTCGCC 
               
               
                   
                   
                 TGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTG 
               
               
                   
                   
                 CTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAGCTGCTG 
               
               
                   
                   
                 TACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAG 
               
               
                   
                   
                 GACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTG 
               
               
                   
                   
                 CGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAG 
               
               
                   
                   
                 AACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTG 
               
               
                   
                   
                 CTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGA 
               
               
                   
                   
                 AAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCA 
               
               
                   
                   
                 GAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGC 
               
               
                   
                   
                 CACGACGGACTGTACCAGGGACTCAGCGACCGCCACCAAGGACACCTATGA 
               
               
                   
                   
                 GCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-A10 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                  995 
                 MALPVTALLLPLALLLHAARPEVQLVETGGGLVQPGGSLRLSCAASGFTFS 
               
               
                 C1978-A10- 
                   
                 SYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTMSRENDKNSVFL 
               
               
                 aa 
                   
                 QMNSLRVEDTGVYYCARANYKRELRYYYGMDVWGQGTMVTVSSGGGGSGGG 
               
               
                 Full CART 
                   
                 GSGGGGSEIVMTQSPGTLSLSPGESATLSCRASQEVASNYLAWYQHKPGQA 
               
               
                   
                   
                 PSLLISGASSRATPVDPRFSGSGSGTDFTLAISRLEPEDSAVYYCQHYDSS 
               
               
                   
                   
                 PSWTFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHT 
               
               
                   
                   
                 RGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPV 
               
               
                   
                   
                 QTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGR 
               
               
                   
                   
                 REEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGE 
               
               
                   
                   
                 RRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 BCMA_EBB- 
                 1017 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 C1978-A10- 
                   
                 GCCGCTCGGCCCGAAGTGCAACTGGTGGAAACCGGTGGAGGACTCGTGCAG 
               
               
                 nt 
                   
                 CCTGGCGGCAGCCTCCGGCTGAGCTGCGCCGCTTCGGGATTCACCTTTTCC 
               
               
                 Full CART 
                   
                 TCCTACGCGATGTCTTGGGTCAGACAGGCCCCCGGAAAGGGGCTGGAATGG 
               
               
                   
                   
                 GTGTCAGCCATCTCCGGCTCCGGCGGATCAACGTACTACGCCGACTCCGTG 
               
               
                   
                   
                 AAAGGCCGGTTCACCATGTCGCGCGAGAATGACAAGAACTCCGTGTTCCTG 
               
               
                   
                   
                 CAAATGAACTCCCTGAGGGTGGAGGACACCGGAGTGTACTATTGTGCGCGC 
               
               
                   
                   
                 GCCAACTACAAGAGAGAGCTGCGGTACTACTACGGAATGGACGTCTGGGGA 
               
               
                   
                   
                 CAGGGAACTATGGTGACCGTGTCATCCGGTGGAGGGGGAAGCGGCGGTGGA 
               
               
                   
                   
                 GGCAGCGGGGGCGGGGGTTCAGAAATTGTCATGACCCAGTCCCCGGGAACT 
               
               
                   
                   
                 CTTTCCCTCTCCCCCGGGGAATCCGCGACTTTGTCCTGCCGGGCCAGCCAG 
               
               
                   
                   
                 CGCGTGGCCTCGAACTACCTCGCATGGTACCAGCATAAGCCAGGCCAAGCC 
               
               
                   
                   
                 CCTTCCCTGCTGATTTCCGGGGCTAGCAGCCGCGCCACTGGCGTGCCGGAT 
               
               
                   
                   
                 AGGTTCTCGGGAAGCGGCTCGGGTACCGATTTCACCCTGGCAATCTCGCGG 
               
               
                   
                   
                 CTGGAACCGGAGGATTCGGCCGTGTACTACTGCCAGCACTATGACTCATCC 
               
               
                   
                   
                 CCCTCCTGGACATTCGGACAGGGCACCAAGGTCGAGATCAAGACCACTACC 
               
               
                   
                   
                 CCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTG 
               
               
                   
                   
                 TCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACC 
               
               
                   
                   
                 CGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGT 
               
               
                   
                   
                 ACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGC 
               
               
                   
                   
                 GGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTG 
               
               
                   
                   
                 CAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAG 
               
               
                   
                   
                 GAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCA 
               
               
                   
                   
                 GCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGG 
               
               
                   
                   
                 AGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATG 
               
               
                   
                   
                 GGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTC 
               
               
                   
                   
                 CAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAA 
               
               
                   
                   
                 CGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCC 
               
               
                   
                   
                 ACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-D4 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                  996 
                 MALPVTALLLPLALLLHAARPEVQLLETGGGLVQPGGSLRLSCAASGFSFS 
               
               
                 C1978-D4-aa 
                   
                 SYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYL 
               
               
                 Full CART 
                   
                 QMNSLRAEDTAVYYCAKALVGATGAFDIWGQGTLVTVSSGGGGSGGGGSGG 
               
               
                   
                   
                 GGSEIVLTQSPGTLSLSPGERATLSCRASQSLSSNFLAWYQQKPGQAPGLL 
               
               
                   
                   
                 IYGASNWATGTPDRFSGSGSGTDFTLTITRLEPEDFAVYYCQYYGTSPMYT 
               
               
                   
                   
                 FGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLD 
               
               
                   
                   
                 FACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQ 
               
               
                   
                   
                 EEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEY 
               
               
                   
                   
                 DVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRG 
               
               
                   
                   
                 KGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 BCMA_EBB- 
                 1018 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 C1978-D4-nt 
                   
                 GCCGCTCGGCCCGAAGTGCAGCTGCTCGAAACCGGTGGAGGGCTGGTGCAG 
               
               
                 Full CART 
                   
                 CCAGGGGGCTCCCTGAGGCTTTCATGCGCCGCTAGCGGATTCTCCTTCTCC 
               
               
                   
                   
                 TCTTACGCCATGTCGTGGGTCCGCCAAGCCCCTGGAAAAGGCCTGGAATGG 
               
               
                   
                   
                 GTGTCCGCGATTTCCGGGAGCGGAGGTTCGACCTATTACGCCGACTCCGTG 
               
               
                   
                   
                 AAGGGCCGCTTTACCATCTCCCGGGATAACTCCAAGAACACTCTGTACCTC 
               
               
                   
                   
                 CAAATGAACTCGCTGAGAGCCGAGGACACCGCCGTGTATTACTGCGCGAAG 
               
               
                   
                   
                 GCGCTGGTCGGCGCGACTGGGGCATTCGACATCTGGGGACAGGGAACTCTT 
               
               
                   
                   
                 GTGACCGTGTCGAGCGGAGGCGGCGGCTCCGGCGGAGGAGGGAGCGGGGGC 
               
               
                   
                   
                 GGTGGTTCCGAAATCGTGTTGACTCAGTCCCCGGGAACCCTGAGCTTGTCA 
               
               
                   
                   
                 CCCGGGGAGCGGGCCACTCTCTCCTGTCGCGCCTCCCAATCGCTCTCATCC 
               
               
                   
                   
                 AATTTCCTGGCCTGGTACCAGCAGAAGCCCGGACAGGCCCCGGGCCTGCTC 
               
               
                   
                   
                 ATCTACGGCGCTTCAAACTGGGCAACGGGAACCCCTGATCGGTTCAGCGGA 
               
               
                   
                   
                 AGCGGATCGGGTACTGACTTTACCCTGACCATCACCAGACTGGAACCGGAG 
               
               
                   
                   
                 GACTTCGCCGTGTACTACTGCCAGTACTACGGCACCTCCCCCATGTACACA 
               
               
                   
                   
                 TTCGGACAGGGTACCAAGGTCGAGATTAAGACCACTACCCCAGCACCGAGG 
               
               
                   
                   
                 CCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCG 
               
               
                   
                   
                 GAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGAC 
               
               
                   
                   
                 TTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTC 
               
               
                   
                   
                 CTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAG 
               
               
                   
                   
                 CTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAA 
               
               
                   
                   
                 GAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGC 
               
               
                   
                   
                 GAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAG 
               
               
                   
                   
                 GGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTAC 
               
               
                   
                   
                 GACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCG 
               
               
                   
                   
                 CGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAG 
               
               
                   
                   
                 ATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGC 
               
               
                   
                   
                 AAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACC 
               
               
                   
                   
                 TATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1980-A2 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                  997 
                 MALPVTALLLPLALLLHAARPEVQLLESGGGLVQPGGSLRLSCAASGFTFS 
               
               
                 C1980-A2-aa 
                   
                 SYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTIARDNSKNTLYL 
               
               
                 Full CART 
                   
                 QMNSLRAEDTAVYYCVLWFGEGFDPWGQGTLVTVSSGGGGSGGGGSGGGGS 
               
               
                   
                   
                 DIVLTQSPLSLPVTPGEPASISVRSSQSLLHSNGYNYLDWYLQKPGQSPQL 
               
               
                   
                   
                 LIYLGSNRASGPVDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPLT 
               
               
                   
                   
                 FGGGTKVDIKTTTPAPRPPTPAPTIASQPLSLREPACRPAAGGAVHTRGLD 
               
               
                   
                   
                 FACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQ 
               
               
                   
                   
                 EEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQGQLYNELNLGRREEY 
               
               
                   
                   
                 DVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRG 
               
               
                   
                   
                 KGHDGLYQGLSTATKDTYDALHMQALPPR 
               
               
                 BCMA_EBB- 
                 1019 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 C1980-A2-nt 
                   
                 GCCGCTCGGCCCGAAGTGCAGCTGCTTGAGAGCGGTGGAGGTCTGGTGCAG 
               
               
                 Full CART 
                   
                 CCCGGGGGATCACTGCGCCTGTCCTGTGCCGCGTCCGGTTTCACTTTCTCC 
               
               
                   
                   
                 TCGTACGCCATGTCGTGGGTCAGACAGGCACCGGGAAAGGGACTGGAATGG 
               
               
                   
                   
                 GTGTCAGCCATTTCGGGTTCGGGGGGCAGCACCTACTACGCTGACTCCGTG 
               
               
                   
                   
                 AAGGGCCGGTTCACCATTTCCCGCGACAACTCCAAGAACACCTTGTACCTC 
               
               
                   
                   
                 CAAATGAACTCCCTGCGGGCCGAAGATACCGCCGTGTATTACTGCGTGCTG 
               
               
                   
                   
                 TGGTTCGGAGAGGGATTCGACCCGTGGGGACAAGGAACACTCGTGACTGTG 
               
               
                   
                   
                 TCATCCGGCGGAGGCGGCAGCGGTGGCGGCGGTTCCGGCGGCGGCGGATCT 
               
               
                   
                   
                 GACATCGTGTTGACCCAGTCCCCTCTGAGCCTGCCGGTCACTCCTGGCGAA 
               
               
                   
                   
                 CCAGCCAGCATCTCCTGCCGGTCGAGCCAGTCCCTCCTGCACTCCAATGGG 
               
               
                   
                   
                 TACAACTACCTCGATTGGTATCTGCAAAAGCCGGGCCAGAGCCCCCAGCTG 
               
               
                   
                   
                 CTGATCTACCTTGGGTCAAACCGCGCTTCCGGGGTGCCTGATAGATTCTCC 
               
               
                   
                   
                 GGGTCCGGGAGCGGAACCGACTTTACCCTGAAAATCTCGAGGGTGGAGGCC 
               
               
                   
                   
                 GAGGACGTCGGAGTGTACTACTGCATGCAGGCGCTCCAGACTCCCCTGACC 
               
               
                   
                   
                 TTCGGAGGAGGAACGAAGGTCGACATCAAGACCACTACCCCAGCACCGAGG 
               
               
                   
                   
                 CCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTGCGTCCG 
               
               
                   
                   
                 GAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGTCTTGAC 
               
               
                   
                   
                 TTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTC 
               
               
                   
                   
                 CTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGGAAGAAG 
               
               
                   
                   
                 CTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAA 
               
               
                   
                   
                 GAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGC 
               
               
                   
                   
                 GAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAG 
               
               
                   
                   
                 GGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTAC 
               
               
                   
                   
                 GACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCG 
               
               
                   
                   
                 CGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAG 
               
               
                   
                   
                 ATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGC 
               
               
                   
                   
                 AAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACC 
               
               
                   
                   
                 TATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1981-C3 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                  998 
                 MALPVTALLLPLALLLHAARPQVQLVESGGGLVQPGGSLRLSCAASGFTFS 
               
               
                 C1981-C3-aa 
                   
                 SYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYL 
               
               
                 Full CART 
                   
                 QMNSLRAEDTAVYYCAKVGYDSSGYYRDYYGMDVWGQGTTVTVSSGGGGSG 
               
               
                   
                   
                 GGGSGGGGSEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPG 
               
               
                   
                   
                 QAPRLLIYGTSSRATGISDRFSGSGSGTDFTLTISRLEPEDFAVYYCQHYG 
               
               
                   
                   
                 NSPPKFTFGPGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGA 
               
               
                   
                   
                 VHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFM 
               
               
                   
                   
                 RPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELN 
               
               
                   
                   
                 LGRREEYDVLDKRRGRDPEMGGKPRRKNPQELGYNELQKDKMAEAYSEIGM 
               
               
                   
                   
                 KGERRRGKGHDGLYQGLSTATDKTYDALHMQALPPR 
               
               
                 BCMA_EBB- 
                 1020 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 C1981-C3-nt 
                   
                 GCCGCTCGGCCCCAAGTGCAGCTCGTGGAGTCAGGCGGAGGACTGGTGCAG 
               
               
                 Full CART 
                   
                 CCCGGGGGCTCCCTGAGACTTTCCTGCGCGGCATCGGGTTTTACCTTCTCC 
               
               
                   
                   
                 TCCTATGCTATGTCCTGGGTGCGCCAGGCCCCGGGAAAGGGACTGGAATGG 
               
               
                   
                   
                 GTGTCCGCAATCAGCGGTAGCGGGGGCTCAACATACTACGCCGACTCCGTC 
               
               
                   
                   
                 AAGGGTCGCTTCACTATTTCCCGGGACAACTCCAAGAATACCCTGTACCTC 
               
               
                   
                   
                 CAAATGAACAGCCTCAGGGCCGAGGATACTGCCGTGTACTACTGCGCCAAA 
               
               
                   
                   
                 GTCGGATACGATAGCTCCGGTTACTACCGGGACTACTACGGAATGGACGTG 
               
               
                   
                   
                 TGGGGACAGGGCACCACCGTGACCGTGTCAAGCGGCGGAGGCGGTTCAGGA 
               
               
                   
                   
                 GGGGGAGGCTCCGGCGGTGGAGGGTCCGAAATCGTCCTGACTCAGTCGCCT 
               
               
                   
                   
                 GGCACTCTGTCGTTGTCCCCGGGGGAGCGCGCTACCCTGTCGTGTCGGGCG 
               
               
                   
                   
                 TCGCAGTCCGTGTCGAGCTCCTACCTCGCGTGGTACCAGCAGAAGCCCGGA 
               
               
                   
                   
                 CAGGCCCCTAGACTTCTGATCTACGGCACTTCTTCACGCGCCACCGGGATC 
               
               
                   
                   
                 AGCGACAGGTTCAGCGGCTCCGGCTCCGGGACCGACTTCACCCTGACCATT 
               
               
                   
                   
                 AGCCGGCTGGAGCCTGAAGATTTCGCCGTGTATTACTGCCAACACTACGGA 
               
               
                   
                   
                 AACTCGCCGCCAAAGTTCACGTTCGGACCCGGAACCAAGCTGGAAATCAAG 
               
               
                   
                   
                 ACCACTACCCCAGCACCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCC 
               
               
                   
                   
                 CAGCCTCTGTCCCTGCGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCC 
               
               
                   
                   
                 GTGCATACCCGGGGTCTTGACTTCGCCTGCGATATCTACATTTGGGCCCCT 
               
               
                   
                   
                 CTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTAC 
               
               
                   
                   
                 TGTAAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATG 
               
               
                   
                   
                 AGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCA 
               
               
                   
                   
                 GAGGAGGAGGAAGGCGGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCA 
               
               
                   
                   
                 GATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAAT 
               
               
                   
                   
                 CTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGAC 
               
               
                   
                   
                 CCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTAC 
               
               
                   
                   
                 AACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATG 
               
               
                   
                   
                 AAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTC 
               
               
                   
                   
                 AGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCG 
               
               
                   
                   
                 CCTCGG 
               
               
                   
               
            
           
           
               
            
               
                 BCMA_EBB-C1978-G4 
               
            
           
           
               
               
               
            
               
                 BCMA_EBB- 
                  999 
                 MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGFTFS 
               
               
                 C1978-G4-aa 
                   
                 SYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYL 
               
               
                 Full CART 
                   
                 QMNSLRAEDTAVYYCAKMGWSSGYLGAFDIWGQGTTVTVSSGGGGSGGGGS 
               
               
                   
                   
                 GGGGSEIVLTQSPGTLSLSPGERATLSCRASQSVASSFLAWYQQKPGQAPR 
               
               
                   
                   
                 LLIYGASGRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQHYGGSPR 
               
               
                   
                   
                 LTFGGGTKVDIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRG 
               
               
                   
                   
                 LDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQT 
               
               
                   
                   
                 TQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRRE 
               
               
                   
                   
                 EYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERR 
               
               
                   
                   
                 RGKGHDGLYQGLSTATDKTYDALHMQALPPR 
               
               
                 BCMA_EBB- 
                 1021 
                 ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCAC 
               
               
                 C1978-G4-nt 
                   
                 GCCGCTCGGCCCGAAGTCCAACTGGTGGAGTCCGGGGGAGGGCTCGTGCAG 
               
               
                 Full CART 
                   
                 CCCGGAGGCAGCCTTCGCCTGTCGTGCGCCGCCTCCGGGTTCACGTTCTCA 
               
               
                   
                   
                 TCCTACGCGATGTCGTGGGTCAGACAGGCACCAGGAAAGGGACTGGAATGG 
               
               
                   
                   
                 GTGTCCGCCATTAGCGGCTCCGGCGGTAGCACCTACTATGCCGACTCAGTG 
               
               
                   
                   
                 AAGGGAAGGTTCACTATCTCCCGCGACAACAGCAAGAACACCCTGTACCTC 
               
               
                   
                   
                 CAAATGAACTCTCTGCGGGCCGAGGATACCGCGGTGTACTATTGCGCCAAG 
               
               
                   
                   
                 ATGGGTTGGTCCAGCGGATACTTGGGAGCCTTCGACATTTGGGGACAGGGC 
               
               
                   
                   
                 ACTACTGTGACCGTGTCCTCCGGGGGTGGCGGATCGGGAGGCGGCGGCTCG 
               
               
                   
                   
                 GGTGGAGGGGGTTCCGAAATCGTGTTGACCCAGTCACCGGGAACCCTCTCG 
               
               
                   
                   
                 CTGTCCCCGGGAGAACGGGCTACACTGTCATGTAGAGCGTCCCAGTCCGTG 
               
               
                   
                   
                 GCTTCCTCGTTCCTGGCCTGGTACCAGCAGAAGCCGGGACAGGCACCCCGC 
               
               
                   
                   
                 CTGCTCATCTACGGAGCCAGCGGCCGGGCGACCGGCATCCCTGACCGCTTC 
               
               
                   
                   
                 TCCGGTTCCGGCTCGGGCACCGACTTTACTCTGACCATTAGCAGGCTTGAG 
               
               
                   
                   
                 CCCGAGGATTTTGCCGTGTACTACTGCCAACACTACGGGGGGAGCCCTCGC 
               
               
                   
                   
                 CTGACCTTCGGAGGCGGAACTAAGGTCGATATCAAAACCACTACCCCAGCA 
               
               
                   
                   
                 CCGAGGCCACCCACCCCGGCTCCTACCATCGCCTCCCAGCCTCTGTCCCTG 
               
               
                   
                   
                 CGTCCGGAGGCATGTAGACCCGCAGCTGGTGGGGCCGTGCATACCCGGGGT 
               
               
                   
                   
                 CTTGACTTCGCCTGCGATATCTACATTTGGGCCCCTCTGGCTGGTACTTGC 
               
               
                   
                   
                 GGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGTAAGCGCGGTCGG 
               
               
                   
                   
                 AAGAAGCTGCTGTACATCTTTAAGCAACCCTTCATGAGGCCTGTGCAGACT 
               
               
                   
                   
                 ACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGC 
               
               
                   
                   
                 GGCTGCGAACTGCGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTAC 
               
               
                   
                   
                 AAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAG 
               
               
                   
                   
                 GAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGG 
               
               
                   
                   
                 AAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAG 
               
               
                   
                   
                 GATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGA 
               
               
                   
                   
                 AGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAG 
               
               
                   
                   
                 GACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG 
               
               
                   
               
            
           
         
       
     
     In one embodiment, the CAR molecule of the BCA CAR comprises (e.g., consists of) an amino acid sequence provided in Table 16, or Table 1 of WO2016/014565, or as otherwise described herein. In one embodiment, the CAR molecule of the BCA CAR comprises (e.g., consists of) an amino acid sequence of SEQ ID NO: 949, SEQ ID NO: 950, SEQ ID NO: 951, SEQ ID NO: 952, SEQ ID NO: 953, SEQ ID NO: 954, SEQ ID NO: 955, SEQ ID NO: 956, SEQ ID NO: 957, SEQ ID NO: 958, SEQ ID NO: 959, SEQ ID NO: 960, SEQ ID NO: 961, SEQ ID NO: 962, SEQ ID NO: 963, SEQ ID NO: 979, SEQ ID NO: 980, SEQ ID NO: 981, SEQ ID NO: 982, SEQ ID NO: 983, SEQ ID NO: 984, SEQ ID NO: 985, SEQ ID NO: 986, SEQ ID NO: 987, SEQ ID NO: 988, SEQ ID NO: 989, SEQ ID NO: 990, SEQ ID NO: 991, SEQ ID NO: 992, SEQ ID NO: 993, SEQ ID NO: 994, SEQ ID NO: 995, SEQ ID NO: 996, SEQ ID NO: 997, SEQ ID NO: 998, or SEQ ID NO: 999; or an amino acid sequence having at least one, two, three, four, five, 10, 15, 20 or 30 modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 60, 50, or 40 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of SEQ ID NO: 949, SEQ ID NO: 950, SEQ ID NO: 951, SEQ ID NO: 952, SEQ ID NO: 953, SEQ ID NO: 954, SEQ ID NO: 955, SEQ ID NO: 956, SEQ ID NO: 957, SEQ ID NO: 958, SEQ ID NO: 959, SEQ ID NO: 960, SEQ ID NO: 961, SEQ ID NO: 962, SEQ ID NO: 963, SEQ ID NO: 979, SEQ ID NO: 980, SEQ ID NO: 981, SEQ ID NO: 982, SEQ ID NO: 983, SEQ ID NO: 984, SEQ ID NO: 985, SEQ ID NO: 986, SEQ ID NO: 987, SEQ ID NO: 988, SEQ ID NO: 989, SEQ ID NO: 990, SEQ ID NO: 991, SEQ ID NO: 992, SEQ ID NO: 993, SEQ ID NO: 994, SEQ ID NO: 995, SEQ ID NO: 996, SEQ ID NO: 997, SEQ ID NO: 998, or SEQ ID NO: 999; or an amino acid sequence having 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to an amino acid sequence of SEQ ID NO: 949, SEQ ID NO: 950, SEQ ID NO: 951, SEQ ID NO: 952, SEQ ID NO: 953, SEQ ID NO: 954, SEQ ID NO: 955, SEQ ID NO: 956, SEQ ID NO: 957, SEQ ID NO: 958, SEQ ID NO: 959, SEQ ID NO: 960, SEQ ID NO: 961, SEQ ID NO: 962, SEQ ID NO: 963, SEQ ID NO: 979, SEQ ID NO: 980, SEQ ID NO: 981, SEQ ID NO: 982, SEQ ID NO: 983, SEQ ID NO: 984, SEQ ID NO: 985, SEQ ID NO: 986, SEQ ID NO: 987, SEQ ID NO: 988, SEQ ID NO: 989, SEQ ID NO: 990, SEQ ID NO: 991, SEQ ID NO: 992, SEQ ID NO: 993, SEQ ID NO: 994, SEQ ID NO: 995, SEQ ID NO: 996, SEQ ID NO: 997, SEQ ID NO: 998, or SEQ ID NO: 999. 
     In one aspect, the cell of the invention (e.g., a cell comprising both a TA CAR and a BCA CAR) comprises a TA CAR molecule comprising an antigen binding domain that binds to a tumor antigen. In one embodiment, the TA CAR comprises a CAR molecule comprising a mesothelin antigen binding domain (e.g., a murine, human or humanized antibody or antibody fragment that specifically binds to mesothelin), a transmembrane domain, and an intracellular signaling domain (e.g., an intracellular signaling domain comprising a costimulatory domain and/or a primary signaling domain). 
     Exemplary TA CAR molecules that target mesothelin are described herein, and are provided in Table 11. The CAR molecules in Table 11 comprise a mesothelin antigen binding domain, e.g., an amino acid sequence of any mesothelin antigen binding domain provided in Table 2. The leader sequence is in bold and underlined, CDRs are underlined, and the linker sequence between the heavy and light chain of the antigen binding region is shaded in grey. 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Exemplary mesothelin CAR molecules 
               
            
           
           
               
               
               
            
               
                   
                   
                 SEQ 
               
               
                   
                   
                 ID 
               
               
                 Name 
                 Amino Acid Sequence 
                 NO: 
               
               
                   
               
            
           
           
               
               
               
            
               
                 M5 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 286 
               
               
                   
                 APGQGLEWMG WINPNSGGTNYAQKFQG RVTMTRDTSISTAYMELSRLRSDDTAVYYCAS G   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                   ASQSIRYYLS WYQQKPGKARKLLIY TASILQN GVPSRFSGSGSGTDFTLTISSLQPEDFA 
                   
               
               
                   
               
               
                   
                 TYYC LQTYTTPD FGPGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTR 
                   
               
               
                   
               
               
                   
                 GLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMPPVQTTQEEDGCS 
                   
               
               
                   
               
               
                   
                 CRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGG 
                   
               
               
                   
               
               
                   
                 KPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQ 
                   
               
               
                   
               
               
                   
                 ALPPR 
                   
               
               
                   
               
               
                 M11 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 292 
               
               
                   
                 APGQGLEWMG WINPNSGGTNYAQNFQG RVTMTRDTSISTAYMELRRLRSDDTAVYYCAS G   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                   ASQSIRYYLS WYQQKPGKAPKLLIY TASILQN GVPSRFSGSGSGTDFTLTISSLQPEDFA 
                   
               
               
                   
               
               
                   
                 TYYC LQTYTTPD FGPGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTR 
                   
               
               
                   
               
               
                   
                 GLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCS 
                   
               
               
                   
               
               
                   
                 CRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGG 
                   
               
               
                   
               
               
                   
                 KPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQ 
                   
               
               
                   
               
               
                   
                 ALPPR 
                   
               
               
                   
               
               
                 SS1 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 306 
               
               
                   
                 QSHGKSLEWIG LITPYNGASSYNQKFR GKATLTVDKSSSTAYMDLLSLTSEDSAVYFCA 
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 C SASSSVSYMH WYQQKSGTSPKRWIY DTSKLAS GVPGRFSGSGSGNSYSLTISSVEAED 
                   
               
               
                   
               
               
                   
                 DATYYC QQWSGYPLT FGAGTKLEITTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAV 
                   
               
               
                   
               
               
                   
                 HTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEE 
                   
               
               
                   
               
               
                   
                 DGCSCRFPEEEEGGCELRVKFSRSADAPA 
                   
               
               
                   
               
               
                 M1 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 282 
               
               
                   
                 APGQGLEWMG RINPNSGGTNYAQKFQG RVTMTRDTSISTAYMELSRLRSEDTAVYYCAR G   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 C RASQSVSSNFA WYQQRPGQAPRLLIY DASNRAT GIPPRFSGSGSGTDFTLTISSLEPED 
                   
               
               
                   
               
               
                   
                 FAAYYC HQRSNWLYT FGQGTKVDIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAV 
                   
               
               
                   
               
               
                   
                 HTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEED 
                   
               
               
                   
               
               
                   
                 GCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPE 
                   
               
               
                   
               
               
                   
                 MGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDAL 
                   
               
               
                   
               
               
                   
                 HMQALPPR 
                   
               
               
                   
               
               
                 M2 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 283 
               
               
                   
                 APGQGLEWMG WINPNSGGTNYAQKFQG RVTMTRDTSISTAYMELSRLRSDDTAVYYCAR D   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 SVGDRVTITC QASQDISNSLN WYQQKAGKAPKLLIY DASTLET GVPSRFSGSGSGTDFSF 
                   
               
               
                   
               
               
                   
                 TISSLQPEDIATYYC QQHDNLPLT FGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEA 
                   
               
               
                   
               
               
                   
                 CRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMR 
                   
               
               
                   
               
               
                   
                 PVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVL 
                   
               
               
                   
               
               
                   
                 DKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLST 
                   
               
               
                   
               
               
                   
                 ATKDTYDALHMQALPPR 
                   
               
               
                   
               
               
                 M3 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 284 
               
               
                   
                 APGQGLEWMG WINPNSGGTNYAQKFQG RVTMTRDTSISTAYMELSRLRSDDTAVYYCAR G   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 TITC RASQSINTYLN WYQHKPGKAPKLLIY AASSLQS GVPSRFSGSGSGTDFTLTISSLQ 
                   
               
               
                   
               
               
                   
                 PEDFATYYC QQSFSPLT FGGGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGG 
                   
               
               
                   
               
               
                   
                 AVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQE 
                   
               
               
                   
               
               
                   
                 EDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRD 
                   
               
               
                   
               
               
                   
                 PEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYD 
                   
               
               
                   
               
               
                   
                 ALHMQALPPR 
                   
               
               
                   
               
               
                 M4 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 285 
               
               
                   
                 VPGKGLVWVS RINTDGSTTTYADSVEG RFTISRDNAKNTLYLQMNSLRDDDTAVYYCVG G   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                   SQSISDRLA WYQQKPGKAPKLLIY KASSLE SGVPSRFSGSGSGTEFTLTISSLQPDDFAV 
                   
               
               
                   
               
               
                   
                 YYC QQYGHLPMYT FGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHT 
                   
               
               
                   
               
               
                   
                 RGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGC 
                   
               
               
                   
               
               
                   
                 SCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMG 
                   
               
               
                   
               
               
                   
                 GKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHM 
                   
               
               
                   
               
               
                   
                 QALPPR 
                   
               
               
                   
               
               
                 M6 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 287 
               
               
                   
                 APGQGLEWMG IINPSGGSTSYAQKFQG RVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR Y   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 SVGDPVTITC RASQGVGRWLA WYQQKPGTAPKLLIY AASTLQS GVPSRFSGSGSGTDFTL 
                   
               
               
                   
               
               
                   
                 TINNLQPEDFATYYC QQANSFPLT FGGGTRLEIKTTTPAPRPPTPAPTIASQPLSLRPEA 
                   
               
               
                   
               
               
                   
                 CRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMR 
                   
               
               
                   
               
               
                   
                 PVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVL 
                   
               
               
                   
               
               
                   
                 DKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLST 
                   
               
               
                   
               
               
                   
                 ATKDTYDALHMQALPPR  
                   
               
               
                   
               
               
                 M7 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 288 
               
               
                   
                 APGKGLEWVA VISYDGSNKYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR W   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 AILSC RASQSVYTKYLG WYQQKPGQAPRLLIY DASTRAT GIPDRFSGSGSGTDFTLTTNR 
                   
               
               
                   
               
               
                   
                 LEPEDFAVYYC QHYGGSPLIT FGQGTRLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRP 
                   
               
               
                   
               
               
                   
                 AAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQ 
                   
               
               
                   
               
               
                   
                 TTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKR 
                   
               
               
                   
               
               
                   
                 RGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATK 
                   
               
               
                   
               
               
                   
                 DTYDALHMQALPPR 
                   
               
               
                   
               
               
                 M8 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 289 
               
               
                   
                 APGQGLEWMG WINPNSGGTNYAQKFQG RVTMTRDTSISTAYMELSRLRSDDTAVYYCAR D   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 ITC RASQDSGTWLA WYQQKPGKAPNLLMY DASTLED GVPSRFSGSASGTEFTLTVNRLQP 
                   
               
               
                   
               
               
                   
                 EDSATYYC QQYNSYPLT FGGGTKVDIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGG 
                   
               
               
                   
               
               
                   
                 AVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQE 
                   
               
               
                   
               
               
                   
                 EDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNIGRREEYDVLDKRRGRD 
                   
               
               
                   
               
               
                   
                 PEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYD 
                   
               
               
                   
               
               
                   
                 ALHMQALPPR 
                   
               
               
                   
               
               
                 M9 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 290 
               
               
                   
                 APGQGLEWMG IINPSGGSTGYAQKFQG RVTMTRDTSTSTVHMELSSLRSEDTAVYYCAR G   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 VTITC RASQDISSALA WYQQKPGTPPKLLIY DASSLES GVPSRESGSGSGTDFILTISSL 
                   
               
               
                   
               
               
                   
                 QPEDFATYYC QQFSSYPLT FGGGTRLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAA 
                   
               
               
                   
               
               
                   
                 GGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTT 
                   
               
               
                   
               
               
                   
                 QEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRG 
                   
               
               
                   
               
               
                   
                 RDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDT 
                   
               
               
                   
               
               
                   
                 YDALHMQALPPR 
                   
               
               
                   
               
               
                 M10 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 291 
               
               
                   
                 APGQGLEWMG WISAYNGNTNYAQKLQ GRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR V   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 RATISC KSSHSVLYNRNNKNYLA WYQQKPGQPPKLLFY WASTRKS GVPDRFSGSGSGTDF 
                   
               
               
                   
               
               
                   
                 TLTISSLQPEDFATYFC QQTQTFPLT FGQGTRLEINTTTPAPRPPTPAPTIASQPLSLRP 
                   
               
               
                   
               
               
                   
                 EACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPF 
                   
               
               
                   
               
               
                   
                 MRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSPSADAPAYKQGQNQLYNELNLGRREEYD 
                   
               
               
                   
               
               
                   
                 VLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGL 
                   
               
               
                   
               
               
                   
                 STATKDTYDALHMQALPPR 
                   
               
               
                   
               
               
                 M12 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 293 
               
               
                   
                 APGQGLEWMG RINPNSGGTNYAQKFQG RVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR T   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 TC RASQSISTWLA WYQQKPGKAPNLLIY KASTLES GVPSRFSGSGSGTEFTLTISSLQPD 
                   
               
               
                   
               
               
                   
                 DFATYYC QQYNTYSPYT FGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGG 
                   
               
               
                   
               
               
                   
                 AVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQE 
                   
               
               
                   
               
               
                   
                 EDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRD 
                   
               
               
                   
               
               
                   
                 PEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYD 
                   
               
               
                   
               
               
                   
                 ALHMQALPPR 
                   
               
               
                   
               
               
                 M13 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 294 
               
               
                   
                 APGKGLEWVS YIGRSGSSMYYA DSVKGRFTFSRDNAKNSLYLQMNSLRAEDTAVYYCAA S   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 ATLSC RASQSVTSNYLA WYQQKPGQAPRLLLF GASTRAT GIPDRFSGSGSGTDFTLTINR 
                   
               
               
                   
               
               
                   
                 LEPEDFAMYYC QQYGSAPVT FGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPA 
                   
               
               
                   
               
               
                   
                 AGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQT 
                   
               
               
                   
               
               
                   
                 TQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRR 
                   
               
               
                   
               
               
                   
                 GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQG1STATKD 
                   
               
               
                   
               
               
                   
                 TYDALHMQALPPR 
                   
               
               
                   
               
               
                 M14 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 295 
               
               
                   
                 APGQGLEWMG IINPSGGSRAYAQKFQG RVTMTRDTSTSTVYMELSSLRSDDTAMYYCAR T   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 RVTITC RASENVNIWLA WYQQKPGKAPKLLIY KSSSLAS GVPSRFSGSGSGAEFTLTISS 
                   
               
               
                   
               
               
                   
                 LQPDDFATYYC QQYQSYPLT FGGGTKVDIKTTTPAPRPPTPAPTIASQPLSLRPEACRPA 
                   
               
               
                   
               
               
                   
                 AGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQT 
                   
               
               
                   
               
               
                   
                 TQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRR 
                   
               
               
                   
               
               
                   
                 GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKD 
                   
               
               
                   
               
               
                   
                 TYDALHMQALPPR 
                   
               
               
                   
               
               
                 M15 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 296 
               
               
                   
                 APGKGLEWVS GISWNSGSIGYADSVK GRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAK D   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                   QGDALRSYYAS WYQQKPGQAPMLVIY GKNNRPS GIPDRFSGSDSGDTASLTITGAQAEDE 
                   
               
               
                   
               
               
                   
                 ADYYC NSRDSSGYPV FGTGTKVTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAV 
                   
               
               
                   
               
               
                   
                 HTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEED 
                   
               
               
                   
               
               
                   
                 GCSCRFPFEEEGGCELRVKFSPSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPE 
                   
               
               
                   
               
               
                   
                 MGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDAL 
                   
               
               
                   
               
               
                   
                 HMQALPPR 
                   
               
               
                   
               
               
                 M16 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 297 
               
               
                   
                 APGKGLEWVS GISWNSGSTGYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTALYYCAK D   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 C QGDSLRSYYAS WYQQKPGQAPVLVIF GRSRRPS GIPDRFSGSSSGNTASLIITGAQAED 
                   
               
               
                   
               
               
                   
                 EADYYC NSRDNTANHYV FGTGTKLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGG 
                   
               
               
                   
               
               
                   
                 AVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQE 
                   
               
               
                   
               
               
                   
                 EDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRD 
                   
               
               
                   
               
               
                   
                 PEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYD 
                   
               
               
                   
               
               
                   
                 ALHMQALPPR 
                   
               
               
                   
               
               
                 M17 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 298 
               
               
                   
                 APGKGLEWVS GISWNSGSTGYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTALYYCAK D   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 C QGDSLPSYYAS WYQQKPGQAPVLVIY GKNNRPS GIPDRFSGSSSGNTASLTITGAQAED 
                   
               
               
                   
               
               
                   
                 EADYYC NSRGSSGNHYV FGTGTKVTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGG 
                   
               
               
                   
               
               
                   
                 AVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQE 
                   
               
               
                   
               
               
                   
                 EDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRD 
                   
               
               
                   
               
               
                   
                 PEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYD 
                   
               
               
                   
               
               
                   
                 ALHMQALPPR 
                   
               
               
                   
               
               
                 M18 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 299 
               
               
                   
                 APGKGLVWVS RINSDGSSTSYADSVKG RFTISRDNAKNTLYLQMNSLRAEDTAVYYCVR T   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 RATLSC RASQSVSSNYLA WYQQKTGQPPRLLIY DVSTRAT GIPARFSGGGSGTDFTLTIS 
                   
               
               
                   
               
               
                   
                 SLEPEDFAVYYC QQRSNWPPWT FGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACR 
                   
               
               
                   
               
               
                   
                 PAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPV 
                   
               
               
                   
               
               
                   
                 QTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDK 
                   
               
               
                   
               
               
                   
                 RRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTAT 
                   
               
               
                   
               
               
                   
                 KDTYDALHMQALPPR 
                   
               
               
                   
               
               
                 M19 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 300 
               
               
                   
                 APGKGLEWVA VISYDGSNKYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK G   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 AILSC RASQSVYTKYLG WYQQKPGQAPRLLIY DASTRAT GIPDRFSGSGSGTDFTLTINR 
                   
               
               
                   
               
               
                   
                 LEPEDFAVYYC QHYGGSPLIT FGQGTKVDIKTTTPAPRPPTPAPTIASQPLSLRPEACRP 
                   
               
               
                   
               
               
                   
                 AAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQ 
                   
               
               
                   
               
               
                   
                 TTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKR 
                   
               
               
                   
               
               
                   
                 RGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATK 
                   
               
               
                   
               
               
                   
                 DTYDALHMQALPPR 
                   
               
               
                   
               
               
                 M20 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 301 
               
               
                   
                 APGKGLEWVS AISGSGGSTYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK R   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 RVTITC RASQSISSYLN WYQQKPGKAPKLLIY AASSLQS GVPSRFSGSGSGTDFTLTISS 
                   
               
               
                   
               
               
                   
                 LQPEDFATYYC QQSYSIPLT FGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPA 
                   
               
               
                   
               
               
                   
                 AGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQT 
                   
               
               
                   
               
               
                   
                 TQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRR 
                   
               
               
                   
               
               
                   
                 GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKD 
                   
               
               
                   
               
               
                   
                 TYDALHMQALPPR 
                   
               
               
                   
               
               
                 M21 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 302 
               
               
                   
                 APGQGLEWMG IINPSGGSTSYAQKFQG RVTMTRDTSTSTVYMELSNLRSEDTAVYYCAR S   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 TITC RASQSISSWLA WYQQKPGKAPKLLIY KASSLE SGVPSRFSGSGSGTEFTLTISSLQ 
                   
               
               
                   
               
               
                   
                 PDDFATYYC QQYSSYPLT FGGGTRLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAG 
                   
               
               
                   
               
               
                   
                 GAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQ 
                   
               
               
                   
               
               
                   
                 EEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGR 
                   
               
               
                   
               
               
                   
                 DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTY 
                   
               
               
                   
               
               
                   
                 DALHMQALPPR 
                   
               
               
                   
               
               
                 M22 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 303 
               
               
                   
                 APGQGPEWMG VINPTTGPATGSPAYAQMLQG RVTMTRDTSTRTVYMELRSLRFEDTAVYY 
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 SVGDRVTITC RASQGISDYS AWYQQKPGKAPKLLIY AASTLQS GVPSRFSGSGSGTDFTL 
                   
               
               
                   
               
               
                   
                 TISYLQSEDFATYYC QQYYSYPLT FGGGTKVDIKTTTPAPRPPTPAPTIASQPLSLRPEA 
                   
               
               
                   
               
               
                   
                 CRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMR 
                   
               
               
                   
               
               
                   
                 PVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVL 
                   
               
               
                   
               
               
                   
                 DKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLST 
                   
               
               
                   
               
               
                   
                 ATKDTYDALHMQALPPR 
                   
               
               
                   
               
               
                 M23 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 304 
               
               
                   
                 APGQGLEWMG IINPSGGYTTYAQKFQG RLTMTRDTSTSTVYMELSSLRSEDTAVYYCAR I   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 RVTITC RASENVNIWLA WYQQKPGKAPKLLIY KSSSLAS GVPSRFSGSGSGAEFTLTISS 
                   
               
               
                   
               
               
                   
                 LQPDDFATYYC QQYQSYPLT FGGGTKVDIKTTTPAPRPPTPAPTIASQPLSLRPEACRPA 
                   
               
               
                   
               
               
                   
                 AGGAVHTRGLDFACDIYTWATLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQT 
                   
               
               
                   
               
               
                   
                 TQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQDYNELNLGRREEYDVLDKRR 
                   
               
               
                   
               
               
                   
                 GRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKD 
                   
               
               
                   
               
               
                   
                 TYDALHMQATPPR 
                   
               
               
                   
               
               
                 M24 CAR 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 305 
               
               
                   
                 RQPPGKALEW LALISWADDKRYRPSLRS RLDITRVTSKDQVVLSMTNMQPEDTATYYCAL 
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
               
               
                   
                 ITC RASRGISSALA WYQQKPGKPPKLLIY DASSLES GVPSRFSGSGSGTDFTLTIDSLEP 
                   
               
               
                   
               
               
                   
                 EDFATYYC QQSYSTPWT FGQGTKVDIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGG 
                   
               
               
                   
               
               
                   
                 AVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQE 
                   
               
               
                   
               
               
                   
                 EDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRD 
                   
               
               
                   
               
               
                   
                 PEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYD 
                   
               
               
                   
               
               
                   
                 ALHMQALPPR 
               
               
                   
               
            
           
         
       
     
     In one embodiment, the cell of the invention (e.g., a cell comprising both a TA CAR and a BCA CAR) comprises a TA CAR molecule that binds mesothelin, and comprises (e.g., consists of) an amino acid sequence as provided in Table 11 and Table 2 of International Publication No. WO2015/090230, filed Dec. 19, 2014; incorporated herein by reference. In one embodiment, the TA CAR molecule comprises (e.g., consists of) an amino acid sequence of SEQ ID NO: 282, SEQ ID NO: 283, SEQ ID NO: 284, SEQ ID NO: 285, SEQ ID NO: 286, SEQ ID NO: 287, SEQ ID NO: 288, SEQ ID NO: 289, SEQ ID NO: 290, SEQ ID NO: 291, SEQ ID NO: 292, SEQ ID NO: 293, SEQ ID NO: 294, SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, SEQ ID NO: 299, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 305, or SEQ ID NO: 306; or an amino acid sequence having at least one, two, three, four, five, 10, 15, 20 or 30 modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 60, 50, or 40 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of SEQ ID NO: 282, SEQ ID NO: 283, SEQ ID NO: 284, SEQ ID NO: 285, SEQ ID NO: 286, SEQ ID NO: 287, SEQ ID NO: 288, SEQ ID NO: 289, SEQ ID NO: 290, SEQ ID NO: 291, SEQ ID NO: 292, SEQ ID NO: 293, SEQ ID NO: 294, SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, SEQ ID NO: 299, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 305, or SEQ ID NO: 306; or an amino acid sequence having 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to an amino acid sequence of SEQ ID NO: 282, SEQ ID NO: 283, SEQ ID NO: 284, SEQ ID NO: 285, SEQ ID NO: 286, SEQ ID NO: 287, SEQ ID NO: 288, SEQ ID NO: 289, SEQ ID NO: 290, SEQ ID NO: 291, SEQ ID NO: 292, SEQ ID NO: 293, SEQ ID NO: 294, SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, SEQ ID NO: 299, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 305, or SEQ ID NO: 306. 
     In one aspect, the cell of the invention (e.g., a cell comprising both a TA CAR and a BCA CAR) comprises a TA CAR molecule comprising an antigen binding domain that binds to a tumor antigen. In one embodiment, the TA CAR comprises a CAR molecule comprising a EGFRvII antigen binding domain (e.g., a murine, human or humanized antibody or antibody fragment that specifically binds to mesothelin), a transmembrane domain, and an intracellular signaling domain (e.g., an intracellular signaling domain comprising a costimulatory domain and/or a primary signaling domain). 
     Exemplary TA CAR molecules that target EGFRvIII are described herein, and are provided in Table 17, or in Table 2 of WO/2014/130657 or as described in WO2016/014789. 
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 Humanized EGFRvIII CAR Constructs. Sequences are provided with a leader, and 
               
               
                 the CDRs are underlined. Nt stands for nucleic acid and aa stands for amino acid 
               
            
           
           
               
               
               
            
               
                   
                 SEQ ID 
                   
               
               
                 Name 
                 NO: 
                 Sequence 
               
               
                   
               
            
           
           
               
            
               
                 CAR 1 
               
            
           
           
               
               
               
            
               
                 CAR 1- 
                 1042 
                 atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgctcggcc 
               
               
                 Full-nt 
                   
                 cgagatccagctggtgcagtcgggagctgaagtcaaaaagcctggcgcaaccgtcaagatct 
               
               
                   
                   
                 cgtgcaaaggatcagggttcaacatcgaggactactacatccattgggtgcaacaggcaccc 
               
               
                   
                   
                 ggaaaaggcctggagtggatggggaggattgacccagaaaatgacgaaaccaagtacggacc 
               
               
                   
                   
                 gatcttccaaggacgggtgaccatcacggctgacacttccactaacaccgtctacatggaac 
               
               
                   
                   
                 tctcgagccttcgctcggaagataccgcggtgtactactgcgcctttagaggtggagtctac 
               
               
                   
                   
                 tggggacaagggactaccgtcaccgtgtcgtcaggtggcggaggatcaggcggaggcggctc 
               
               
                   
                   
                 cggtggaggaggaagcggaggaggtggctccgacgtggtgatgacgcagtcaccggactcct 
               
               
                   
                   
                 tggcggtgagcctgggtgaacgcgccactatcaactgcaagagctcccagagcttgctggac 
               
               
                   
                   
                 tccgatggaaagacttatctcaattggctgcaacagaagcctggccagccgccaaagagact 
               
               
                   
                   
                 catctcactggtgagcaagctggatagcggagtgccagatcggttttcgggatcgggctcag 
               
               
                   
                   
                 gcaccgacttcaccctgactatttcctccctccaagccgaggatgtggccgtctactactgt 
               
               
                   
                   
                 tggcaggggactcacttcccggggaccttcggtggaggcactaaggtggagatcaaaaccac 
               
               
                   
                   
                 taccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgc 
               
               
                   
                   
                 gtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcc 
               
               
                   
                   
                 tgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgt 
               
               
                   
                   
                 gatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttca 
               
               
                   
                   
                 tgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggag 
               
               
                   
                   
                 gaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctacaagca 
               
               
                   
                   
                 ggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctgg 
               
               
                   
                   
                 acaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagag 
               
               
                   
                   
                 ggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaa 
               
               
                   
                   
                 aggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccacca 
               
               
                   
                   
                 aggacacctatgacgctcttcacatgcaggccctgccgcctcgg 
               
               
                   
               
               
                 CAR 1- 
                 1043 
                 malpvtalllplalllhaarpeiqlvqsgaevkkpgatvkisckgsgfnie   dyyih   wvqqap 
               
               
                 Full-aa 
                   
                 gkglewmg   ridpendetkygpifqg   rvtitadtstntvymelsslrsedtavyycaf   rggv   y 
               
               
                   
                   
                 wgqgttvtvssggggsggggsggggsggggsdvvmtqspdslavslgeratinc   kssgslld     
               
               
                   
                   
                     sdgktyln   wlqqkpgqppkrlis   lvsklds   gvpdrfsgsgsgtdftltisslqaedvavyyc 
               
               
                   
                   
                     wqgthfpgt   fgggtkveiktttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfa 
               
               
                   
                   
                 cdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeee 
               
               
                   
                   
                 eggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqe 
               
               
                   
                   
                 glynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
            
           
           
               
            
               
                 CAR 2 
               
            
           
           
               
               
               
            
               
                 CAR 2- 
                 1048 
                 atggccctccctgtaccgccctgctgcttccgctggctcttctgctccacgccgctcggccc 
               
               
                 Full-nt 
                   
                 gacgtggtcatgactcaaagcccagattccttggctgtctcccttggagaaagagcaacgat 
               
               
                   
                   
                 caattgcaaaagctcgcagtccctgttggactccgatggaaaaacctacctcaactggctgc 
               
               
                   
                   
                 agcagaagccgggacaaccaccaaagcggctgatttccctcgtgtccaagctggacagcggc 
               
               
                   
                   
                 gtgccggatcgcttctcgggcagcggctcgggaaccgattttactctcactatttcgtcact 
               
               
                   
                   
                 gcaagcggaggacgtggcggtgtattactgctggcagggcactcacttcccgggtacttttg 
               
               
                   
                   
                 gtggaggtaccaaagtcgaaatcaagggtggaggcgggagcggaggaggcgggtcgggagga 
               
               
                   
                   
                 ggaggatcgggtggcggaggctcagaaatccagctggtgcagtcaggtgccgaagtgaagaa 
               
               
                   
                   
                 gcctggggccacggtgaagatctcgtgcaaggggagcggattcaacatcgaggattactaca 
               
               
                   
                   
                 tccattgggtgcaacaggcccctggcaaagggctggaatggatgggaaggatcgaccccaag 
               
               
                   
                   
                 aatgacgagactaagtacggcccgatcttccaaggacgggtgaccatcactgcagacacttc 
               
               
                   
                   
                 aaccaacaccgtctacatggaactctcctcgctgcgctccgaggacaccgccgtgtactact 
               
               
                   
                   
                 gtgctttcagaggaggagtctactggggacagggaacgaccgtgaccgtcagctcaaccact 
               
               
                   
                   
                 accccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcg 
               
               
                   
                   
                 tccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcct 
               
               
                   
                   
                 gcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtg 
               
               
                   
                   
                 atcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcat 
               
               
                   
                   
                 gaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggagg 
               
               
                   
                   
                 aaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctacaagcag 
               
               
                   
                   
                 gggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctgga 
               
               
                   
                   
                 caagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagg 
               
               
                   
                   
                 gcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaa 
               
               
                   
                   
                 ggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaa 
               
               
                   
                   
                 ggacacctatgacgctcttcacatgcaggccctgccgcctcgg 
               
               
                   
               
               
                 CAR 2- 
                 1049 
                 malpvtalllplalllhaarpdvvmtqspdslavslgerantinc   kssqslldsdgktyln   w 
               
               
                 Full-aa 
                   
                 lqqkpgqppkrlis   lvsklds   gvpdrfsgsgsgtdftltisslqaedvavyyc   wqgthfpgt     
               
               
                   
                   
                 fgggtkveikggggsggggsggggsggggseiqlvqsgaevkkpgatvkisckgsgfnie   dy     
               
               
                   
                   
                     yih   wvqqapgkglewmg   ridpendetkygpifqg   rvtitadtstntvymelsslrsedtavy 
               
               
                   
                   
                 yca   frggvy   wgqgttvtvsstttpaprpptpaptiasqplslrpeacrpaaggavhtrgldf 
               
               
                   
                   
                 acdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpee 
               
               
                   
                   
                 eeggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpq 
               
               
                   
                   
                 eglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
            
           
           
               
            
               
                 CAR 3 
               
            
           
           
               
               
               
            
               
                 CAR 3- 
                 1054 
                 atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgctcggcc 
               
               
                 Full-nt 
                   
                 cgaaatccagctggtgcaaagcggagccgaggtgaagaagcccggagaatccctgcgcatct 
               
               
                   
                   
                 cgtgtaagggttccggctttaacatcgaggattactacatccactgggtgagacagatgccg 
               
               
                   
                   
                 ggcaaaggtctggaatggatgggccgcatcgacccggagaacgacgaaaccaaatacggacc 
               
               
                   
                   
                 aatcttccaaggacatgtgactatttccgcggatacctccatcaacactgtctacttgcagt 
               
               
                   
                   
                 ggagctcgctcaaggcgtcggataccgccatgtactactgcgcattcagaggaggtgtgtac 
               
               
                   
                   
                 tggggccagggcactacggtcaccgtgtcctcgggaggtggagggtcaggaggcggaggctc 
               
               
                   
                   
                 gggcggtggaggatcaggcggaggaggaagcgatgtggtcatgactcaatccccactgtcac 
               
               
                   
                   
                 tgcctgtcactctggggcaaccggcttccatctcatgcaagtcaagccaatcgctgctcgac 
               
               
                   
                   
                 tccgacggaaaaacctacctcaattggcttcagcagcgcccaggccagtcgcctcggaggct 
               
               
                   
                   
                 gatctcactcgtgtcgaagcttgactccggggtgccggatcggtttagcggaagcggatcgg 
               
               
                   
                   
                 ggaccgacttcacgttgaagattagccgggtggaagccgaggacgtgggagtctattactgc 
               
               
                   
                   
                 tggcaggggacccacttcccggggactttcggaggaggcaccaaagtcgagattaagaccac 
               
               
                   
                   
                 taccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgc 
               
               
                   
                   
                 gtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcc 
               
               
                   
                   
                 tgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgt 
               
               
                   
                   
                 gatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttca 
               
               
                   
                   
                 tgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggag 
               
               
                   
                   
                 gaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctacaagca 
               
               
                   
                   
                 ggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctgg 
               
               
                   
                   
                 acaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagag 
               
               
                   
                   
                 ggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaa 
               
               
                   
                   
                 aggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccacca 
               
               
                   
                   
                 aggacacctatgacgctcttcacatgcaggccctgccgcctcgg 
               
               
                   
               
               
                 CAR 3- 
                 1055 
                 malpvtalllplalllhaarpeiqlvqsgaevkkpgeslrisckgsgfnie   dyyih   wvrqmp 
               
               
                 Full-aa 
                   
                 gkglewmg   ridpendetkygpifqg   hvtisadtsintvylqwsslkasdtamyycaf   rggvy     
               
               
                   
                   
                 wgqgttvtvssggggsggggsggggsggggsdvvmtqsplslpvtlgqpasisc   ks   sqslld     
               
               
                   
                   
                     sdgktyln   wlqqrpgqsprrlis   lvsklds   gvpdrfsgsgsgtdftlkisrveaedvgvyyc 
               
               
                   
                   
                     wqgthfpgt   fgggtkveiktttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfa 
               
               
                   
                   
                 cdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeee 
               
               
                   
                   
                 eggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqe 
               
               
                   
                   
                 glynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
            
           
           
               
            
               
                 CAR 4 
               
            
           
           
               
               
               
            
               
                 CAR 4- 
                 1060 
                 atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgctcggcc 
               
               
                 Full-nt 
                   
                 cgacgtcgtcatgacccaatcccctctctccctgccggtcaccctgggtcagccggcgtcga 
               
               
                   
                   
                 tctcatgcaaaagctcacagtccctgctggattcggacggaaaaacctacttgaactggctc 
               
               
                   
                   
                 caacagaggccgggtcagtcccctcgcagactgatctcgctggtgagcaagctcgactcggg 
               
               
                   
                   
                 tgtgccggatcggttctccgggtcaggatcgggcaccgactttacgctcaagatttcgagag 
               
               
                   
                   
                 tggaggccgaggatgtgggagtgtactattgctggcagggcacgcatttccccgggaccttt 
               
               
                   
                   
                 ggaggcgggactaaggtggaaatcaagggaggtggcggatcaggcggaggaggcagcggcgg 
               
               
                   
                   
                 aggtggatcaggaggcggagggtcagagatccagctggtccaaagcggagcagaggtgaaga 
               
               
                   
                   
                 agccaggcgagtcccttcgcatttcgtgcaaagggagcggcttcaacattgaagattactac 
               
               
                   
                   
                 atccactgggtgcggcaaatgccaggaaagggtctggaatggatgggacggatcgacccaga 
               
               
                   
                   
                 aaatgatgaaactaagtacggaccgatcttccaaggacacgtcactatctccgcggacactt 
               
               
                   
                   
                 cgatcaacaccgtgtacctccagtggagcagcttgaaagcctccgacaccgctatgtactac 
               
               
                   
                   
                 tgtgccttccgcggaggagtctactggggacaggggactactgtgaccgtgtcgtccaccac 
               
               
                   
                   
                 taccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgc 
               
               
                   
                   
                 gtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcc 
               
               
                   
                   
                 tgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgt 
               
               
                   
                   
                 gatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttca 
               
               
                   
                   
                 tgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggag 
               
               
                   
                   
                 gaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctacaagca 
               
               
                   
                   
                 ggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctgg 
               
               
                   
                   
                 acaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagag 
               
               
                   
                   
                 ggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaa 
               
               
                   
                   
                 aggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccacca 
               
               
                   
                   
                 aggacacctatgacgctcttcacatgcaggccctgccgcctcgg 
               
               
                   
               
               
                 CAR 4- 
                 1061 
                 malpvtalllplalllhaarpdvvmtqsplslpvtlgqpasisc   kssqlldsdgktyln   wlq 
               
               
                 Full-aa 
                   
                 qrpgqsprrlis   lvsklds   gvpdrfsgsgsgtdftlkisrveaedvgvyyc   wqgthfpgt   fg 
               
               
                   
                   
                 ggtkveikggggsggggsggggsggggseiqlvqsgaevkkpgeslrisckgsgfnie dyyi   
               
               
                   
                   
                   h wvrqmpgkglewmg   ridpendetkygpifqg   hvtisadtsintvylqwsslkasdtamyyc 
               
               
                   
                   
                 af   rggvy   wgqgttvtvsstttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfac 
               
               
                   
                   
                 diyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeee 
               
               
                   
                   
                 ggcelrvkfsrsadapaykqgqnglynelnlgrreeydvldkrrgrdpemggkprrknpqeg 
               
               
                   
                   
                 lynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
            
           
           
               
            
               
                 CAR 5 
               
            
           
           
               
               
               
            
               
                 CAR 5- 
                 1066 
                 atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgctcggcc 
               
               
                 Full-nt 
                   
                 cgaaatccagctcgtgcagagcggagccgaggtcaagaaaccgggtgctaccgtgaagattt 
               
               
                   
                   
                 catgcaagggatcgggcttcaacatcgaggattactacatccactgggtgcagcaggcacca 
               
               
                   
                   
                 ggaaaaggacttgaatggatgggccggatcgacccggaaaatgacgagactaagtacggccc 
               
               
                   
                   
                 tatcttccaaggacgggtgacgatcaccgcagacactagcaccaacaccgtctatatggaac 
               
               
                   
                   
                 tctcgtccctgaggtccgaagatactgccgtgtactactgtgcgtttcgcggaggtgtgtac 
               
               
                   
                   
                 tggggacagggtaccaccgtcaccgtgtcatcgggcggtggaggctccggtggaggagggtc 
               
               
                   
                   
                 aggaggcggtggaagcggaggaggcggcagcgacgtggtcatgactcaatcgccgctgtcgc 
               
               
                   
                   
                 tgcccgtcactctgggacaacccgcgtccatcagctgcaaatcctcgcagtcactgcttgac 
               
               
                   
                   
                 tccgatggaaagacctacctcaactggctgcagcaacgcccaggccaatccccaagacgcct 
               
               
                   
                   
                 gatctcgttggtgtcaaagctggactcaggggtgccggaccggttctccgggagcgggtcgg 
               
               
                   
                   
                 gcacggatttcactctcaagatctccagagtggaagccgaggatgtgggagtctactactgc 
               
               
                   
                   
                 tggcagggaacccatttccctggaacttttggcggaggaactaaggtcgagattaaaaccac 
               
               
                   
                   
                 taccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgc 
               
               
                   
                   
                 gtccggagacatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcc 
               
               
                   
                   
                 tgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgt 
               
               
                   
                   
                 gatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttca 
               
               
                   
                   
                 tgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggag 
               
               
                   
                   
                 gaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctacaagca 
               
               
                   
                   
                 ggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctgg 
               
               
                   
                   
                 acaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagag 
               
               
                   
                   
                 ggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaa 
               
               
                   
                   
                 aggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccacca 
               
               
                   
                   
                 aggacacctatgacgctcttcacatgcaggccctgccgcctcgg 
               
               
                   
               
               
                 CAR 5- 
                 1067 
                 malpvtallllpalllhaarpeiqlvqsgaevkkpgatvkisckgsgfnied   yyih   wvqqap 
               
               
                 Full-aa 
                   
                 gkglewmg   ridpendetkygpifqg   rvtitadtstntvymelsslrsedtavyycaf   rggvy     
               
               
                   
                   
                 wgqgttvtvssggggsggggsggggsggggsdvvmtqsplslpvtlgqpasisc   kss   qslld     
               
               
                   
                   
                     sdgktyln   wlqqrpgqsprrlis   lvsklds   gvpdrfsgsgsgtdftlkisrveaedvgvyyc 
               
               
                   
                   
                     wqgthfpgt   fgggtkveiktttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfa 
               
               
                   
                   
                 cdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeee 
               
               
                   
                   
                 eggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqe 
               
               
                   
                   
                 glynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
            
           
           
               
            
               
                 CAR 6 
               
            
           
           
               
               
               
            
               
                 CAR6- 
                 1072 
                 atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgctcggcc 
               
               
                 Full-nt 
                   
                 cgagattcagctcgtgcaatcgggagcggaagtcaagaagccaggagagtccttgcggatct 
               
               
                   
                   
                 catgcaagggtagcggctttaacatcgaggattactacatccactgggtgaggcagatgccg 
               
               
                   
                   
                 gggaagggactcgaatggatgggacggatcgacccagaaaacgacgaaactaagtacggtcc 
               
               
                   
                   
                 gatcttccaaggccatgtgactattagcgccgatacttcaatcaataccgtgtatctgcaat 
               
               
                   
                   
                 ggtcctcattgaaagcctcagataccgcgatgtactactgtgctttcagaggaggggtctac 
               
               
                   
                   
                 tggggacagggaactaccgtgactgtctcgtccggcggaggcgggtcaggaggtggcggcag 
               
               
                   
                   
                 cggaggaggagggtccggcggaggtgggtccgacgtcgtgatgacccagagccctgacagcc 
               
               
                   
                   
                 tggcagtgagcctgggcgaaagagctaccattaactgcaaatcgtcgcagagcctgctggac 
               
               
                   
                   
                 tcggacggaaaaacgtacctcaattggctgcagcaaaagcctggccagccaccgaagcgcct 
               
               
                   
                   
                 tatctcactggtgtcgaagctggattcgggagtgcccgatcgcttctccggctcgggatcgg 
               
               
                   
                   
                 gtactgacttcaccctcactatctcctcgcttcaagcagaggacgtggccgtctactactgc 
               
               
                   
                   
                 tggcagggaacccactttccgggaaccttcggcggagggacgaaagtggagatcaagaccac 
               
               
                   
                   
                 taccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgc 
               
               
                   
                   
                 gtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcc 
               
               
                   
                   
                 tgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgt 
               
               
                   
                   
                 gatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttca 
               
               
                   
                   
                 tgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggag 
               
               
                   
                   
                 gaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctacaagca 
               
               
                   
                   
                 ggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctgg 
               
               
                   
                   
                 acaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagag 
               
               
                   
                   
                 ggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaa 
               
               
                   
                   
                 aggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccacca 
               
               
                   
                   
                 aggacacctatgacgctcttcacatgcaggccctgccgcctcgg 
               
               
                   
               
               
                 CAR6- 
                 1073 
                 malpvtalllplalllhaarpeiqlvqsgaevkkpgeslrisckgsgfnie   dyyih   wvrqmp 
               
               
                 Full-aa 
                   
                 gkglewmg   ridpendetkygpifqg   hvtisadtsintvylqwsslkasdtamyycaf   rggvy     
               
               
                   
                   
                 wgqgttvtvssggggsggggsggggsggggsdvvmtqspdslavslgeratinc   kssqslld     
               
               
                   
                   
                     sdgktyln   wlqqkpgqppkrlis   lvsklds   gvpdrfsgsgsgtdftltisslqaedvavyyc 
               
               
                   
                   
                     wqgthfpgt   fgggtkveiktttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfa 
               
               
                   
                   
                 cdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeee 
               
               
                   
                   
                 eggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqe 
               
               
                   
                   
                 glynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
            
           
           
               
            
               
                 CAR 7 
               
            
           
           
               
               
               
            
               
                 CAR 7 
                 1078 
                 atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgctcggcc 
               
               
                 Full-nt 
                   
                 cgacgtggtgatgactcagtcgcctgactcgctggctgtgtcccttggagagcgggccacta 
               
               
                   
                   
                 tcaattgcaagtcatcccagtcgctgctggattccgacgggaaaacctacctcaattggctg 
               
               
                   
                   
                 cagcaaaaaccgggacagcctccaaagcggctcatcagcctggtgtccaagttggacagcgg 
               
               
                   
                   
                 cgtgccagaccgcttctccggttcgggaagcggtactgatttcacgctgaccatctcatccc 
               
               
                   
                   
                 tccaagcggaggatgtggcagtctactactgttggcagggcacgcattttccgggcactttt 
               
               
                   
                   
                 ggaggagggaccaaggtcgaaatcaagggaggaggtggctcgggcggaggaggctcgggagg 
               
               
                   
                   
                 aggaggatcaggaggcggtggaagcgagattcaactggtccagagcggcgcagaagtcaaga 
               
               
                   
                   
                 agccgggtgaatcgctcagaatctcgtgcaaaggatcgggattcaacatcgaggactactac 
               
               
                   
                   
                 attcactgggtcagacaaatgccgggcaaagggctggaatggatggggaggatcgaccccga 
               
               
                   
                   
                 aaacgatgaaaccaagtacggaccaatcttccaagggcacgtgaccatttcggcggacacct 
               
               
                   
                   
                 caatcaacactgtgtacctccagtggagctcacttaaggccagcgataccgccatgtactat 
               
               
                   
                   
                 tgcgctttccgcggaggggtgtactggggacagggcactactgtgaccgtgtcatccaccac 
               
               
                   
                   
                 taccccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgc 
               
               
                   
                   
                 gtccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcc 
               
               
                   
                   
                 tgcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgt 
               
               
                   
                   
                 gatcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttca 
               
               
                   
                   
                 tgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggag 
               
               
                   
                   
                 gaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctacaagca 
               
               
                   
                   
                 ggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctgg 
               
               
                   
                   
                 acaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagag 
               
               
                   
                   
                 agggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatg 
               
               
                   
                   
                 aaaggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccac 
               
               
                   
                   
                 caaggacacctatgacgctcttcacatgcaggccctgccgcctcgg 
               
               
                   
               
               
                 CAR 7 
                 1079 
                 malpvtalllplalllhaarpdvvmtqspdslavslgeratinc   kssqslldsdgktyln   wl 
               
               
                 Full-aa 
                   
                 qqkpgqppkrlis   lvsklds   gvpdrfsgsgsgtdftltisslqaedvavyyc   wqgthfpgt   f 
               
               
                   
                   
                 gggtkveikggggsggggsggggsggggseiqlvqsgaevkkpgeslrisckgsgfnie   dyy     
               
               
                   
                   
                     ih   wvrqmpgkglewmg   ridpendetkygpifqg   hvtisadtsintvylqwsslkasdtamyy 
               
               
                   
                   
                 caf   rggvy   wgqgttvtvsstttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfa 
               
               
                   
                   
                 cdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeee 
               
               
                   
                   
                 eggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqe 
               
               
                   
                   
                 glynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
               
                 CAR 8- 
                 1084 
                 atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgctcggcc 
               
               
                 Full-nt 
                   
                 cgatgtggtcatgacgcagtcaccactgtccctccccgtgacccttggacagccagcgtcga 
               
               
                   
                   
                 ttagctgcaagtcatcccaatcccgctcgattcggatggaaagacctatctcaactggctgc 
               
               
                   
                   
                 agcaaagacccggtcagagccctaggagactcatctcgttggtgtcaaagctggacagcgga 
               
               
                   
                   
                 gtgccggaccggttttccggttcgggatcggggacggacttcactctgaagatttcacgggt 
               
               
                   
                   
                 ggaagctgaggatgtgggagtgtactactgctggcagggaacccatttccctggcacttttg 
               
               
                   
                   
                 gcggaggaactaaggtcgaaatcaagggaggaggtggctcgggaggaggcggatcgggcgga 
               
               
                   
                   
                 ggcgggagcggcggaggagggtccgaaatccaacttgtccagtcaggagccgaagtgaagaa 
               
               
                   
                   
                 accgggagccaccgtcaaaatcagctgtaagggatcgggattcaatatcgaggactactaca 
               
               
                   
                   
                 tccactgggtgcagcaagctccgggcaaaggactggagtggatggggcgcatcgacccagag 
               
               
                   
                   
                 aacgacgaaaccaaatacggcccgatcttccaagggcgggtgaccatcaccgcggacacctc 
               
               
                   
                   
                 aactaacactgtgtacatggagctgagctccctgcgctccgaagatactgcagtctactact 
               
               
                   
                   
                 gcgccttccgcggtggtgtgtactggggacagggcaccactgtgactgtcagctcgaccact 
               
               
                   
                   
                 accccagcaccgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcg 
               
               
                   
                   
                 tccggaggcatgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcct 
               
               
                   
                   
                 gcgatatctacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtg 
               
               
                   
                   
                 atcactctttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaagcccttca 
               
               
                   
                   
                 tgaggcctgtgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggag 
               
               
                   
                   
                 gaaggcggctgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctacaagca 
               
               
                   
                   
                 ggggcagaaccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctgg 
               
               
                   
                   
                 acaagcggagaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagag 
               
               
                   
                   
                 ggcctgtacaacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaa 
               
               
                   
                   
                 aggggaacgcagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccacca 
               
               
                   
                   
                 aggacacctatgacgctcttcacatgcaggccctgccgcctcgg 
               
               
                   
               
               
                 CAR 8- 
                 1085 
                 malpvtalllplalllhaarpdvvmtqsplslpvtlgqpasisc   kssqslldsdgktyln   wl 
               
               
                 Full-aa 
                   
                 qqrpgqsprrlis   lvsklds   gvpdrfsgsgsgtdftlkisrveaedvgvyyc   wqgthfpgt   f 
               
               
                   
                   
                 gggtkveikggggsggggsggggsggggseiqlvqsgaevkkpgatvkisckgsgfnie   dyy     
               
               
                   
                   
                     ih   wvqqapgkglewmg   ridpendetkygpifqg   rvtitadtstntvymelsslrsedtavyy 
               
               
                   
                   
                 caf   rggvy   wgqgttvtvsstttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfa 
               
               
                   
                   
                 cdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeee 
               
               
                   
                   
                 eggcelrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqe 
               
               
                   
                   
                 glynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
            
           
           
               
            
               
                 CAR 9 Mouse anti-EGFRvIII clone 3C10 
               
            
           
           
               
               
               
            
               
                 CAR 9- 
                 1089 
                 atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgctcggcc 
               
               
                 Full-nt 
                   
                 cgagatccagctccaacagagcggagccgaactggtcaaaccgggagcgtcggtgaagttgt 
               
               
                   
                   
                 catgcactggatcgggcttcaacatcgaggattactacatccactgggtcaagcaacgcacc 
               
               
                   
                   
                 gagcaggggctggaatggatcggacggatcgaccccgaaaacgatgaaaccaagtacgggcc 
               
               
                   
                   
                 tatcttccaaggacgggccaccattacggctgacacgtcaagcaataccgtctacctccagc 
               
               
                   
                   
                 tttccagcctgacctccgaggacactgccgtgtactactgcgccttcagaggaggcgtgtac 
               
               
                   
                   
                 tggggaccaggaaccactttgaccgtgtccagcggaggcggtggatcaggaggaggaggctc 
               
               
                   
                   
                 aggcggtggcggctcgcacatggacgtggtcatgactcagtccccgctgaccctgtcggtgg 
               
               
                   
                   
                 caattggacagagcgcatccatctcgtgcaagagctcacagtcgctgctggattccgacgga 
               
               
                   
                   
                 aagacttatctgaactggctgctccaaagaccagggcaatcaccgaaacgccttatctccct 
               
               
                   
                   
                 ggtgtcgaaactcgactcgggtgtgccggatcggtttaccggtagcgggtccggcacggact 
               
               
                   
                   
                 tcactctccgcatttcgagggtggaagcggaggatctcgggatctactactgttggcaggga 
               
               
                   
                   
                 acccacttccctgggacttttggaggcggaactaagctggaaatcaagaccactaccccagc 
               
               
                   
                   
                 accgaggccacccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggagg 
               
               
                   
                   
                 catgtagacccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatc 
               
               
                   
                   
                 tacatttgggcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactct 
               
               
                   
                   
                 ttactgtaagcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctg 
               
               
                   
                   
                 tgcagactactcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggc 
               
               
                   
                   
                 tgcgaactgcgcgtgaaattcagccgcagcgcagatgctccagcctacaagcaggggcagaa 
               
               
                   
                   
                 ccagctctacaacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcgga 
               
               
                   
                   
                 gaggacgggacccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtac 
               
               
                   
                   
                 aacgagctccaaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacg 
               
               
                   
                   
                 cagaagaggcaaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacct 
               
               
                   
                   
                 atgacgctcttcacatgcaggccctgccgcctcgg 
               
               
                   
               
               
                 CAR 9- 
                 1090 
                 malpvtalllplalllhaarpeiqlqqsgaelvkpgasvklsctgsgfnie   dyyih   wvkqrt 
               
               
                 Full-aa 
                   
                 eqglewig   ridpendetkygpifqg   ratitadtssntvylqlssltsedtavyyca   frggvy     
               
               
                   
                   
                 wgpgttltvssggggsggggsggggshmdvvmtqspltlsvaigqsasisc   kssqslldsdg     
               
               
                   
                   
                     ktyln   wllqrpgqspkrlis   lvsklds   gvpdrftgsgsgtdftlrisrveaedlgiyyc   wqg     
               
               
                   
                   
                     thfpgt   fgggtkleiktttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdi 
               
               
                   
                   
                 yiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeegg 
               
               
                   
                   
                 celrvkfsrsadapaykqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqegly 
               
               
                   
                   
                 nelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
            
           
           
               
            
               
                 CAR10 Anti-EGFRvIII clone 139 
               
            
           
           
               
               
               
            
               
                 CAR 10 
                 1095 
                 atggccctccctgtcaccgccctgctgcttccgctggctcttctgctccacgccgctcggcc 
               
               
                 Full-nt 
                   
                 cgatatccaaatgactcagagcccttcatccctgagcgccagcgtcggagacagggtgacca 
               
               
                   
                   
                 tcacgtgccgggcatcccaaggcattagaaataacttggcgtggtatcagcaaaaaccagga 
               
               
                   
                   
                 aaggccccgaagcgcctgatctacgcggcctccaaccttcagtcaggagtgccctcgcgctt 
               
               
                   
                   
                 caccgggagcggtagcggaactgagtttacccttatcgtgtcgtccctgcagccagaggact 
               
               
                   
                   
                 tcgcgacctactactgcctccagcatcactcgtacccgttgacttcgggaggcggaaccaag 
               
               
                   
                   
                 gtcgaaatcaaacgcactggctcgacgtcagggtccggtaaaccgggatcgggagaaggatc 
               
               
                   
                   
                 ggaagtccaagtgctggagagcggaggcggactcgtgcaacctggcgggtcgctgcggctca 
               
               
                   
                   
                 gctgtgccgcgtcgggttttactttcagctcgtacgctatgtcatgggtgcggcaggctccg 
               
               
                   
                   
                 ggaaaggggctggaatgggtgtccgctatttccggctcgggtggaagcaccaattacgccga 
               
               
                   
                   
                 ctccgtgaagggacgcttcaccatctcacgggataactccaagaatactctgtacctccaga 
               
               
                   
                   
                 tgaactcgctgagagccgaggacaccgcagtgtactactgcgcagggtcaagcggctggtcc 
               
               
                   
                   
                 gaatactggggacagggcaccctcgtcactgtcagctccaccactaccccagcaccgaggcc 
               
               
                   
                   
                 acccaccccggctcctaccatcgcctcccagcctctgtccctgcgtccggaggcatgtagac 
               
               
                   
                   
                 ccgcagctggtggggccgtgcatacccggggtcttgacttcgcctgcgatatctacatttgg 
               
               
                   
                   
                 gcccctctggctggtacttgcggggtcctgctgctttcactcgtgatcactctttactgtaa 
               
               
                   
                   
                 gcgcggtcggaagaagctgctgtacatctttaagcaacccttcatgaggcctgtgcagacta 
               
               
                   
                   
                 ctcaagaggaggacggctgttcatgccggttcccagaggaggaggaaggcggctgcgaactg 
               
               
                   
                   
                 cgcgtgaaattcagccgcagcgcagatgctccagcctacaagcaggggcagaaccagctcta 
               
               
                   
                   
                 caacgaactcaatcttggtcggagagaggagtacgacgtgctggacaagcggagaggacggg 
               
               
                   
                   
                 acccagaaatgggcgggaagccgcgcagaaagaatccccaagagggcctgtacaacgagctc 
               
               
                   
                   
                 caaaaggataagatggcagaagcctatagcgagattggtatgaaaggggaacgcagaagagg 
               
               
                   
                   
                 caaaggccacgacggactgtaccagggactcagcaccgccaccaaggacacctatgacgctc 
               
               
                   
                   
                 ttcacatgcaggccctgccgcctcgg 
               
               
                   
               
               
                 CAR 10 
                 1096 
                 malpvtalllplalllhaarpdiqmtqspsslsasvgdrvtitcrasqgirnnlawyqqkpg 
               
               
                 Full-aa 
                   
                 kapkrliyaasnlqsgvpsrftgsgsgteftlivsslqpedfatyyclqhhsypltsgggtk 
               
               
                   
                   
                 veikrtgstsgsgkpgsgegsevqvlesggglvqpggslrlscaasgftfssyamswvrqap 
               
               
                   
                   
                 gkglewvsaisgsggstnyadsvkgrftisrdnskntlylqmnslraedtavyycagssgws 
               
               
                   
                   
                 eywgqgtlvtvsstttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiw 
               
               
                   
                   
                 aplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcel 
               
               
                   
                   
                 rvkfsrsadapaykqgqnqlynellgrreeydvldkrrgrdpemggkprrknpqeglynelq 
               
               
                   
                   
                 kdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr 
               
               
                   
               
            
           
         
       
     
     In one embodiment, the cell of the invention (e.g., a cell comprising both a TA CAR and a BCA CAR) comprises a TA CAR molecule that binds EGFRvIII that comprises (e.g., consists of) an amino acid sequence as provided in Table 17. In one embodiment, the TA CAR that binds EGFRvIII comprises (e.g., consists of) an amino acid sequence of SEQ ID NO: 1043, SEQ ID NO: 1049, SEQ ID NO: 1055, SEQ ID NO: 1061, SEQ ID NO: 1067, SEQ ID NO: 1073, SEQ ID NO: 1079, SEQ ID NO: 1085, SEQ ID NO: 1090, or SEQ ID NO: 1096; or an amino acid sequence having at least one, two, three, four, five, 10, 15, 20 or 30 modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 60, 50, or 40 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of SEQ ID NO: 1043, SEQ ID NO: 1049, SEQ ID NO: 1055, SEQ ID NO: 1061, SEQ ID NO: 1067, SEQ ID NO: 1073, SEQ ID NO: 1079, SEQ ID NO: 1085, SEQ ID NO: 1090, or SEQ ID NO: 1096; or an amino acid sequence having 85%, 90%, 95%, 96%, 97%, 98%, 99°/identity to an amino acid sequence of SEQ ID NO: 1043, SEQ ID NO: 1049, SEQ ID NO: 1055, SEQ ID NO: 1061, SEQ ID NO: 1067, SEQ ID NO: 1073, SEQ ID NO: 1079, SEQ ID NO: 1085, SEQ ID NO: 1090, or SEQ ID NO: 1096. 
     In one aspect, the cell of the invention (e.g., a cell comprising both a TA CAR and a BCA CAR) comprises a TA CAR molecule comprising an antigen binding domain that binds to a tumor antigen. In one embodiment, the TA CAR comprises a CAR molecule comprising a CD123 antigen binding domain (e.g., a murine, human or humanized antibody or antibody fragment that specifically binds to mesothelin), a transmembrane domain, and an intracellular signaling domain (e.g., an intracellular signaling domain comprising a costimulatory domain and/or a primary signaling domain). 
     Exemplary TA CAR molecules that target CD123 are described herein, and are provided in Tables 2, 6 and 9 of WO2016/028896. Other exemplary TA CAR molecules that target CD123 are described in WO/2014/130635 (e.g., Table 1 of WO/2014/130635). Other exemplary TA CAR molecules that target CD123 are described in WO/2014/144622. 
     In one aspect, the cell of the invention (e.g., a cell comprising both a TA CAR and a BCA CAR) comprises a TA CAR molecule comprising an antigen binding domain that binds to a tumor antigen. In one embodiment, the TA CAR comprises a CAR molecule comprising a CD33 antigen binding domain (e.g., a murine, human or humanized antibody or antibody fragment that specifically binds to mesothelin), a transmembrane domain, and an intracellular signaling domain (e.g., an intracellular signaling domain comprising a costimulatory domain and/or a primary signaling domain). Exemplary TA CAR molecules that target CD33 are described herein, and are provided in WO2016/014576, e.g., in Table 2 of WO2016/014576. 
     In one aspect, the cell of the invention (e.g., a cell comprising both a TA CAR and a BCA CAR) comprises a TA CAR molecule comprising an antigen binding domain that binds to a tumor antigen. In one embodiment, the TA CAR comprises a CAR molecule comprising a CLL-1 antigen binding domain (e.g., a murine, human or humanized antibody or antibody fragment that specifically binds to mesothelin), a transmembrane domain, and an intracellular signaling domain (e.g., an intracellular signaling domain comprising a costimulatory domain and/or a primary signaling domain). Exemplary TA CAR molecules that target CLL-1 are described herein, and are provided in WO/2016/014535, e.g., in Table 2 of WO2016/014535. 
     Natural Killer Cell Receptor (NKR) CARs 
     In an embodiment, the CAR molecule described herein, e.g., the CAR molecule that targets a tumor antigen (TA CAR) or the CAR molecule that targets a B cell antigen (BCA CAR), 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. 
     Split CAR 
     In some embodiments, the CAR-expressing cell, e.g., the cell expressing a BCA CAR and a TA CAR, described herein, uses a split CAR The split CAR approach is described in more detail in publications WO2014/055442 and WO2014/055657, incorporated herein by reference. 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. In embodiments the first antigen binding domain recognizes the tumor antigen or B cell antigen described herein, e.g., comprises an antigen binding domain described herein, and the second antigen binding domain recognizes a second antigen, e.g., a second tumor antigen or a second B cell antigen described herein. 
     Strategies for Regulating Chimeric Antigen Receptors 
     There are many ways CAR activities can be regulated. 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. 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 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 1a/LFA-1, CD15, CD18/ITGB2, CD19, CD20, CD22, CD23/IgE 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 other embodiments, 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. 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. 
     Co-Expression of CAR with a Chemokine Receptor 
     In embodiments, the CAR-expressing cell (e.g., the cell expressing both a TA CAR and a BCA CAR) 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 (e.g., the cell expressing both a TA CAR and a BCA CAR) that recognize chemokines secreted by tumors, e.g., solid tumors, can improve homing of the CAR-expressing cell (e.g., the cell expressing both a TA CAR and a BCA CAR) to the tumor, facilitate the infiltration of the CAR-expressing cell to the tumor, and enhances antitumor efficacy of the CAR-expressing cell (e.g., the cell expressing both a TA CAR and a BCA CAR). 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 (e.g., the cell expressing both a TA CAR and a BCA CAR) 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 (e.g., the cell expressing both a TA CAR and a BCA CAR) described herein further comprises, e.g., expresses, a CCR2b receptor or a CXCR2 receptor. In an embodiment, the CAR described herein (e.g., the cell expressing both a TA CAR and a BCA CAR) 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 e.g., the cell expressing both a TA CAR and a BCA CAR) and the chemokine receptor molecule are each under control of two different promoters or are under the control of the same promoter. 
     Nucleic Acid Constructs Encoding a CAR 
     The present disclosure also provides nucleic acid molecules encoding one or more of the CAR constructs targeting a tumor antigen and/or a B cell antigen described herein. 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 a nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain that binds to a tumor antigen described herein or a B cell antigen described herein, a transmembrane domain (e.g., a transmembrane domain described herein), and an intracellular signaling domain (e.g., an intracellular signaling domain described herein) comprising a stimulatory domain, e.g., a costimulatory signaling domain (e.g., a costimulatory signaling domain described herein) and/or a primary signaling domain (e.g., a primary signaling domain described herein, e.g., a zeta chain described herein). 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 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, 1L2R 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, NKG2D, NKG2C, 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, and NKG2C. 
     In one embodiment, the transmembrane domain comprises a sequence of SEQ ID NO: 12, or a sequence with 95-99% identity thereof. In one embodiment, the antigen 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:4 or SEQ ID NO:6 or SEQ ID NO:8 or SEQ ID NO: 10, 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). 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, NKG2D, and NKG2C. 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: 14 or SEQ ID NO: 16, 42, or 44, or a sequence with 95-99% identity thereof, and the sequence of SEQ ID NO: 18 or SEQ ID NO:20, 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: 2, a scFv domain as described herein, a hinge region of SEQ ID NO:4 or SEQ ID NO:6 or SEQ ID NO:8 or SEQ ID NO:10 (or a sequence with 95-99% identity thereof), a transmembrane domain having a sequence of SEQ ID NO: 12 (or a sequence with 95-99% identity thereof), a 4-1BB costimulatory domain having a sequence of SEQ ID NO: 14, a CD27 costimulatory domain having a sequence of SEQ ID NO: 16 (or a sequence with 95-99% identity thereof), a ICOS costimulatory domain having a sequence of SEQ ID NO: 42 (or a sequence with 95-99% identity thereof) or a CD28 costimulatory domain having a sequence of SEQ ID NO:44, and a CD3 zeta stimulatory domain having a sequence of SEQ ID NO: 18 or SEQ ID NO:20 (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 disclosure also provides vectors in which a nucleic acid of the present disclosure 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. 
     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, crisper, CAS9, and zinc finger nucleases. See below June et al. 2009 Nature Reviews Immunology  9.10: 704-716, is incorporated herein by reference. 
     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. 
     The expression constructs of the present disclosure 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-1α, ubiquitin C, or phosphoglycerokinase (PGK) promoters. 
     An example of a promoter that is capable of expressing a CAR encoding nucleic acid molecule 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 nucleic acid molecules 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: 1. 
     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-1α 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: 101)       ACCCCTCTCTCCAGCCACTAAGCCAGTTGCTCCCTCGGCTGACGGCTGCA               CGCGAGGCCTCCGAACGTCTTACGCCTTGTGGCGCGCCCGTCCTTGTCCC               GGGTGTGATGGCGGGGTGTGGGGCGGAGGGCGTGGCGGGGAAGGGCCGGC               GACGAGAGCCGCGCGGGACGACTCGTCGGCGATAACCGGTGTCGGGTAGC               GCCAGCCGCGCGACGGTAACGAGGGACCGCGACAGGCAGACGCTCCCATG               ATCACTCTGCACGCCGAAGGCAAATAGTGCAGGCCGTGCGGCGCTTGGCG               TTCCTTGGAAGGGCTGAATCCCCGCCTCGTCCTTCGCAGCGGCCCCCCGG               GTGTTCCCATCGCCGCTTCTAGGCCCACTGCGACGCTTGCCTGCACTTCT               TACACGCTCTGGGTCCCAGCCGCGGCGACGCAAAGGGCCTTGGTGCGGGT               CTCGTCGGCGCAGGGACGCGTTTGGGTCCCGACGGAACCTTTTCCGCGTT               GGGGTTGGGGCACCATAAGCT            
Exemplary truncated PGK Promoters:
 
     
       
         
           
               
            
               
                 PGK100: 
               
               
                 (SEQ ID NO: 102) 
               
               
                 ACCCCTCTCTCCAGCCACTAAGCCAGTTGCTCCCTCGGCTGACGGCTGCA 
               
               
                   
               
               
                 CGCGAGGCCTCCGAACGTCTTACGCCTTGTGGCGCGCCCGTCCTTGTCCC 
               
               
                   
               
               
                 GGGTGTGATGGCGGGGTG 
               
               
                   
               
               
                 PGK200: 
               
               
                 (SEQ ID NO: 103) 
               
               
                 ACCCCTCTCTCCAGCCACTAAGCCAGTTGCTCCCTCGGCTGACGGCTGCA 
               
               
                   
               
               
                 CGCGAGGCCTCCGAACGTCTTACGCCTTGTGGCGCGCCCGTCCTTGTCCC 
               
               
                   
               
               
                 GGGTGTGATGGCGGGGTGTGGGGCGGAGGGCGTGGCGGGGAAGGGCCGGC 
               
               
                   
               
               
                 GACGAGAGCCGCGCGGGACGACTCGTCGGCGATAACCGGTGTCGGGTAGC 
               
               
                   
               
               
                 GCCAGCCGCGCGACGGTAACG 
               
               
                   
               
               
                 PGK300: 
               
               
                 (SEQ ID NO: 104) 
               
               
                 ACCCCTCTCTCCAGCCACTAAGCCAGTTGCTCCCTCGGCTGACGGCTGCA 
               
               
                   
               
               
                 CGCGAGGCCTCCGAACGTCTTACGCCTTGTGGCGCGCCCGTCCTTGTCCC 
               
               
                   
               
               
                 GGGTGTGATGGCGGGGTGTGGGGCGGAGGGCGTGGCGGGGAAGGGCCGGC 
               
               
                   
               
               
                 GACGAGAGCCGCGCGGGACGACTCGTCGGCGATAACCGGTGTCGGGTAGC 
               
               
                   
               
               
                 GCCAGCCGCGCGACGGTAACGAGGGACCGCGACAGGCAGACGCTCCCATG 
               
               
                   
               
               
                 ATCACTCTGCACGCCGAAGGCAAATAGTGCAGGCCGTGCGGCGCTTGGCG 
               
               
                   
               
               
                 TTCCTTGGAAGGGCTGAATCCCCG 
               
               
                   
               
               
                 PGK400: 
               
               
                 (SEQ ID NO: 105) 
               
               
                 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 some embodiments, the a vector comprising a nuclei acid sequence encoding a CAR molecules described herein, e.g., a TA CAR and/or a BCA CAR, can further comprises a second nucleic acid sequence encoding a polypeptide, e.g., an agent that increases the activity of the CAR molecule. In some embodiments a single nucleic acid molecule, or vector comprising said nucleic acid molecule, encodes both the TA CAR, described herein, and the BCA CAR, described herein. In some embodiments, the nucleic acid encoding the TA CAR is under separate regulatory control (e.g., by a promoter described herein) from the nucleic acid endocing the BCA CAR (e.g., by a promoter described herein). In other embodiments, the two or more nucleic acid sequences 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 (e.g., the TA CAR and the BCA CAR), 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: 106) 
               
               
                 (GSG) E G R G S L L T C G D V E E N P G P 
               
               
                   
               
               
                 P2A: 
               
               
                 (SEQ ID NO: 107) 
               
               
                 (GSG) A T N F S L L K Q A G D V E E N P G P 
               
               
                   
               
               
                 E2A: 
               
               
                 (SEQ ID NO: 108) 
               
               
                 (GSG) Q C T N Y A L L K L A G D V E S N P G P 
               
               
                   
               
               
                 F2A: 
               
               
                 (SEQ ID NO: 109) 
               
               
                 (GSG) V K Q T L N F D L L K L A G D V E S N P G P 
               
            
           
         
       
     
     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 preferred method for the introduction of a polynucleotide into a host cell is calcium phosphate transfection or electroporation. 
     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 disclosure, 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 disclosure further provides a vector comprising a CAR encoding nucleic acid molecule. In one embodiment, the vector comprises a TA CAR encoding nucleic acid molecule, e.g., as described herein. In one embodiment, the vector comprises a BCA CAR encoding nucleic acid molecule, e.g., as described herein. In one embodiment, the vector comprises a BCA CAR encoding nucleic acid molecule and a TA CAR encoding nucleic acid molecule. In one aspect, the one or more CAR vectors (e.g., the vector comprising the TA CAR encoding nucleic acid molecule and the vector comprising the BCA CAR encoding nucleic acid molecule, or the vector comprising the TA CAR encoding nucleic acid and the BCA CAR encoding nucleic acid) can be directly transduced into a cell, e.g., a T cell or a NK 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 immune effector cells (e.g., T cells, NK cells). 
     In one embodiment, where stable expression of a TA CAR and/or a BCA CAR is desired, a vector comprising a TA CAR- and/or BCA CAR-encoding nucleic acid molecule is transduced into an immune effector cell. For example, immune effector cells with stable expression of a TA CAR and a BCA CAR can be generated using lentiviral vectors. Cells that exhibit stable expression of a TA CAR and a BCA CAR express the TA CAR and BCA CAR for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 6 months, 9 months, or 12 months after transduction. 
     In one embodiment, where transient expression of a TA CAR and/or a BCA CAR is desired, a TA CAR- and/or BCA CAR-encoding nucleic acid molecule is transfected into an immune effector cell. The TA CAR- and/or BCA CAR-encoding nucleic acid molecule may be a vector comprising a TA CAR- and/or BCA-CAR encoding nucleic acid molecule, or an in vitro transcribed RNA encoding TA CAR and/or BCA CAR. In vitro transcribed RNA CARs and methods for transfection into immune effector cells are further described below. Cells that exhibit transient expression of a TA CAR and/or a BCA CAR express the TA CAR and/or BCA CAR for 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 days after transfection. 
     RNA Transfection 
     Disclosed herein are methods for producing an in vitro transcribed RNA CAR, e.g., an in vitro transcribed RNA TA CAR and/or an in vitro transcribed RNA BCA CAR. The present disclosure also includes 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:32). RNA so produced can efficiently transfect different kinds of cells. In one aspect, the template includes sequences for the CAR. 
     In one aspect, a CAR of the present disclosure, e.g., a TA CAR and/or a BCA CAR, is encoded by a messenger RNA (mRNA). In one aspect, the mRNA encoding a TA CAR described herein and/or a BCA CAR described herein is introduced into a T cell or a NK cell for production of a cell that expresses both a TA CAR and a BCA CAR. 
     In one embodiment, the in vitro transcribed RNA CAR can be introduced to a cell as a form of transient transfection. The RNA is produced by in vitro transcription using a polymerase chain reaction (PCR)-generated template. DNA of interest from any source can be directly converted by PCR into a template for in vitro mRNA synthesis using appropriate primers and RNA polymerase. The source of the DNA can be, for example, genomic DNA, plasmid DNA, phage DNA, cDNA, synthetic DNA sequence or any other appropriate source of DNA. The desired template for in vitro transcription is a CAR described herein. For example, the template for the RNA CAR comprises an extracellular region comprising a single chain variable domain of an antibody to a tumor antigen or B cell antigen described herein; a hinge region (e.g., a hinge region described herein), a transmembrane domain (e.g., a transmembrane domain described herein such as a transmembrane domain of CD8a); and a cytoplasmic region that includes an intracellular signaling domain, e.g., an intracellular signaling domain described herein, e.g., comprising the signaling domain of CD3-zeta and the signaling domain of 4-1BB. 
     In one embodiment, the DNA to be used for PCR contains an open reading frame. The DNA can be from a naturally occurring DNA sequence from the genome of an organism. In one embodiment, the nucleic acid can include some or all of the 5′ and/or 3′ untranslated regions (UTRs). The nucleic acid can include exons and introns. In one embodiment, the DNA to be used for PCR is a human nucleic acid sequence. In another embodiment, the DNA to be used for PCR is a human nucleic acid sequence including the 5′ and 3′ UTRs. The DNA can alternatively be an artificial DNA sequence that is not normally expressed in a naturally occurring organism. An exemplary artificial DNA sequence is one that contains portions of genes that are ligated together to form an open reading frame that encodes a fusion protein. The portions of DNA that are ligated together can be from a single organism or from more than one organism. 
     PCR is used to generate a template for in vitro transcription of mRNA which is used for transfection. Methods for performing PCR are well known in the art. Primers for use in PCR are designed to have regions that are substantially complementary to regions of the DNA to be used as a template for the PCR. “Substantially complementary,” as used herein, refers to sequences of nucleotides where a majority or all of the bases in the primer sequence are complementary, or one or more bases are non-complementary, or mismatched. Substantially complementary sequences are able to anneal or hybridize with the intended DNA target under annealing conditions used for PCR The primers can be designed to be substantially complementary to any portion of the DNA template. For example, the primers can be designed to amplify the portion of a nucleic acid that is normally transcribed in cells (the open reading frame), including 5′ and 3′ UTRs. The primers can also be designed to amplify a portion of a nucleic acid that encodes a particular domain of interest. In one embodiment, the primers are designed to amplify the coding region of a human cDNA, including all or portions of the 5′ and 3′ UTRs. Primers useful for PCR can be generated by synthetic methods that are well known in the art. “Forward primers” are primers that contain a region of nucleotides that are substantially complementary to nucleotides on the DNA template that are upstream of the DNA sequence that is to be amplified. “Upstream” is used herein to refer to a location 5, to the DNA sequence to be amplified relative to the coding strand. “Reverse primers” are primers that contain a region of nucleotides that are substantially complementary to a double-stranded DNA template that are downstream of the DNA sequence that is to be amplified. “Downstream” is used herein to refer to a location 3′ to the DNA sequence to be amplified relative to the coding strand. 
     Any DNA polymerase useful for PCR can be used in the methods disclosed herein. The reagents and polymerase are commercially available from a number of sources. 
     Chemical structures with the ability to promote stability and/or translation efficiency may also be used. The RNA preferably has 5′ and 3′ UTRs. In one embodiment, the 5′ UTR is between one and 3000 nucleotides in length. The length of 5′ and 3′ UTR sequences to be added to the coding region can be altered by different methods, including, but not limited to, designing primers for PCR that anneal to different regions of the UTRs. Using this approach, one of ordinary skill in the art can modify the 5′ and 3′ UTR lengths required to achieve optimal translation efficiency following transfection of the transcribed RNA. 
     The 5′ and 3′ UTRs can be the naturally occurring, endogenous 5′ and 3′ UTRs for the nucleic acid of interest. Alternatively, UTR sequences that are not endogenous to the nucleic acid of interest can be added by incorporating the UTR sequences into the forward and reverse primers or by any other modifications of the template. The use of UTR sequences that are not endogenous to the nucleic acid of interest can be useful for modifying the stability and/or translation efficiency of the RNA. For example, it is known that AU-rich elements in 3′ UTR sequences can decrease the stability of mRNA. Therefore, 3′ UTRs can be selected or designed to increase the stability of the transcribed RNA based on properties of UTRs that are well known in the art. 
     In one embodiment, the 5′ UTR can contain the Kozak sequence of the endogenous nucleic acid. Alternatively, when a 5′ UTR that is not endogenous to the nucleic acid of interest is being added by PCR as described above, a consensus Kozak sequence can be redesigned by adding the 5′ UTR sequence. Kozak sequences can increase the efficiency of translation of some RNA transcripts, but does not appear to be required for all RNAs to enable efficient translation. The requirement for Kozak sequences for many mRNAs is known in the art. In other embodiments the 5′ UTR can be 5′UTR of an RNA virus whose RNA genome is stable in cells. In other embodiments various nucleotide analogues can be used in the 3′ or 5′ UTR to impede exonuclease degradation of the mRNA. 
     To enable synthesis of RNA from a DNA template without the need for gene cloning, a promoter of transcription should be attached to the DNA template upstream of the sequence to be transcribed. When a sequence that functions as a promoter for an RNA polymerase is added to the 5′ end of the forward primer, the RNA polymerase promoter becomes incorporated into the PCR product upstream of the open reading frame that is to be transcribed. In one preferred embodiment, the promoter is a T7 polymerase promoter, as described elsewhere herein. Other useful promoters include, but are not limited to, T3 and SP6 RNA polymerase promoters. Consensus nucleotide sequences for T7, T3 and SP6 promoters are known in the art. 
     In a preferred embodiment, the mRNA has both a cap on the 5′ end and a 3′ poly(A) tail which determine ribosome binding, initiation of translation and stability mRNA in the cell. On a circular DNA template, for instance, plasmid DNA, RNA polymerase produces a long concatameric product which is not suitable for expression in eukaryotic cells. The transcription of plasmid DNA linearized at the end of the 3′ UTR results in normal sized mRNA which is not effective in eukaryotic transfection even if it is polyadenylated after transcription. 
     On a linear DNA template, phage T7 RNA polymerase can extend the 3′ end of the transcript beyond the last base of the template (Schenborn and Mierendorf, Nuc Acids Res., 13:6223-36 (1985); Nacheva and Berzal-Herranz, Eur. J. Biochem., 270:1485-65 (2003). 
     The conventional method of integration of polyA/T stretches into a DNA template is molecular cloning. However polyA/T sequence integrated into plasmid DNA can cause plasmid instability, which is why plasmid DNA templates obtained from bacterial cells are often highly contaminated with deletions and other aberrations. This makes cloning procedures not only laborious and time consuming but often not reliable. That is why a method which allows construction of DNA templates with polyA/T 3′ stretch without cloning highly desirable. 
     The polyA/T segment of the transcriptional DNA template can be produced during PCR by using a reverse primer containing a polyT tail, such as 100T tail (SEQ ID NO: 35) (size can be 50-5000 T (SEQ ID NO: 265)), or after PCR by any other method, including, but not limited to, DNA ligation or in vitro recombination. Poly(A) tails also provide stability to RNAs and reduce their degradation. Generally, the length of a poly(A) tail positively correlates with the stability of the transcribed RNA. In one embodiment, the poly(A) tail is between 100 and 5000 adenosines (SEQ ID NO: 82). 
     Poly(A) tails of RNAs can be further extended following in vitro transcription with the use of a poly(A) polymerase, such as  E. coli  polyA polymerase (E-PAP). In one embodiment, increasing the length of a poly(A) tail from 100 nucleotides to between 300 and 400 nucleotides (SEQ ID NO: 38) results in about a two-fold increase in the translation efficiency of the RNA. Additionally, the attachment of different chemical groups to the 3′ end can increase mRNA stability. Such attachment can contain modified/artificial nucleotides, aptamers and other compounds. For example, ATP analogs can be incorporated into the poly(A) tail using poly(A) polymerase. ATP analogs can further increase the stability of the RNA. 
     5′ caps on also provide stability to RNA molecules. In a preferred embodiment, RNAs produced by the methods disclosed herein include a 5′ cap. The 5′ cap is provided using techniques known in the art and described herein (Cougot, et al., Trends in Biochem. Sci., 29:436-444 (2001); Stepinski, et al., RNA, 7:1468-95 (2001); Elango, et al., Biochim. Biophys. Res. Commun., 330:958-966 (2005)). 
     The RNAs produced by the methods disclosed herein can also contain an internal ribosome entry site (IRES) sequence. The IRES sequence may be any viral, chromosomal or artificially designed sequence which initiates cap-independent ribosome binding to mRNA and facilitates the initiation of translation. Any solutes suitable for cell electroporation, which can contain factors facilitating cellular permeability and viability such as sugars, peptides, lipids, proteins, antioxidants, and surfactants can be included. 
     RNA can be introduced into target cells using any of a number of different methods, for instance, commercially available methods which include, but are not limited to, electroporation (Amaxa Nucleofector-II (Amaxa Biosystems, Cologne, Germany)), (ECM 830 (BTX) (Harvard Instruments, Boston, Mass.) or the Gene Pulser II (BioRad, Denver, Colo.), Multiporator (Eppendort, Hamburg Germany), cationic liposome mediated transfection using lipofection, polymer encapsulation, peptide mediated transfection, or biolistic particle delivery systems such as “gene guns” (see, for example, Nishikawa, et al. Hum Gene Ther., 12(8):861-70 (2001). 
     Non-Viral Delivery Methods 
     In some aspects, non-viral methods can be used to deliver a nucleic acid encoding a CAR described herein, e.g., a TA CAR and/or a BCA CAR, 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. For example, a transposon comprises a DNA sequence made up of inverted repeats flanking genes for transposition. Exemplary methods of nucleic acid delivery using a transposon include a Sleeping Beauty transposon system (SBTS) and a piggyBac (PB) transposon system. See, e.g., Aronovich et al. Hum. Mol. Genet. 20.R1(2011):R14-20; Singh et al. Cancer Res. 15(2008):2961-2971; Huang et al. Mol. Ther. 16(2008):580-589; Grabundzija et al. Mol. Ther. 18(2010):1200-1209; Kebriaei et al. Blood. 122.21(2013):166; Williams. Molecular Therapy 16.9(2008):1515-16; Bell et al. Nat. Protoc. 2.12(2007):3153-65; and Ding et al. Cell. 122.3(2005):473-83, all of which are incorporated herein by reference. 
     The SBTS includes two components: 1) a transposon containing a transgene and 2) a source of transposase enzyme. The transposase can transpose the transposon from a carrier plasmid (or other donor DNA) to a target DNA, such as a host cell chromosome/genome. For example, the transposase binds to the carrier plasmid/donor DNA, cuts the transposon (including transgene(s)) out of the plasmid, and inserts it into the genome of the host cell. See, e.g., Aronovich et al. supra. 
     Exemplary transposons include a pT2-based transposon. See, e.g., Grabundzija et al. Nucleic Acids Res. 41.3(2013):1829-47; and Singh et al. Cancer Res. 68.8(2008): 2961-2971, all of which are incorporated herein by reference. Exemplary transposases include a Tcl/mariner-type transposase, e.g., the SB10 transposase or the SB11 transposase (a hyperactive transposase which can be expressed, e.g., from a cytomegalovirus promoter). See, e.g., Aronovich et al.; Kebriaei et al.: and Grabundzija et al., all of which are incorporated herein by reference. 
     Use of the SBTS permits efficient integration and expression of a transgene, e.g., a nucleic acid encoding a CAR described herein. Provided herein are methods of generating a cell, e.g., T cell or NK cell, that stably expresses a CAR described herein, e.g., using a transposon system such as SBTS. 
     In accordance with methods described herein, in some embodiments, one or more nucleic acids, e.g., plasmids, containing the SBTS components are delivered to a cell (e.g., T or NK cell). For example, the nucleic acid(s) are delivered by standard methods of nucleic acid (e.g., plasmid DNA) delivery, e.g., methods described herein, e.g., electroporation, transfection, or lipofection. In some embodiments, the nucleic acid contains a transposon comprising a transgene, e.g., a nucleic acid encoding a CAR described herein. In some embodiments, the nucleic acid contains a transposon comprising a transgene (e.g., a nucleic acid encoding a CAR described herein) as well as a nucleic acid sequence encoding a transposase enzyme. In other embodiments, a system with two nucleic acids is provided, e.g., a dual-plasmid system, e.g., where a first plasmid contains a transposon comprising a transgene, and a second plasmid contains a nucleic acid sequence encoding a transposase enzyme. For example, the first and the second nucleic acids are co-delivered into a host cell. 
     In some embodiments, cells, e.g., T or NK cells, are generated that express a TA CAR and BCA CAR described herein by using a combination of gene insertion using the SBTS and genetic editing using a nuclease (e.g., Zinc finger nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs), the CRISPR/Cas system, or engineered meganuclease re-engineered homing endonucleases). 
     In some embodiments, use of a non-viral method of delivery permits reprogramming of cells, e.g., T or NK cells, and direct infusion of the cells into a subject. Advantages of non-viral vectors include but are not limited to the ease and relatively low cost of producing sufficient amounts required to meet a patient population, stability during storage, and lack of immunogenicity. 
     Sources of Cells 
     Prior to expansion and genetic modification, e.g., to express both a TA CAR and a BCA CAR described herein, a source of cells, e.g., T cell or NK cells, can be obtained from a subject. The term “subject” is intended to include living organisms in which an immune response can be elicited (e.g., mammals). Examples of subjects include humans, 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 certain aspects of the present disclosure, any number of T cell lines available in the art, may be used. In certain aspects of the present disclosure, 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 preferred 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 to place the cells in an appropriate buffer or media for subsequent processing steps. In one aspect of the invention, the cells are washed with phosphate buffered saline (PBS). In an alternative aspect, 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. A specific subpopulation of T cells, such as CD3+, CD28+, CD4+, CD8+, CD45RA+, and CD45RO+T cells, can be further isolated by positive or negative selection techniques. For example, in one aspect, T cells are 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 preferred 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. The skilled artisan would recognize that multiple rounds of selection can also be used in the context of this invention. In certain aspects, it may be desirable to perform the selection procedure and use the “unselected” cells in the activation and expansion process. “Unselected” cells can also be subjected to further rounds of selection. 
     Enrichment of a T cell population by negative selection can be accomplished 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 typically includes antibodies to CD14, CD20, CD11b, CD16, HLA-DR, and CD8. In certain aspects, it may be desirable to enrich for or positively select for regulatory T cells which typically express CD4+, CD25+, CD62Lhi, G1TR+, and FoxP3+. Alternatively, in certain aspects, T regulatory cells are depleted by anti-C25 conjugated beads or other similar method of selection. 
     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. Preferably, 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′, 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 RE G cells), in a subject prior to apheresis or during manufacturing of a CAR-expressing cell product can reduce the risk of subject relapse. For example, methods of depleting T RE G 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, 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. 
     In an embodiment, a subject is pre-treated with one or more therapies that reduce T REG  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 PD 1+ 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 B7-H1, B7-1, CD160, P1H, 2B4, PD1, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, TIGIT, CTLA-4, BTLA and LAIR1. 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 there, 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. 
     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 2 billion cells/ml is used. In one aspect, a concentration of 1 billion cells/ml is used. In a further 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, 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 5×10e6/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 100/% Dextran 40 and 5% Dextrose, 200% 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 disclosure. 
     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 T cell therapy for any number of diseases or conditions that would benefit from T 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 disclosure, 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 disclosure 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, a T cell population is diaglycerol 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 Immune Effector Cells 
     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 H. 
     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 or engineered such that it produces very little functional TCR on its surface. 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 I and/or HLA class II, is downregulated. 
     In some embodiments, the T cell can lack a functional TCR and a functional HLA, e.g., HLA class I and/or HLA class H. 
     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 expresses or expresses at low levels an inhibitory molecule, e.g. 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, CTLA4, TIM3, 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. 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 cell, e.g., T cell. Expression systems for siRNA and shRNAs, and exemplary shRNAs, are described, e.g., in paragraphs 649 and 650 of International Publication 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 “CRISPRCas” 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), in a cell, e.g., T cell. 
     The CRISPR/Cas system, and uses thereof, are described, e.g., in paragraphs 651-658 of International Publication 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), in a cell, e.g., T cell. 
     TALENs, and uses thereof, are described, e.g., in paragraphs 659-665 of International Publication 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, LAIR, 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 cell, e.g., T cell. 
     ZFNs, and uses thereof, are described, e.g., in paragraphs 666-671 of International Publication 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, 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 follows: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 110) 
               
               
                 MPRAPRCRAVRSLLRSHYREVLPLATFVRRLGPQGWRLVQRGDPAAFRAL 
               
               
                   
               
               
                 VAQCLVCVPWDARPPPAAPSFRQVSCLKELVARVLQRLCERGAKNVLAFG 
               
               
                   
               
               
                 FALLDGARGGPPEAFTTSVRSYLPNTVTDALRGSGAWGLLLRRVGDDVLV 
               
               
                   
               
               
                 HLLARCALFVLVAPSCAYQVCGPPLYQLGAATQARPPPHASGPRRRLGCE 
               
               
                   
               
               
                 RAWNHSVREAGVPLGLPAPGARRRGGSASRSLPLPKRPRRGAAPEPERTP 
               
               
                   
               
               
                 VGQGSWAHPGRTRGPSDRGFCVVSPARPAEEATSLEGALSGTRHSHPSVG 
               
               
                   
               
               
                 RQHHAGPPSTSRPPRPWDTPCPPVYAETKHFLYSSGDKEQLRPSFLLSSL 
               
               
                   
               
               
                 RPSLTGARRLVETIFLGSRPWMPGTPRRLPRLPQRYWQMRPLFLELLGNH 
               
               
                   
               
               
                 AQCPYGVLLKTHCPLRAAVTPAAGVCAREKPQGSVAAPEEEDTDPRRLVQ 
               
               
                   
               
               
                 LLRQHSSPWQVYGFVRACLRRLVPPGLWGSRHNERRFLRNTKKFISLGKH 
               
               
                   
               
               
                 AKLSLQELTWKMSVRGCAWLRRSPGVGCVPAAEHRLREEILAKFLHWLMS 
               
               
                   
               
               
                 VYVVELLRSFFYVTETTFQKNRLFFYRKSVWSKLQSIGIRQHLKRVQLRE 
               
               
                   
               
               
                 LSEAEVRQHREARPALLTSRLRFIPKPDGLRPIVNMDYVVGARTFRREKR 
               
               
                   
               
               
                 AERLTSRVKALFSVLNYERARRPGLLGASVLGLDDIHRAWRTFVLRVRAQ 
               
               
                   
               
               
                 DPPPELYFVKVDVTGAYDTIPQDRLTEVIASIIKPQNTYCVRRYAVVQKA 
               
               
                   
               
               
                 AHGHVRKAFKSHVSTLTDLQPYMRQFVAHLQETSPLRDAVVIEQSSSLNE 
               
               
                   
               
               
                 ASSGLFDVFLRFMCHHAVRIRGKSYVQCQGIPQGSILSTLLCSLCYGDME 
               
               
                   
               
               
                 NKLFAGIRRDGLLLRLVDDFLLVTPHLTHAKTFLRTLVRGVPEYGCVVNL 
               
               
                   
               
               
                 RKTVVNFPVEDEALGGTAFVQMPAHGLFPWCGLLLDTRTLEVQSDYSSYA 
               
               
                   
               
               
                 RTSIRASLTFNRGFKAGRNMRRKLFGVLRLKCHSLFLDLQVNSLQTVCTN 
               
               
                   
               
               
                 IYKILLLQAYRFHACVLQLPFHQQVWKNPTFFLRVISDTASLCYSILKAK 
               
               
                   
               
               
                 NAGMSLGAKGAAGPLPSEAVQWLCHQAFLLKLTRHRVTYVPLLGSLRTAQ 
               
               
                   
               
               
                 TQLSRKLPGTTLTALEAAANPALPSDFKTILD 
               
            
           
         
       
     
     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: 110. In an embodiment, the hTERT has a sequence of SEQ ID NO: 110. 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 follows: 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 111) 
                   
               
               
                    1 caggcagcgt ggtcctgctg cgcacgtggg aagccctggc cccggccacc cccgcgatgc 
                   
               
               
                   
               
               
                   61 cgcgcgctcc ccgctgccga gccgtgcgct ccctgctgcg cagccactac cgcgaggtgc 
               
               
                   
               
               
                  121 tgccgctggc cacgttcgtg cggcgcctgg ggccccaggg ctggcggctg gtgcagcgcg 
               
               
                   
               
               
                  181 gggacccggc ggctttccgc gcgctggtgg cccagtgcct ggtgtgcgtg ccctgggacg 
               
               
                   
               
               
                  241 cacggccgcc ccccgccgcc ccctccttcc gccaggtgtc ctgcctgaag gagctggtgg 
               
               
                   
               
               
                  301 cccgagtgct gcagaggctg tgcgagcgcg gcgcgaagaa cgtgctggcc ttcggcttcg 
               
               
                   
               
               
                  361 cgctgctgga cggggcccgc gggggccccc ccgaggcctt caccaccagc gtgcgcagct 
               
               
                   
               
               
                  421 acctgcccaa cacggtgacc gacgcactgc gggggagcgg ggcgtggggg ctgctgttgc 
               
               
                   
               
               
                  481 gccgcgtggg cgacgacgtg ctggttcacc tgctggcacg ctgcgcgctc tttgtgctgg 
               
               
                   
               
               
                  541 tggctcccag ctgcgcctac caggtgtgcg ggccgccgct gtaccagctc ggcgctgcca 
               
               
                   
               
               
                  601 ctcaggcccg gcccccgcca cacgctagtg gaccccgaag gcgtctggga tgcgaacggg 
               
               
                   
               
               
                  661 cctggaacca tagcgtcagg gaggccgggg tccccctggg cctgccagcc ccgggtgcga 
               
               
                   
               
               
                  721 ggaggcgcgg gggcagtgcc agccgaagtc tgccgttgcc caagaggccc aggcgtggcg 
               
               
                   
               
               
                  781 ctgcccctga gccggagcgg acgcccgttg ggcaggggtc ctgggcccac ccgggcagga 
               
               
                   
               
               
                  841 cgcgtggacc gagtgaccgt ggtttctgtg tggtgtcacc tgccagaccc gccgaagaag 
               
               
                   
               
               
                  901 ccacctcttt ggagggtgcg ctctctggca cgcgccactc ccacccatcc gtgggccgcc 
               
               
                   
               
               
                  961 agcaccacgc gggcccccca tccacatcgc ggccaccacg tccctgggac acgccttgtc 
               
               
                   
               
               
                 1021 ccccggtgta cgccgagacc aagcacttcc tctactcctc aggcgacaag gagcagctgc 
               
               
                   
               
               
                 1081 ggccctcctt cctactcagc tctctgaggc ccagcctgac tggcgctcgg aggctcgtgg 
               
               
                   
               
               
                 1141 agaccatctt tctgggttcc aggccctgga tgccagggac tccccgcagg ttgccccgcc 
               
               
                   
               
               
                 1201 tgccccagcg ctactggcaa atgcggcccc tatttctgga gctgcttggg aaccacgcgc 
               
               
                   
               
               
                 1261 agtgccccta cggggtgctc ctcaagacgc actgcccgct gcgagctgcg gtcaccccag 
               
               
                   
               
               
                 1321 cagccggtgt ctgtgcccgg gagaagcccc agggctctgt ggcggccccc gaggaggagg 
               
               
                   
               
               
                 1381 acacagaccc ccgtcgcctg gtgcagctgc tccgccagca cagcagcccc tggcaggtgt 
               
               
                   
               
               
                 1441 acggcttcgt gcgggcctgc ctgcgccggc tggtgccccc aggcctctgg ggctccaggc 
               
               
                   
               
               
                 1501 acaacgaacg ccgcttcctc aggaacacca agaagttcat ctccctgggg aagcatgcca 
               
               
                   
               
               
                 1561 agctctcgct gcaggagctg acgtggaaga tgagcgtgcg gggctgcgct tggctgcgca 
               
               
                   
               
               
                 1621 ggagcccagg ggttggctgt gttccggccg cagagcaccg tctgcgtgag gagatcctgg 
               
               
                   
               
               
                 1681 ccaagttcct gcactggctg atgagtgtgt acgtcgtcga gctgctcagg tctttatttt 
               
               
                   
               
               
                 1741 atgtcacgga gaccacgttt caaaagaaca ggctcttttt ctaccggaag agtgtctgga 
               
               
                   
               
               
                 1801 gcaagttgca aagcattgga atcagacagc acttgaagag ggtgcagctg cgggagctgt 
               
               
                   
               
               
                 1861 cggaagcaga ggtcaggcag catcgggaag ccaggcccgc cctgctgacg tccagactcc 
               
               
                   
               
               
                 1921 gcttcatccc caagcctgac gggctgcggc cgattgtgaa catggactac gtcgtgggag 
               
               
                   
               
               
                 1981 ccagaacgtt ccgcagagaa aagagggccg agcgtctcac ctcgagggtg aaggcactgt 
               
               
                   
               
               
                 2041 tcagcgtgct caactacgag cgggcgcggc gccccggcct cctgggcgcc tctgtgctgg 
               
               
                   
               
               
                 2101 gcctggacga tatccacagg gcctggcgca ccttcgtgct gcgtgtgcgg gcccaggacc 
               
               
                   
               
               
                 2161 cgccgcctga gctgtacttt gtcaaggtgg atgtgacggg cgcgtacgac accatccccc 
               
               
                   
               
               
                 2221 aggacaggct cacggaggtc atcgccagca tcatcaaacc ccagaacacg tactgcgtgc 
               
               
                   
               
               
                 2281 gtcggtatgc cgtggtccag aaggccgccc atgggcacgt ccgcaaggcc ttcaagagcc 
               
               
                   
               
               
                 2341 acgtctctac cttgacagac ctccagccgt acatgcgaca gttcgtggct cacctgcagg 
               
               
                   
               
               
                 2401 agaccagccc gctgagggat gccgtcgtca tcgagcagag ctcctccctg aatgaggcca 
               
               
                   
               
               
                 2461 gcagtggcct cttcgacgtc ttcctacgct tcatgtgcca ccacgccgtg cgcatcaggg 
               
               
                   
               
               
                 2521 gcaagtccta cgtccagtgc caggggatcc cgcagggctc catcctctcc acgctgctct 
               
               
                   
               
               
                 2581 gcagcctgtg ctacggcgac atggagaaca agctgtttgc ggggattcgg cgggacgggc 
               
               
                   
               
               
                 2641 tgctcctgcg tttggtggat gatttcttgt tggtgacacc tcacctcacc cacgcgaaaa 
               
               
                   
               
               
                 2701 ccttcctcag gaccctggtc cgaggtgtcc ctgagtatgg ctgcgtggtg aacttgcgga 
               
               
                   
               
               
                 2761 agacagtggt gaacttccct gtagaagacg aggccctggg tggcacggct tttgttcaga 
               
               
                   
               
               
                 2821 tgccggccca cggcctattc ccctggtgcg gcctgctgct ggatacccgg accctggagg 
               
               
                   
               
               
                 2881 tgcagagcga ctactccagc tatgcccgga cctccatcag agccagtctc accttcaacc 
               
               
                   
               
               
                 2941 gcggcttcaa ggctgggagg aacatgcgtc gcaaactctt tggggtcttg cggctgaagt 
               
               
                   
               
               
                 3001 gtcacagcct gtttctggat ttgcaggtga acagcctcca gacggtgtgc accaacatct 
               
               
                   
               
               
                 3061 acaagatcct cctgctacag gcgtacaggt ttcacgcatg tgtgctgcag ctcccatttc 
               
               
                   
               
               
                 3121 atcagcaagt ttggaagaac cccacatttt tcctgcgcgt catctctgac acggcctccc 
               
               
                   
               
               
                 3181 tctgctactc catcctgaaa gccaagaacg cagggatgtc gctgggggcc aagggcgccg 
               
               
                   
               
               
                 3241 ccggccctct gccctccgag gccgtgcagt ggctgtgcca ccaagcattc ctgctcaagc 
               
               
                   
               
               
                 3301 tgactcgaca ccgtgtcacc tacgtgccac tcctggggtc actcaggaca gcccagacgc 
               
               
                   
               
               
                 3361 agctgagtcg gaagctcccg gggacgacgc tgactgccct ggaggccgca gccaacccgg 
               
               
                   
               
               
                 3421 cactgccctc agacttcaag accatcctgg actgatggcc acccgcccac agccaggccg 
               
               
                   
               
               
                 3481 agagcagaca ccagcagccc tgtcacgccg ggctctacgt cccagggagg gaggggcggc 
               
               
                   
               
               
                 3541 ccacacccag gcccgcaccg ctgggagtct gaggcctgag tgagtgtttg gccgaggcct 
               
               
                   
               
               
                 3601 gcatgtccgg ctgaaggctg agtgtccggc tgaggcctga gcgagtgtcc agccaagggc 
               
               
                   
               
               
                 3661 tgagtgtcca gcacacctgc cgtcttcact tccccacagg ctggcgctcg gctccacccc 
               
               
                   
               
               
                 3721 agggccagct tttcctcacc aggagcccgg cttccactcc ccacatagga atagtccatc 
               
               
                   
               
               
                 3781 cccagattcg ccattgttca cccctcgccc tgccctcctt tgccttccac ccccaccatc 
               
               
                   
               
               
                 3841 caggtggaga ccctgagaag gaccctggga gctctgggaa tttggagtga ccaaaggtgt 
               
               
                   
               
               
                 3901 gccctgtaca caggcgagga ccctgcacct ggatgggggt ccctgtgggt caaattgggg 
               
               
                   
               
               
                 3961 ggaggtgctg tgggagtaaa atactgaata tatgagtttt tcagttttga aaaaaaaaaa 
               
               
                   
               
               
                 4021 aaaaaaa 
               
            
           
         
       
     
     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: 111. In an embodiment, the hTERT is encoded by a nucleic acid of SEQ ID NO: 111. 
     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. 
     Generally, a population of immune effector cells, e.g., T 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 immune effector cells, e.g., 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 30 anti-CD28 antibody. Examples of an anti-CD28 antibody include 9.3, B-T3, XR-CD28 (Diaclone, Besancon, 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 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 disclosure. 
     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 of the present disclosure, 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 of the present disclosure, 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 of the invention, 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 preferred 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 preferred 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 preferred 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 preferred 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 disclosure. 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 disclosure, 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 disclosure. 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 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-expressing 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 CAR-expressing 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-expressing cell described herein, expanded for 5 days show at least a one, two, three, four, five, tenfold 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 disclosure, 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 embodiments, methods described herein, e.g., CAR-expressing cell manufacturing methods, comprise removing T regulatory cells, e.g., CD25+ T cells, from a cell population, e.g., using an anti-CD25 antibody, or fragment thereof, or a CD25-binding ligand, IL-2. Methods of removing T regulatory cells, e.g., CD25+ T cells, from a cell population are described herein. In embodiments, the methods, e.g., manufacturing methods, further comprise contacting a cell population (e.g., a cell population in which T regulatory cells, such as CD25+ T cells, have been depleted; or a cell population that has previously contacted an anti-CD25 antibody, fragment thereof, or CD25-binding ligand) with IL-15 and/or IL-7. For example, the cell population (e.g., that has previously contacted an anti-CD25 antibody, fragment thereof, or CD25-binding ligand) is expanded in the presence of IL-15 and/or IL-7. 
     In some embodiments a CAR-expressing cell described herein 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 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 one embodiment, the cells are cultured (e.g., expanded, simulated, and/or transduced) in media comprising serum. The serum may be, e.g., human AB serum (hAB). In some embodiments, the hAB serum is present at about 2%, about 5%, about 2-3%, about 3-4%, about 4-5%, or about 2-5%. 2% and 5% serum are each suitable levels that allow for many fold expansion of T cells. Furthermore, as shown 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, medium containing 2% human AB serum is suitable for ex vivo expansion of T cells. 
     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. 
     In some embodiments, cells transduced with a nucleic acid encoding a CAR, e.g., a CAR described herein, can be selected for administration based upon, e.g., protein expression levels of one or more of CCL20, GM-CSF, IFNγ, IL-10, IL-13, IL-17a, IL-2, IL-21, IL-4, IL-5, IL-6, IL-9, TNFα and/or combinations thereof. In some embodiments, cells transduced with a nucleic acid encoding a CAR, e.g., a CAR described herein, can be selected for administration based upon, e.g., protein expression levels of CCL20, IL-17a, IL-6 and combinations thereof. 
     Once a TA 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 TA CAR or a cell expressing both a BCA CAR and a TA CAR (e.g., a cell of the invention) are described in further detail in paragraphs 695-703 of International Publication WO2015/142675, filed Mar. 13, 2015, which is incorporated by reference in its entirety. 
     Once a BCA CAR is constructed, various assays can be used to evaluate the activity of the molecule, such as but not limited to, the ability to deplete B cells (or other preferred populations) in appropriate in vitro and animal models, and the ability to persist upon exposure to B cells. Assays to evaluate the effects of a BCA CAR or a cell expressing both a BCA CAR and a TA CAR (e.g., a cell of the invention) are described in further detail below. 
     For example, the cytotoxicity assay described above can be modified to evaluate the cytotoxic activity of a BCA CAR-expressing cell (e.g., a cell expressing both a BCA CAR and a TA CAR) in vitro. Cells of the invention (e.g., a cell expressing both a BCA CAR and a TA CAR) can be mixed with target cells, e.g., cells expressing the B cell antigen targeted by the BCA CAR, at varying ratios of effector to target (E:T). After sufficient incubation to allow cell-mediated cytolysis the supernatant from each ratio sample is harvested and then measured for released 51Cr. To monitor cell-mediated persistence or proliferation, the cells of the invention can be monitored by, for example, flow cytometry. 
     Furthermore, animal models similar to those described above can be administered a cell of the invention (e.g., a cell expressing both a BCA CAR and a TA CAR), to evaluate the ability of the cell, including its ability to persist and/or proliferate to a greater degree or for a longer time than the same cell which does not express the BCA CAR. 
     Therapeutic Application 
     Some methods for treating a disease associated with the expression of a tumor antigen with CAR therapy have had variable success, in part due to stimulation of the immune response of the subject to the CAR-expressing cells which can result in subsequent rejection of the CAR-expressing cells, and/or adverse response to the CAR-expressing cells. 
     In one aspect, the present disclosure provides methods for treating a disease associated with expression of a tumor antigen, e.g., a cancer, described herein, by administering a cell of the invention (e.g., a cell expressing both a BCA CAR and a TA CAR). In some embodiments, in some embodiments, the therapy with the cell of the invention is preceded by, or accompanied by, lymphodepleting therapy. In other embodiments, the therapy with the cell of the invention is not preceded by, or accompanied by, lymphdepleting therapy, e.g., the subject is not administered lymphodepleting therapy 1 year, 9 months, 6, months, 3 months, 2 months, 1 month, 4 weeks, 3 weeks, 2 weeks, 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or fewer months, weeks or days than any of the foregoing, prior to administration of the cell of the invention. Suitable examples of lymphodepleting agents include, but are not limited to, fludarabine and cyclophosphamide, and are further described in the section entitled “Combination Therapies”. 
     In another aspect, the present disclosure provides methods for treating a cancer, e.g., a solid tumor described herein, by administering an immune effector cell comprising (e.g., engineered to express) a TA CAR, e.g., a mesothelin CAR (as described herein) or EGFRvIII CAR (as described herein), and comprising (e.g., engineered to express) a BCA CAR, e.g., a CD19 CAR (as described herein) or a BCMA CAR (as described herein), as described herein. In embodiments, the cell therapy may be administered with an anti-cancer therapeutic agent described herein. In one embodiment, the anti-cancer therapeutic agent is a chemotherapeutic agent, e.g., as described in the section titled “Combination Therapies”. In another embodiment, the anti-cancer therapeutic agent is a therapeutic agent which treats a solid tumor. 
     In another aspect, the present disclosure provides methods for treating a cancer, e.g., a myeloid tumor described herein, by administering an immune effector cell comprising (e.g., engineered to express) a TA CAR, e.g., a CD123 CAR (as described herein), a CD33 CAR (as described herein) or CLL-1 CAR (as described herein), and comprising (e.g., engineered to express) a BCA CAR, e.g., a CD19 CAR (as described herein) or a BCMA CAR (as described herein), as described herein. In embodiments, the cell therapy may be administered with an anti-cancer therapeutic agent described herein. In one embodiment, the anti-cancer therapeutic agent is a chemotherapeutic agent, e.g., as described in the section titled “Combination Therapies”. In another embodiment, the anti-cancer therapeutic agent is a therapeutic agent which treats a myeloid tumor. 
     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. 
     Anti-Cancer Therapy 
     In one aspect, the present disclosure provides methods of treating a disease, e.g., cancer, by providing to the subject in need thereof a cell of the invention, e.g., an immune effector cell (e.g., T cells, NK cells) that comprises (e.g., is engineered to express) a TA CAR described herein, and a BCA CAR described herein, wherein the diseased cells, e.g., cancer cells, express a tumor antigen, e.g., a tumor antigen targeted by the TA CAR. 
     Without wishing to be bound by any particular theory, the anti-tumor immunity response elicited by the CAR-expressing cell of the invention 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-expressing cell of the invention exhibits specific proinflammatory cytokine secretion and potent cytolytic activity in response to human cancer cells expressing the tumor antigen described herein, resist inhibition by soluble tumor antigen as described herein, mediate bystander killing and mediate regression of an established human tumor. For example, antigen-less tumor cells within a heterogeneous field of antigen-positive tumor cells may be susceptible to indirect destruction by the CAR-expressing cell of the invention that has previously reacted against the adjacent antigen-positive tumor cells. 
     In one embodiment, the present disclosure provides methods for inhibiting the proliferation or reducing the population of cancer cells expressing a tumor antigen described herein, the methods comprising contacting a tumor antigen described herein-expressing cancer cell population with a cell of the invention, e.g., an immune effector cell (e.g., T cells, NK cells) that comprises (e.g., is engineered to express) a TA CAR described herein, and a BCA CAR described herein, that binds to a tumor antigen described herein-expressing cell. In certain embodiments, a cell of the invention, e.g., an immune effector cell (e.g., T cells, NK cells) that comprises (e.g., is engineered to express) a TA CAR described herein, and a BCA CAR 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 of a cancer associated with the expression of a tumor antigen as described herein, relative to a negative control. In one aspect, the subject is a human. 
     The present disclosure also provides methods for preventing, treating and/or managing a disease associated with a tumor antigen described herein. These methods comprise administering to a subject in need thereof a cell of the invention, e.g., an immune effector cell (e.g., T cells, NK cells) that comprises (e.g., is engineered to express) a TA CAR described herein, and a BCA CAR described herein, that binds to a tumor antigen-expressing cell. 
     The present disclosure provides methods for preventing relapse of a cancer associated with a tumor antigen as described herein, the methods comprising administering to a subject in need thereof a cell of the invention, e.g., an immune effector cell (e.g., T cells, NK cells) that comprises (e.g., is engineered to express) a TA CAR described herein, and a BCA CAR described herein, that binds to a tumor antigen-expressing cell. Without being bound by theory, it is believed that expression of a BCA CAR on the cell of the invention allows the cell to persist longer in vivo, or proliferate to a greater degree in vivo, than an identical cell which does not express the BCA CAR, thereby allowing for the generation of persisting populations of cells expressing a TA CAR, which may effectively treat a relapse without another administration of the cells for the invention. 
     In one aspect, the methods comprise administering to the subject in need thereof an effective amount of a CAR-expressing cell described herein (e.g., a cell comprising (e.g., engineered to express) both a TA CAR and a BCA CAR) that binds to a tumor antigen-expressing cell in combination with an effective amount of another therapy, e.g., an administration of a therapy as described in the section titled “Combination Therapies.” 
     In embodiments, administering of the cells of the invention (e.g., a cell comprising (e.g., engineered to express) both a TA CAR and a BCA CAR) results in partial or complete elimination of said tumor cells (e.g., targeted by the TA CAR) and, thereafter, continue to persist in said subject at a level greater than, or for a length of time longer than, otherwise identical cells that lack the BCA CAR. 
     A cell of the invention (e.g., a cell comprising (e.g., engineered to express) both a TA CAR and a BCA CAR) can stably express a TA CAR molecule that targets a tumor antigen and/or a BCA CAR molecule. Alternatively, a cell of the invention (e.g., a cell comprising (e.g., engineered to express) both a TA CAR and a BCA CAR) can transiently express a TA CAR molecule that targets a tumor antigen and/or a BCA CAR molecule. In embodiments where the TA CAR or the BCA CAR, or both the TA CAR and the BCA CAR are transiently expressed, multiple sequential infusions (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10 infusions) of the cell of the invention may be required to effectively treat or manage the disease associated with expression of the tumor antigen. In some embodiments, stable expression of both the BCA CAR and the TA CAR may be preferred for long-term anti-tumor activity. In various aspects, the cell of the invention, or their progeny, persist in the subject 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 cell. In embodiments, such persistence is substantially longer than the persistence of an otherwise identical cell which does not express a BCA CAR, e.g., is 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 longer than the persistence of an otherwise identical molecule which does not express a BCA CAR. 
     In one aspect, the cell of the invention 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 disclosure. Other suitable methods are known in the art, therefore the present disclosure is not limited to any particular method of ex vivo expansion of the cells. Briefly, ex vivo culture and expansion of immune effector cells (e.g., T cells, NK cells) comprises: (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. 
     Exemplary CAR-expressing cells that target a tumor antigen, e.g., expressing a solid tumor CAR or a myeloid tumor CAR, are further described herein. Exemplary cells of the invention express a CAR molecule that binds to a tumor antigen described herein, e.g., a solid tumor associated antigen, a myeloid tumor antigen, or a hematological tumor not of B-Cell origin, and also express a BCA CAR molecule that binds a B-Cell antigen described herein. 
     In one embodiment, the cell of the invention comprises (e.g., is engineered to express) a TA CAR targeting mesothelin, as described herein, and a BCA CAR targeting CD19, as described herein. In one embodiment, the cell of the invention comprises (e.g., is engineered to express) a TA CAR targeting mesothelin, as described herein, and a BCA CAR targeting BCMA, as described herein. In one embodiment, the cell of the invention comprises (e.g., is engineered to express) a TA CAR targeting EGFRvIII, as described herein, and a BCA CAR targeting CD19, as described herein. In one embodiment, the cell of the invention comprises (e.g., is engineered to express) a TA CAR targeting EGFRvII, as described herein, and a BCA CAR targeting BCMA, as described herein. In one embodiment, the cell of the invention comprises (e.g., is engineered to express) a TA CAR targeting CD123, as described herein, and a BCA CAR targeting CD19, as described herein. In one embodiment, the cell of the invention comprises (e.g., is engineered to express) a TA CAR targeting CD123, as described herein, and a BCA CAR targeting BCMA, as described herein. In one embodiment, the cell of the invention comprises (e.g., is engineered to express) a TA CAR targeting CD33, as described herein, and a BCA CAR targeting CD19, as described herein. In one embodiment, the cell of the invention comprises (e.g., is engineered to express) a TA CAR targeting CD33, as described herein, and a BCA CAR targeting BCMA, as described herein. In one embodiment, the cell of the invention comprises (e.g., is engineered to express) a TA CAR targeting CLL-1, as described herein, and a BCA CAR targeting CD19, as described herein. In one embodiment, the cell of the invention comprises (e.g., is engineered to express) a TA CAR targeting CLL-1, as described herein, and a BCA CAR targeting BCMA, as described herein. Other embodiments are described herein as well. 
     Diseases Associated with Expression of a Tumor Antigen 
     The methods described herein relate to treating diseases associated with expression of a tumor antigen. A disease associated with expression of a tumor antigen may be a cancer or other proliferative disease, such as an atypical and/or non-classical cancer, malignancy, or precancerous condition, e.g., a hyperplasia, myelodysplasia, a myelodypslastic syndrome, or a preleukemia, associated with expression of the tumor antigen. Non-cancer related indications associated with expression of a tumor antigen as described herein include, but are not limited to, e.g., autoimmune disease (e.g., lupus), inflammatory disorders (e.g., allergy and asthma), and transplantation. 
     Methods described herein can be used to treat any of the following cancers: 
     Digestive/gastrointestinal cancers such as anal cancer; bile duct cancer; extrahepatic bile duct cancer; appendix cancer; carcinoid tumor, gastrointestinal cancer; colon cancer; colorectal cancer including childhood colorectal cancer; esophageal cancer including childhood esophageal cancer; gallbladder cancer; gastric (stomach) cancer including childhood gastric (stomach) cancer; hepatocellular (liver) cancer including adult (primary) hepatocellular (liver) cancer and childhood (primary) hepatocellular (liver) cancer; pancreatic cancer including childhood pancreatic cancer; sarcoma, rhabdomyosarcoma; islet cell pancreatic cancer; rectal cancer; and small intestine cancer; 
     Endocrine cancers such as islet cell carcinoma (endocrine pancreas); adrenocortical carcinoma including childhood adrenocortical carcinoma; gastrointestinal carcinoid tumor; parathyroid cancer; pheochromocytoma; pituitary tumor; thyroid cancer including childhood thyroid cancer; childhood multiple endocrine neoplasia syndrome; and childhood carcinoid tumor; 
     Eye cancers such as intraocular melanoma; and retinoblastoma; 
     Musculoskeletal cancers such as Ewing&#39;s family of tumors; osteosarcoma/malignant fibrous histiocytoma of the bone; childhood rhabdomyosarcoma; soft tissue sarcoma including adult and childhood soft tissue sarcoma; clear cell sarcoma of tendon sheaths; and uterine sarcoma; 
     Breast cancer such as breast cancer including childhood and male breast cancer and pregnancy; 
     Neurologic cancers such as childhood brain stem glioma; brain tumor; childhood cerebellar astrocytoma; childhood cerebral astrocytoma/malignant glioma; childhood ependymoma; childhood medulloblastoma; childhood pineal and supratentorial primitive neuroectodermal tumors; childhood visual pathway and hypothalamic glioma; other childhood brain cancers; adrenocortical carcinoma; central nervous system lymphoma, primary; childhood cerebellar astrocytoma; neuroblastoma; craniopharyngioma; spinal cord tumors; central nervous system atypical teratoid/rhabdoid tumor; central nervous system embryonal tumors; and childhood supratentorial primitive neuroectodermal tumors and pituitary tumor; 
     Genitourinary cancers such as bladder cancer including childhood bladder cancer; renal cell (kidney) cancer; ovarian cancer including childhood ovarian cancer; ovarian epithelial cancer; ovarian low malignant potential tumor; penile cancer; prostate cancer; renal cell cancer including childhood renal cell cancer; renal pelvis and ureter, transitional cell cancer; testicular cancer; urethral cancer; vaginal cancer; vulvar cancer; cervical cancer; Wilms tumor and other childhood kidney tumors; endometrial cancer; and gestational trophoblastic tumor; 
     Germ cell cancers such as childhood extracranial germ cell tumor; extragonadal germ cell tumor; ovarian germ cell tumor; and testicular cancer; 
     Head and neck cancers such as lip and oral cavity cancer; oral cancer including childhood oral cancer; hypopharyngeal cancer; laryngeal cancer including childhood laryngeal cancer; metastatic squamous neck cancer with occult primary; mouth cancer; nasal cavity and paranasal sinus cancer; nasopharyngeal cancer including childhood nasopharyngeal cancer; oropharyngeal cancer; parathyroid cancer; pharyngeal cancer; salivary gland cancer including childhood salivary gland cancer; throat cancer; and thyroid cancer; 
     Hematological cancers such as a leukemia or a lymphoma; 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 hematological cancers include, 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. 
     Lung cancer such as non-small cell lung cancer; and small cell lung cancer; 
     Respiratory cancers such as malignant mesothelioma, adult; malignant mesothelioma, childhood; malignant thymoma; childhood thymoma; thymic carcinoma; bronchial adenomas/carcinoids including childhood bronchial adenomas/carcinoids; pleuropulmonary blastoma; non-small cell lung cancer; and small cell lung cancer; 
     Skin cancers such as Kaposi&#39;s sarcoma; Merkel cell carcinoma; melanoma; and childhood skin cancer; 
     AIDS-Related Malignancies; 
     Other childhood cancers, unusual cancers of childhood and cancers of unknown primary site; 
     and metastases of the aforementioned cancers can also be treated or prevented in accordance with the methods described herein. Treatment of metastatic cancers, e.g., metastatic cancers that express PD-L (Iwai et al. (2005) Int. Immunol. 17:133-144) can be effected using the methods described herein. Exemplary cancers whose growth can be inhibited include cancers typically responsive to immunotherapy. Additionally, refractory or recurrent malignancies can be treated using the molecules described herein. 
     In one embodiment, the present disclosure provides therapy described herein wherein cells or compostions of the invention is administered to treat a solid tumor, e.g., to inhibit the growth of a solid tumor. In embodiments the cells comprise a TA CAR molecule that targets, e.g., binds, to a tumor antigen present on a cell or population of cells in the solid tumor. Examples of solid tumors that can be treated with methods disclosed herein include malignancies, e.g., sarcomas, adenocarcinomas, and carcinomas, of the various organ systems, such as those affecting pancreas, liver, lung, breast, ovary, lymphoid, gastrointestinal (e.g., colon), genitourinary tract (e.g., renal, urothelial cells), prostate, and pharynx. Adenocarcinomas include malignancies such as most colon cancers, rectal cancer, renal-cell carcinoma, liver cancer, non-small cell carcinoma of the lung, cancer of the small intestine and cancer of the esophagus. In one embodiment, the solid tumor is a mesothelioma. Metastatic lesions of the aforementioned cancers can also be treated or prevented using the methods and compositions of the invention. 
     In one embodiment, the combination therapy described herein is administered to treat a CD19 negative cancer. A CD19 negative cancer can be characterized 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). It shall be understood that a CD19-negative cancer need not have 100% loss of CD19, and may retain some partial CD19 expression (e.g., retain some cancer cells that express CD19). 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express an EGFRvIIICAR, wherein the cancer cells express EGFRvIII. In one embodiment, the cancer to be treated is glioblastoma. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a mesothelinCAR, wherein the cancer cells express mesothelin. In one embodiment, the cancer to be treated is mesothelioma, malignant pleural mesothelioma, non-small cell lung cancer, small cell lung cancer, squamous cell lung cancer, or large cell lung cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, pancreatic metatstatic, esophageal adenocarcinoma, breast cancer, ovarian cancer, colorectal cancer and bladder cancer, or any combination thereof. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a GD2CAR, wherein the cancer cells express GD2. In one embodiment, the cancer to be treated is neuroblastoma. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a TnCAR, wherein the cancer cells express Tn antigen. In one embodiment, the cancer to be treated is ovarian cancer, colon cancer, breast cancer, or pancreatic cancer. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a sTnCAR, wherein the cancer cells express sTn antigen. In one embodiment, the cancer to be treated is ovarian cancer, colon cancer, breast cancer, or pancreatic cancer. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a PSMACAR, wherein the cancer cells express PSMA. In one embodiment, the cancer to be treated is prostate cancer. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a TAG72CAR, wherein the cancer cells express TAG72. In one embodiment, the cancer to be treated is gastrointestinal cancer. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a CD44v6CAR, wherein the cancer cells express CD44v6. In one embodiment, the cancer to be treated is cervical cancer, AML, or MM. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express an EPCAMCAR, wherein the cancer cells express EPCAM. In one embodiment, the cancer to be treated is gastrointestinal cancer. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a KITCAR, wherein the cancer cells express KIT. In one embodiment, the cancer to be treated is gastrointestinal cancer. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a IL-13Ra2CAR, wherein the cancer cells express IL-13Ra2. In one embodiment, the cancer to be treated is glioblastoma. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a CD171CAR, wherein the cancer cells express CD171. In one embodiment, the cancer to be treated is neuroblastoma, ovarian cancer, melanoma, breast cancer, pancreatic cancer, colon cancers, or NSCLC (non-small cell lung cancer). 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a PSCACAR, wherein the cancer cells express PSCA. In one embodiment, the cancer to be treated is prostate cancer. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a LewisYCAR, wherein the cancer cells express LewisY. In one embodiment, the cancer to be treated is ovarian cancer, or AML. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a PDGFR-betaCAR, wherein the cancer cells express PDGFR-beta. In one embodiment, the cancer to be treated is breast cancer, prostate cancer, GIST (gastrointestinal stromal tumor), CML, DFSP (dermatofibrosarcoma protuberans), or glioma. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a SSEA-4CAR, wherein the cancer cells express SSEA-4. In one embodiment, the cancer to be treated is glioblastoma, breast cancer, lung cancer, or stem cell cancer. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a Folate receptor alphaCAR, wherein the cancer cells express folate receptor alpha. 
     In one embodiment, the cancer to be treated is ovarian cancer, NSCLC, endometrial cancer, renal cancer, or other solid tumors. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express an ERBB2CAR, wherein the cancer cells express ERBB2 (Her2/neu). In one embodiment, the cancer to be treated is breast cancer, gastric cancer, colorectal cancer, lung cancer, or other solid tumors. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a MUC1 CAR, wherein the cancer cells express MUC1. In one embodiment, the cancer to be treated is breast cancer, lung cancer, or other solid tumors. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express an EGFRCAR, wherein the cancer cells express EGFR In one embodiment, the cancer to be treated is glioblastoma, SCLC (small cell lung cancer), SCCHN (squamous cell carcinoma of the head and neck), NSCLC, or other solid tumors. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a NCAMCAR, wherein the cancer cells express NCAM. In one embodiment, the cancer to be treated is neuroblastoma, or other solid tumors. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a CAIXCAR, wherein the cancer cells express CAIX. In one embodiment, the cancer to be treated is renal cancer, CRC, cervical cancer, or other solid tumors. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a HMWMAACAR, wherein the cancer cells express HMWMAA. In one embodiment, the cancer to be treated is melanoma, glioblastoma, or breast cancer. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express an o-acetyl-GD2CAR, wherein the cancer cells express o-acetyl-GD2. In one embodiment, the cancer to be treated is neuroblastoma, or melanoma. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a CLDN6CAR, wherein the cancer cells express CLDN6. In one embodiment, the cancer to be treated is ovarian cancer, lung cancer, or breast cancer. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a TSHRCAR, wherein the cancer cells express TSHR. In one embodiment, the cancer to be treated is thyroid cancer, or multiple myeloma. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a CD97CAR, wherein the cancer cells express CD97. In one embodiment, the cancer to be treated is B cell malignancies, gastric cancer, pancreatic cancer, esophageal cancer, glioblastoma, breast cancer, or colorectal cancer. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a Plysialic acid CAR, wherein the cancer cells express Plysialic acid. In one embodiment, the cancer to be treated is small cell lung cancer. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a PLAC1CAR, wherein the cancer cells express PLAC1. In one embodiment, the cancer to be treated is HCC (hepatocellular carcinoma). 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a GloboHCAR, wherein the cancer cells express GloboH. In one embodiment, the cancer to be treated is ovarian cancer, gastric cancer, prostate cancer, lung cancer, breast cancer, or pancreatic cancer. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a NY-BR-1CAR, wherein the cancer cells express NY-BR-1. In one embodiment, the cancer to be treated is breast cancer. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a MAD-CT-1CAR, wherein the cancer cells express MAD-CT-1. In one embodiment, the cancer to be treated is prostate cancer, or melanoma. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a MAD-CT-2CAR, wherein the cancer cells express MAD-CT-2. In one embodiment, the cancer to be treated is prostate cancer, melanoma. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a Fos-related antigen 1 CAR, wherein the cancer cells express Fos-related antigen 1. 
     In one embodiment, the cancer to be treated is glioma, squamous cell cancer, or pancreatic cancer. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a ML-IAP CAR, wherein the cancer cells express ML-IAP. In one embodiment, the cancer to be treated is melanoma. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a NA17CAR, wherein the cancer cells express NA17. In one embodiment, the cancer to be treated is melanoma. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a TRP-2CAR, wherein the cancer cells express TRP-2. In one embodiment, the cancer to be treated is melanoma. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a CYPIBICAR, wherein the cancer cells express CYP1B1. In one embodiment, the cancer to be treated is breast cancer, colon cancer, lung cancer, esophagus cancer, skin cancer, lymph node cancer, brain cancer, or testis cancer. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a RAGE-1CAR, wherein the cancer cells express RAGE-1. In one embodiment, the cancer to be treated is RCC (renal cell cancer), or other solid tumors 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a human telomerase reverse transcriptaseCAR, wherein the cancer cells express human telomerase reverse transcriptase. In one embodiment, the cancer to be treated is solid tumors. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express an intestinal carboxyl esteraseCAR, wherein the cancer cells express intestinal carboxyl esterase. In one embodiment, the cancer to be treated is thyroid cancer, RCC, CRC (colorectal cancer), breast cancer, or other solid tumors. 
     In one aspect, the present disclosure provides methods of treating cancer by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a mut hsp70-2CAR, wherein the cancer cells express mut hsp70-2. In one embodiment, the cancer to be treated is melanoma. 
     Combination Therapies 
     The CAR-expressing cells (e.g., a cell comprising, e.g., engineered to express, a TA CAR and a BCA CAR) described herein may be used in combination with other known agents and therapies. 
     The combination therapy described herein, e.g., comprising a cell of the invention, can be administered in combination with at least one additional therapeutic agent. In an embodiment, a CAR-expressing cell described herein, and 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. 
     In further aspects, a CAR-expressing cell described herein may be used in a treatment regimen in combination with surgery, chemotherapy, radiation, 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, irradiation, and peptide vaccine, such as that described in Izumoto et al. 2008 J Neurosurg 108:963-971. 
     In one embodiment, a CAR-expressing cell described herein may be used in combination with a lymphodepleting agent. An exemplary lymphodepleting agent reduces or decreases lymphocytes, e.g., B cell lymphocytes and/or T cell lymphocytes, prior to immunotherapy. Exemplary lymphodepleting agents include fludarabine, cyclophosphamide, corticosteroids, alemtuzumab, or total body irradiation (TBI), or a combination thereof. For example, a combination of fludarabine and cyclophosphamide is administered prior to or simultaneously with administration of a cell of the invention described herein. 
     In one embodiment, a CAR-expressing cell described herein may be used in combination with an agent that treats B cell aplasia. Persistent B cell aplasia leads to hypogammaglobulinemia and may increase the risk of infection. Agents for treating B cell aplasia includes intravenous immunoglobulin (IVIG), e.g., FLEBOGAMMA™, GAMUNEX-C®, PRIVIGEN®, and GAMMAGARD®. 
     In one embodiment, a CAR-expressing cell described herein 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)), an mTOR inhibitor, 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®), 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®). 
     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®). 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-(SEQ ID NO: 264), inner salt (SF1126, CAS 936487-67-1), and XL765. 
     Exemplary immunomodulators include, e.g., afutuzumab (available from Roche®); pegfilgrastim (Neulasta®); lenalidomide (CC-5013, Revlimid®); thalidomide (Thalomid®), actimid (CC4047); and 1RX-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.govdrugsatfda_docs/label/2010/103705s5311b1.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 IgG1K 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/2009/1253261b1.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 R05072759) 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/2013/125486s0001b1. 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 PRO 131921. PRO 131921 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 CHI 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. The structure of venetoclax (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) is shown below. 
     
       
         
         
             
             
         
       
     
     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, a CAR-expressing cell 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 (ColoAd1) (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 1COVIR-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 Català 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 Jesus, 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 E1a 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 one embodiment, cells expressing a CAR 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, the GITR binding molecules and/or molecules modulating GITR functions (e.g., GITR agonist and/or Treg depleting GITR antibodies) are administered prior to the CAR-expressing cell. For example, in one embodiment, the GITR agonist can be administered prior to apheresis of the cells. In one embodiment, the subject has CLL. 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 an mTOR inhibitor, e.g., an mTOR inhibitor described herein, e.g., a rapalog such as everolimus. In one embodiment, the mTOR inhibitor is administered prior to the CAR-expressing cell. For example, in one embodiment, the mTOR inhibitor 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. 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 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. 
     In one embodiment, a CAR-expressing cell described herein 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 CDK4/6 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 MNK1a, MNK1b, MNK2a and/or MNK2b inhibitor. In one embodiment, the kinase inhibitor is a dual PI3K/mTOR inhibitor described herein, such as, e.g., PF-04695102. 
     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]-H-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), the structure of which is shown below. 
     
       
         
         
             
             
         
       
     
     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 a preferred 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 structure of ibrutinib (1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one) is shown below. 
     
       
         
         
             
             
         
       
     
     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 some embodiments, ibrutinib is administered at a dosage of about 300-600 mg/day (e.g., about 300-350, 350-400, 400-450, 450-500, 500-550, or 550-600 mg/day, e.g., about 420 mg/day or about 560 mg/day), e.g., orally. In embodiments, 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 (Th1) phenotype. Th1 and Th2 are phenotypes of helper T cells, with Th1 versus Th2 directing different immune response pathways. A Th 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-cyclopropl-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-cyclopropl-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-cyclopropl-2-fluorobenzamide; N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methyl phenyl)-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-Acrylamiidopropoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamiide; (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-fluorobenzamiide; (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-cyclopropl-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-(hydro)ylmethyl)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-fluorobenzamiide; N-(3-(5-(((2S,4R)-1-Acryloyl-4-cyanopyrrolidine-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[30.3.1.0 4 ′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-a-aspartylL-serine-(SEQ ID NO: 264), inner salt (SF1126); 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, 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 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]-N-[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 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, 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 structure of idelalisib (5-Fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]-4(3H)-quinazolinone) is shown below. 
     
       
         
         
             
             
         
       
     
     Duvelisib (also called IPI-145; Infinity Pharmaceuticals and Abbvie) is a small molecule that blocks PI3K-δ,γ. The structure of duvelisib (8-Chloro-2-phenyl-3-[(1S)-1-(9H-purin-6-ylamino)ethyl]-1(2H)-isoquinolinone) is shown below. 
     
       
         
         
             
             
         
       
     
     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 (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 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/m 2  (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]-N-[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-O11 (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-[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. 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 disclosure 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 disclosure 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 disclosure. 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; NCTO1792050), 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 (CSFIR). See, e.g., Pyonteck et al. Nat. Med. 19(2013):1264-72. The structure of BLZ945 is shown below. 
     
       
         
         
             
             
         
       
     
     In embodiments, a CAR-expressing cell described herein is administered to a subject in combination with an agent that inhibits or reduces the activity of immunosuppressive plasma cells. Immunosuppressive plasma cells have been shown to impede T cell-dependent immunogenic chemotherapy, such as oxaliplatin (Shalapour et al., Nature 2015, 521:94-101). In an embodiment, immunosuppressive plasma cells can express one or more of IgA, interleukin (IL)-10, and PD-L1. In an embodiment, the agent is a CD19 CAR-expressing cell or a BCMA CAR-expressing cell. 
     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 (Plk1), 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 of the invention, or 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 BCA CAR and/or TA CAR, e.g., by electroporation of an mRNA encoding a BCA CAR and/or TA CAR, whereby the expression of either or both CARs is terminated prior to infusion of donor stem cells to avoid engraftment failure. 
     Some patients may experience allergic reactions to the compounds of the present disclosure 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 compound of the present disclosure 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 disclosure, can be prepared and administered as described in the art, such as in the documents cited above. 
     In one embodiment, the present disclosure provides pharmaceutical compositions comprising at least one compound of the present disclosure (e.g., a compound of the present disclosure) 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 disclosure provides methods of treating human or animal subjects suffering from a cellular proliferative disease, such as cancer. The present disclosure 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 disclosure (e.g., a compound of the present disclosure) 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 disclosure 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 disclosure 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 disclosure 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 disclosure, kits that include one or more compound of the present disclosure and a combination partner as disclosed herein are provided. Representative kits include (a) a compound of the present disclosure 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 disclosure 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 disclosure may in particular be used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy. 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. CRS may include clinical constitutional signs and symptoms such as fever, fatigue, anorexia, myalgias, arthalgias, nausea, vomiting, and headache. CRS may include clinical skin signs and symptoms such as rash. CRS may include clinical gastrointestinal signs and symptoms such as nausea, vomiting and diarrhea. CRS may include clinical respiratory signs and symptoms such as tachypnea and hypoxemia. CRS may include clinical cardiovascular signs and symptoms such as tachycardia, widened pulse pressure, hypotension, increased cardac output (early) and potentially diminished cardiac output (late). CRS may include clinical coagulation signs and symptoms such as elevated d-dimer, hypofibrinogenemia with or without bleeding. CRS may include clinical renal signs and symptoms such as azotemia. CRS may include clinical hepatic signs and symptoms such as transaminitis and hyperbilirubinemia. CRS may include clinical neurologic signs and symptoms such as headache, mental status changes, confusion, delirium, word finding difficulty or frank aphasia, hallucinations, tremor, dymetria, altered gait, and seizures. 
     Accordingly, the methods described herein can comprise administering a CAR-expressing cell described herein to a subject and further administering one or more agents 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. In an embodiment, the factor elevated in the subject is one or more of IL-1, GM-CSF, IL-10, IL-8, IL-5 and fraktalkine. Therefore, an agent administered to treat this side effect can be an agent that neutralizes one or more of these soluble factors. In one embodiment, the agent that neutralizes one or more of these soluble forms is an antibody or antigen binding fragment thereof. 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 TNFα inhibitor is an anti-TNFα antibody molecule such as, infliximab, adalimumab, certolizumab pegol, and golimumab. Another example of a TNFα inhibitor is a fusion protein such as entanercept. Small molecule inhibitor of TNFα 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 some embodiment, the subject is administered a corticosteroid, such as, e.g., methylprednisolone, hydrocortisone, among others. 
     In some embodiments, the subject is administered a vasopressor, such as, e.g., norepinephrine, dopamine, phenylephrine, epinephrine, vasopressin, or a combination thereof. 
     In an embodiment, the subject can be administered an antipyretic agent. In an embodiment, the subject can be administered an analgesic agent. 
     In one embodiment, the subject can be administered an agent which 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., Programmed Death 1 (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, 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. Inhibition of a molecule that modulates or regulates, e.g., inhibits, T cell function, e.g., by inhibition at the DNA, RNA or protein level, can optimize a CAR-expressing cell performance. In embodiments, an agent, e.g., an inhibitory nucleic acid, e.g., 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 an inhibitory molecule in the CAR-expressing cell. In an embodiment, the inhibitor is an shRNA. 
     In an embodiment, the agent that modulates or regulates, e.g., inhibits, T-cell function is inhibited within a CAR-expressing cell. In these embodiments, 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 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. Configurations of exemplary vectors for expressing a component, e.g., all of the components, of the CAR with a dsRNA molecule that inhibits expression of the molecule that modulates or regulates, e.g., inhibits, T-cell function, is provided, e.g., in  FIG. 47  of International Publication WO2015/090230, filed Dec. 19, 2014, which is herein incorporated by reference. Examples of dsRNA molecules useful for inhibiting expression of a molecule that modulates or regulates, e.g., inhibits, T-cell function, wherein the molecule that modulates or regulates, e.g., inhibits, T-cell function is PD-1 include RNAi agents that target PD-1, as described, e.g., in paragraph [00489] and Tables 16 and 17 of International Publication WO2015/090230, filed Dec. 19, 2014, which is incorporated by reference in its entirety. 
     In one embodiment, the agent that modulates or regulates, e.g., inhibits, T-cell function 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 PD-1, PD-L, 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. 
     PD-1 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 PD-1, PD-L1 and PD-L2 have been shown to downregulate T cell activation upon binding to PD-1 (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-L 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 PD-1 with PD-L1. Antibodies, antibody fragments, and other inhibitors of PD-1, PD-L1 and PD-L2 are available in the art and may be used combination with a cars of the present disclosure 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 PD-1. Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD-1 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 PD-1. Pidilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in WO2009/101611. Pembrolizumab (formerly known as lambrolizumab, and also referred to as MK03475; Merck) is a humanized IgG4 monoclonal antibody that binds to PD-1. Pembrolizumab and other humanized anti-PD-1 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 PD-1 and B7-H1. Other anti-PD-1 antibodies include AMP 514 (Amplimmune), among others, e.g., anti-PD-1 antibodies disclosed in U.S. Pat. No. 8,609,089, US 2010028330, and/or US 20120114649. 
     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-hum 1, BAP049-hum 12, BAP049-hum 13, BAP049-hum 14, BAP049-hum 15, BAP049-hum16, BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-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, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum 10, BAP049-hum11, BAP049-hum 12, BAP049-hum 13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-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%/0, 85%, 90%/a, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences. 
     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), phosphotidylserine (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-hum 11, ABTIM3-hum12, ABTIM3-hum13, ABTIM3-hum14, ABTIM3-hum15, ABTIM3-hum 16, ABTIM3-hum17, ABTIM3-hum 18, 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 Jun.; 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 (Immutep), 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-hum113, BAP050-hum14, BAP050-hum 15, BAP050-hum 16, BAP050-hum 17, BAP050-hum 18, BAP050-hum 19, 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-hum100-Ser, BAP050-hum11-Ser, BAP050-hum 12-Ser, BAP050-hum 13-Ser, BAP050-hum 14-Ser, BAP050-hum 15-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-hum 10, BAP050-hum 11, BAP050-hum 12, BAP050-hum 13, BAP050-hum 14, BAP050-hum 15, 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-hum 10-Ser, BAP050-hum 11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum 18-Ser, BAP050-hum 19-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 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 antracellular 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 a CAR of the present disclosure. 
     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 homeostatis. 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 preferred 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 T cells. The cytokine can be administered simultaneously or concurrently with the CAR-expressing T cells, e.g., administered on the same day. The cytokine may be prepared in the same pharmaceutical composition as the CAR-expressing T 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 T 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 T 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 T cells are administered to the subject, and on the second day, a cytokine is administered once a day for the next 7 days. In a preferred embodiment, the cytokine to be administered in combination with CAR-expressing T cells is IL-7, IL-15, or IL-21. 
     In other embodiments, the cytokine is administered a period of time after administration of 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 or anti-tumor activity. In a preferred embodiment, the cytokine administered after administration of CAR-expressing cells is IL-7. 
     Combination with a low dose of an mTOR inhibitor 
     In one embodiment, the CAR-expressing cells described herein, are administered in combination with a low, immune enhancing dose of an mTOR inhibito, e.g., as described in PCT publication WO/2016/014530. 
     In another embodiment, administration of a low, immune enhancing, dose of an mTOR inhibitor results in increased or prolonged proliferation 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 is associated with in an increase in the number of CAR-expressing cells. Methods for measuring increased or prolonged proliferation are described in Examples 4 and 5. 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. 
     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. In an embodiment an mTOR inhibitor is a catalytic 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. 
     Rapamycin is a known macrolide antibiotic produced by  Streptomyces hygroscopicus  having the structure shown in Formula A. 
     
       
         
         
             
             
         
       
     
     Other suitable rapamycin analogs include, but are not limited to, RAD001, otherwise known as everolimus (Afinitor®), has the chemical name (1R,9S,12S, 15R, 16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,32S,35R)-1,18-dihydroxy-12-{(I R)-2-[(1 S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-1,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone,sirolimus (rapamycin, AY-22989), 40-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]-rapamycin (also called temsirolimus or CCI-779) and ridaforolimus (AP-23573/MK-8669).b Other examples of allosteric mTor inhibitors include zotarolimus (ABT578) and umirolimus as described in US2005/0101624 the contents of which are incorporated by reference. Other suitable mTOR inhibitors are described in paragraphs 946 to 964 of International Publication WO2015/142675, filed Mar. 13, 2015, which is incorporated by reference in its entirety. Low, immune enhancing doses of an mTOR inhibitor, suitable levels of mTOR inhibition associated with low doses of an mTOR inhibitor, methods for detecting the level of mTOR inhibition, and suitable pharmaceutical compositions thereof are further described in paragraphs 936 to 945 and 965 to 1003 of International Publication WO2015/142675, filed Mar. 13, 2015, which is incorporated by reference in its entirety. 
     Pharmaceutical Compositions and Treatments 
     Pharmaceutical compositions of the present disclosure may comprise 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 disclosure are in one aspect formulated for intravenous administration. 
     Pharmaceutical compositions of the present disclosure 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 disclosure 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). It can generally be stated that a pharmaceutical composition comprising the immune effector cells (e.g., T cells, NK cells) described herein may be administered at a dosage of 10 4  to 10′ cells/kg body weight, in some instances 10′ to 10 6  cells/kg body weight, including all integer values within those ranges. T 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-expressing cells described herein (e.g., cells comprising, e.g., engineered to express, a TA CAR and a BCA CAR) comprises 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 ,2×10,3×108, or 5×10 8  cells/kg. In some embodiments, a dose of CAR cells (e.g., cells comprising, e.g., engineered to express, a TA CAR and a BCA CAR) 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., cells comprising, e.g., engineered to express, a TA CAR and a BCA CAR) 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, 2×10 8 , 3×10 8 , or 5×10 8  cells/kg. In some embodiments, a dose of CAR cells (e.g., cells comprising, e.g., engineered to express, a TA CAR and a BCA CAR) comprises about 1.1×10 6 -1.8×10 7  cells/kg. In some embodiments, a dose of CAR cells (e.g., cells comprising, e.g., engineered to express, a TA CAR and a BCA CAR) 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., cells comprising, e.g., engineered to express, a TA CAR and a BCA CAR) 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 , 2×10 9 , or 5×10 9  cells. In some embodiments, a dose of CAR cells (e.g., cells comprising, e.g., engineered to express, a TA CAR and a BCA CAR) comprises up to about 1×10, 2×10′, 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., cells comprising, e.g., engineered to express, a TA CAR and a BCA CAR) comprises up to about 1×10′, 1.5×10 7 , 2×10′, 2.5×10 7 ,3×10 7 ,3.5×10 7 ,4×10 7 ,5×10, 1×10 8 ,1.5×10,2×10 8 ,2.5×10 8 ,3×10, 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., cells comprising, e.g., engineered to express, a TA CAR and a BCA CAR) comprises up to about 1-3×10 7  to 1-3×10 8  of cells. In some embodiments, the subject is administered about 1-3×10 7  of the cells. In other embodiments, the subject is administered about 1-3×10 8  of the cells. 
     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 certain aspects, it may be desired to administer activated immune effector cells (e.g., T cells, NK cells) to a subject and then subsequently redraw blood (or have an apheresis performed), activate immune effector cells (e.g., T cells, NK cells) therefrom according to the present disclosure, and reinfuse the patient with these activated and expanded immune effector cells (e.g., T cells, NK cells). This process can be carried out multiple times every few weeks. In certain aspects, immune effector cells (e.g., T cells, NK cells) can be activated from blood draws of from 10 cc to 400 cc. In certain aspects, immune effector cells (e.g., T cells, 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 T cell compositions of the present disclosure are administered to a patient by intradermal or subcutaneous injection. In one aspect, the T cell compositions of the present disclosure are administered by i.v. injection. The compositions of immune effector cells (e.g., T cells, NK cells) 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 T 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 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 T cells of the present disclosure. 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 CAMPATH, for example, will generally be in the range 1 to about 100 mg for an adult patient, usually administered daily for a period between 1 and 30 days. The preferred 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 immune effector cells (e.g., T cells, NK cells), e.g., using in vitro transcription, and the subject (e.g., human) receives an initial administration of CAR immune effector cells (e.g., T cells, NK cells) of the invention, and one or more subsequent administrations of the CAR immune effector cells (e.g., T cells, NK 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 immune effector cells (e.g., T cells, NK cells) of the invention are administered to the subject (e.g., human) per week, e.g., 2, 3, or 4 administrations of the CAR immune effector cells (e.g., T cells, NK 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 immune effector cells (e.g., T cells, NK 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 immune effector cells (e.g., T cells, NK cells) administrations, and then one or more additional administration of the CAR immune effector cells (e.g., T cells, NK cells) (e.g., more than one administration of the CAR immune effector cells (e.g., T cells, NK cells) per week) is administered to the subject. In another embodiment, the subject (e.g., human subject) receives more than one cycle of CAR immune effector cells (e.g., T cells, NK 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 immune effector cells (e.g., T cells, NK cells) are administered every other day for 3 administrations per week. In one embodiment, the CAR immune effector cells (e.g., T cells, NK cells) of the invention are administered for at least two, three, four, five, six, seven, eight or more weeks. 
     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. 
     Example 1 
     Human T lymphocytes are taken from a subject and are provided ex vivo, stimulated using anti-CD3/CD28, and transduced with a lentivirus vector encoding a second-generation CD19 CAR (a CAR comprising a CD19 binding domain, a transmembrane domain, and an intracellular signaling domain comprising a CD3z primary signaling domain and a 4-1BB costimulatory signaling domain) under the control of the EF1a promoter, and with a lentiviral vector encoding a second-generation EGFRvIII CAR (a CAR comprising a EGFRvIII binding domain, a transmembrane domain, and an intracellular signaling domain comprising a CD3z primary signaling domain and a 4-1BB costimulatory signaling domain) under the control of the EF1a promoter. Systems such as this, for engineering a cell to express both the CD19 CAR and the EGFRvIII CAR, are illustrated in  FIG. 2 . As well, a single bicistronic lentivirus vector is constructed which encodes a second generation CD19 CAR and a second generation EGFRvIII CAR with an intervening P2A site, all under the control of the EF1a promoter. Such a construct, for engineering a cell to express both the CD19 CAR and the EGFRvIII CAR, is illustrated in  FIG. 1 . Cells expressing both the second-generation CD19 CAR and the second-generation EGFRvIII CAR are provided by transducing T cells either with a mixture of the two lentiviral vectors (each encoding either the CD19 CAR or the EGFRvIII CAR;  FIG. 2 ) or with the single lentiviral vector encoding the bicistronic construct ( FIG. 1 ), and CAR T cell proliferation, cytokine release and cytotoxicity are assayed against CD19+/EGFRvIII-cells, CD19−/EGFRvIII+ cells, CD19+/EGFRVII+ cells and a population of cells comprising CD19+/EGFRvII− cells and CD19−/EGFRvIII+ cells, using methods disclosed herein (e.g., as described in WO2014/130657), and the activities are compared to cells expressing only the second-generation EGFRvIII CAR. Cells are further assayed in vivo (proliferation, long term persistence and tumor toxicity, e.g., by methods described in WO2014/130657) by administering the cells intravenously in xenogeneic immune-compromised NOD/SCID/common-gamma chain−/− mice with established EGFRvIII U87vIII glioma tumors. Autologous B cells or immortalized B cells expressing CD19 are co-infused with the CAR T cells to enhance CAR T cell activation. For clinical application, autologous T cells are transduced to express an EGFRvIII CAR and a CD19 CAR and are administered to a patient suffering from glioblastoma multiforme (GBM). CART cell persistence, proliferation/expansion and anti-tumor efficacy are monitored. In patients, their normal B cells expressing CD19 provide a source of stimulation for the second CAR 
     Example 2 
     Human T lymphocytes are taken from a subject and are provided ex vivo, stimulated using anti-CD3/CD28, and transduced with a lentivirus vector encoding a second-generation BCMA CAR (a CAR comprising a BCMA binding domain, a transmembrane domain, and an intracellular signaling domain comprising a CD3z primary signaling domain and a 4-1BB costimulatory signaling domain) under the control of the EF1a promoter, and with a lentiviral vector encoding a second-generation EGFRvIII CAR (a CAR comprising a EGFRvIII binding domain, a transmembrane domain, and an intracellular signaling domain comprising a CD3z primary signaling domain and a 4-1BB costimulatory signaling domain) under the control of the EF1a promoter. Cells expressing both the second-generation BCMA CAR and the second-generation EGFRvII CAR are provided, and CAR T cell proliferation, cytokine release and cytotoxicity are assayed against BCMA+/EGFRvII− cells, BCMA−/EGFRvII+ cells, BCMA+/EGFRVIII+ cells and a population of cells comprising BCMA+/EGFRvIII− cells and BCMA−/EGFRvIII+ cells, using methods disclosed herein (e.g., as described in WO2014/130657), and the activities are compared to cells expressing only the second-generation EGFRvIII CAR. Cells are further assayed in vivo (proliferation, long term persistence and tumor toxicity, e.g., by methods described in WO2014/130657) by administering the cells intravenously in xenogeneic immune-compromised NOD/SCID/common-gamma chain−/− mice with established EGFRvIII U87vIII glioma tumors. Autologous B cells or immortalized B cells expressing BCMA are co-infused with the CAR T cells to enhance CAR T cell activation. For clinical application, autologous T cells are transduced to express an EGFRvIII CAR and a BCMA CAR and are administered to a patient suffering from glioblastoma multiforme (GBM). CART cell persistence, proliferation/expansion and anti-tumor efficacy are monitored. In patients, their normal B cells expressing BCMA provide a source of stimulation for the second CAR. 
     Example 3 
     Human T lymphocytes are taken from a subject and are provided ex vivo, stimulated using anti-CD3/CD28, and transduced with a lentivirus vector encoding a second-generation CD19 CAR (a CAR comprising a CD19 binding domain, a transmembrane domain, and an intracellular signaling domain comprising a CD3z primary signaling domain and a 4-1BB costimulatory signaling domain) under the control of the EF1a promoter, and with a lentiviral vector encoding a second-generation Mesothelin (“Meso”) CAR (a CAR comprising a Meso binding domain, a transmembrane domain, and an intracellular signaling domain comprising a CD3z primary signaling domain and a 4-1BB costimulatory signaling domain) under the control of the EF1a promoter. As well, a single bicistronic vector is constructed which encodes a second generation CD19 CAR and a second generation Mesothelin CAR with an intervening P2A site, all under the control of the EF1a promoter. Cells expressing both the second-generation CD19 CAR and the second-generation Mesothelin CAR are provided by transducing T cells either with a mixture of the two lentiviral vectors (each encoding either the CD19 CAR or the EGFRvIII CAR) or with the single lentiviral vector encoding the bicistronic construct, and CAR T cell proliferation, cytokine release and cytotoxicity are assayed against CD19+/Meso− cells, CD19−/Meso+ cells, CD19+/Meso+ cells and a population of cells comprising CD19+/Meso− cells and CD19−/Meso+ cells, using methods disclosed herein (e.g., as described in WO2015/090230), and the activities are compared to cells expressing only the second-generation Meso CAR. Cells are further assayed in vivo (proliferation, long term persistence and tumor toxicity, e.g., by methods described in WO2015/090230) by administering the cells intravenously in xenogeneic immune-compromised NOD/SCID/common-gamma chain−/− mice with established Meso-expressing ovarian adenocarcinoma (OVCAR8) xenografts. Autologous B cells or immortalized B cells expressing CD19 are co-infused with the CAR T cells to enhance CAR T cell activation. For clinical application, autologous T cells are transduced to express a Meso CAR and a CD19 CAR and are administered to patients suffering from a mesothelin-expressing cancer such as mesothelioma, pancreatic cancer, or ovarian cancer. CART cell persistence, proliferation/expansion and anti-tumor efficacy are monitored. In patients, their normal B cells expressing CD19 provide a source of stimulation for the second CAR. 
     Example 4 
     Human T lymphocytes are taken from a subject and are provided ex vivo, stimulated using anti-CD3/CD28, and transduced with a lentivirus vector encoding a second-generation BCMA CAR (a CAR comprising a BCMA binding domain, a transmembrane domain, and an intracellular signaling domain comprising a CD3z primary signaling domain and a 4-1BB costimulatory signaling domain) under the control of the EF1a promoter, and with a lentiviral vector encoding a second-generation Mesothelin (“Meso”) CAR (a CAR comprising a Meso binding domain, a transmembrane domain, and an intracellular signaling domain comprising a CD3z primary signaling domain and a 4-1BB costimulatory signaling domain) under the control of the EF1a promoter. Cells expressing both the second-generation BCMA CAR and the second-generation Meso CAR are provided, and CAR T cell proliferation, cytokine release and cytotoxicity are assayed against BCMA+/Meso− cells, BCMA−/Meso+ cells, BCMA+/Meso+ cells and a population of cells comprising BCMA+/Meso− cells and BCMA−/Meso+ cells, using methods disclosed herein (e.g., as described in WO2015/090230), and the activities are compared to cells expressing only the second-generation Meso CAR. Cells are further assayed in vivo (proliferation, long term persistence and tumor toxicity, e.g., by methods described in WO2015/090230) by administering the cells intravenously in xenogeneic immune-compromised NOD/SCID/common-gamma chain−/− mice with established Meso-expressing ovarian adenocarcinoma (OVCAR8) xenografts. Autologous B cells or immortalized B cells expressing BCMA are co-infused with the CAR T cells to enhance CAR T cell activation. For clinical application, autologous T cells are transduced to express a Meso CAR and a BCMA CAR and are administered to patients suffering from a mesothelin-expressing cancer such as mesothelioma, pancreatic cancer, or ovarian cancer. CART cell persistence, proliferation/expansion and anti-tumor efficacy are monitored. In patients, their normal B cells expressing BCMA provide a source of stimulation for the second CAR. 
     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.