Please select the eligibility criteria that correspond to the clinical trial below.
Title: Phase IIa Study of Redirected Autologous T Cells Engineered to Contain Anti-CD19 Attached to TCRz and 4-Signaling Domains in Patients With Chemotherapy Relapsed or Refractory CD19+ Lymphomas
Brief Summary: Phase IIa study to estimate the efficacy of a single infusion of autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR and 4-1BB (TCR /4-1BB) costimulatory domains (referred to as CART-19 or CTL019 cells) in non-Hodgkins Lymphoma (NHL) patients. The duration of active protocol intervention is approximately 24 months from screening visit. The protocol will require approximately 48 months to complete.


Options:
A: Inclusion Criteria:

* Patients with CD19+ B cell malignancy who have persistent, relapsed or progressive disease after hematopoietic stem cell transplant from an human leukocyte antigen (HLA)-matched related donor OR patients with CD19+ B cell malignancy who are planned for or have had a hematopoietic stem cell transplant from an HLA-matched related donor and are at risk of relapse after HCT defined by any one of the disease-specific criteria listed below:

  * Philadelphia chromosome negative acute lymphoblastic leukemia:

    * Beyond first complete remission (CR) at the time of pre-transplant evaluation
    * Required \> 1 cycle of induction chemotherapy to achieve CR
    * First morphologic CR but with evidence of minimal residual disease by flow cytometry, conventional cytogenetics, fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR)
    * First CR with poor risk cytogenetics (t(4:11), t(8;14), hypodiploidy, near triploidy or \> 5 cytogenetic abnormalities) at diagnosis
    * Planned for or have had a reduced intensity conditioned or non-myeloablative transplant
  * Philadelphia positive acute lymphoblastic leukemia

    * Not in CR at the time of pre-transplant evaluation
    * In CR with the following features:

      * Intolerant or unwilling to use a TKI after HCT
      * Current or previous detection of cytogenetic abnormalities in addition to t(9;22) by conventional karyotyping, FISH or molecular methods
  * Chronic lymphocytic leukemia, or low grade B cell lymphomas:

    * Failed or ineligible for prior immunochemotherapy that included a purine analog and anti-CD20 monoclonal antibody AND a lymph node \>= 5 cm at the time of pre-transplant evaluation
  * Mantle cell lymphoma:

    * Failed or ineligible for autologous transplant AND a lymph node \>= 2 cm at the time of pre-transplant evaluation
  * Diffuse large B cell lymphomas, large B cell transformation of an indolent lymphoma or other aggressive B cell lymphomas

    * Failed or ineligible for autologous transplant AND not in CR at the time of pre-transplant evaluation
* Confirmation of tumor diagnosis and expression of CD19 after review by University of Washington Medical Center (UWMC) or Seattle Cancer Care Alliance (SCCA) pathology services
* The patient has signed the informed consent form for this study
* DONOR: Genotypic or phenotypic HLA-identical family members
* DONOR: Express one or more of the following combinations of viral serostatus and HLA allele:

  * CMV seropositive and HLA-A\*0101 positive
  * CMV seropositive and HLA-A\*0201 positive
  * CMV seropositive and HLA-B\*0702 positive
  * CMV seropositive and HLA-B\*0801 positive
  * EBV seropositive and HLA-A\*0201 positive
  * EBV seropositive and HLA-B\*0801 positive
* DONOR: Hematocrit \>= 35% at enrollment
* DONOR: Age \>= 18 years
* DONOR: The donor has signed the informed consent form for the study

Exclusion Criteria:

* Known central nervous system (CNS) tumor (CNS2 or CNS3) that is refractory to intrathecal chemotherapy and/or cranio-spinal radiation; patients with a history of CNS disease that has been effectively treated to CNS1 or lower evidence of disease will be eligible
* Human immunodeficiency virus (HIV) seropositive
* Significant medical or psychological conditions that would make them unsuitable candidates for T cell therapy
* Fertile patients unwilling to use contraception during and for 12 months after protocol enrollment
* Pregnant or breast-feeding
* DONOR: G-CSF administered within one month prior to the blood draw for T cell collection
* DONOR: Unable for any reason to provide a 400 ml blood draw
* DONOR: Inadequate peripheral veins for blood collection
* DONOR: HIV-1, HIV-2, human T-lymphotropic virus (HTLV)-1 or HTLV-2 seropositive
* DONOR: Active hepatitis B or hepatitis C virus infection
* DONOR: Positive serologic test for syphilis
* DONOR: Aberrant CD45RA isoform expression on all T cells
* DONOR: Systolic blood pressure (BP) \< 80 or \> 200
* DONOR: Heart rate \< 50 or \> 120, if considered due to cardiac disease
* DONOR: Oxygen (O2) saturation \< 88% on room air
* DONOR: Serum creatinine (Cr) \> 3.0
* DONOR: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 4 x the upper limit of normal
* DONOR: Unable to provide informed consent to participate
* DONOR: Significant medical conditions (e.g. immunosuppressive therapy) that would make them unsuitable T cell donors
* DONOR: Pregnant or nursing
B: Inclusion Criteria:

* Age ≥ 18 years of age
* Creatinine ≤2.0 mg/100 ml, direct bilirubin ≤2.0 mg/100 ml, AST and ALT ≤3.0x upper limit of normal (ULN)
* Adequate pulmonary function as assessed by ≥92% oxygen saturation on room air by pulse oximetry.
* Histologically confirmed DLBCL and large B cell lymphoma, including

  * DLBCL, not otherwise specified (NOS), or
  * Transformed DLBCL from follicular lymphoma, or
  * High-grade B cell lymphoma (excluding Burkitt's lymphoma), or
  * Primary mediastinal large B cell lymphoma AND
  * Chemotherapy refractory disease, defined as a failure to achieve at least a partial response or disease progression within 12 months to the last therapy, OR
  * Disease progression or recurrence in ≤12 months of prior autologous stem cell transplant (ASCT), OR
  * Relapsed disease after 2 or more prior chemoimmunotherapies with at least one containing an anthracycline and CD20 directed therapy
* Patients need to have radiographically documented disease

Exclusion Criteria:

* ECOG performance status ≥2.
* Patients with active CNS disease
* Pregnant or lactating women. Women and men of childbearing age should use effective contraception while on this study and continue for 1 year after all treatment is finished.
* Impaired cardiac function (LVEF \<40%) as assessed by ECHO or MUGA scan.
* Patients with the following cardiac conditions will be excluded:

  * New York Heart Association (NYHA) stage III or IV congestive heart failure
  * Myocardial infarction ≤6 months prior to enrollment
  * History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration ≤6 months prior to enrollment
* Patients with HIV or active hepatitis B or hepatitis C infection are ineligible.
* Patients with prior allogeneic hematopoietic stem cell transplant are eligible, if more than 3 months from transplant and if patients have no active graft versus host disease (GvHD) and not on systemic immunosuppressive therapy.
* Prior CD19-directed therapy including CD19 CAR T cells is allowed, as long as expression of CD19 is confirmed by flow cytometry or immunohistochemistry.
* Patients with uncontrolled systemic fungal, bacterial, viral or other infection are ineligible.
* Patients with any concurrent active malignancies as defined by malignancies requiring any therapy other than expectant observation or hormonal therapy, with the exception of squamous and basal cell carcinoma of the skin.
* Patients with presence of clinically significant neurological disorders such as epilepsy, generalized seizure disorder, severe brain injuries are ineligible.
* Any other issue which, in the opinion of the treating physician, would make the patient ineligible for the study.
C: Inclusion Criteria:

Eligibility is determined priori to leukapheresis. Patients must satisfy the following criteria to be enrolled in this study:

1. Signed Informed Consent Form
2. Male or female patients who are 18-75 years of age
3. Histologically confirmed ALCL, PTCL- NOS, ENKTCL nasal type, DLBCL-NOS and PMBCL
4. Relapsed or refractory CD30-positive NHL who have failed all available standards of therapy. Patients may or may not have received an autologous or allogeneic HSCT CD30-positive tumor
5. At least 1 measurable lesion according to the Lugano Classification
6. ECOG PS of 0 to 1 or equivalent Karnofsky PS Anticipated life expectancy \>12 weeks

Exclusion Criteria:

1. CNS involvement by malignancy
2. Inadequate laboratory abnormalities at screening:

   Hgb ≤ 8.0 g/dL Total bilirubin \> 1.5 x ULN (\>2 x ULN for patients with Gilbert's syndrome) AST and ALT ≥ 5 x ULN CrCL ≤ 45 mL/min (as measured by Cockcroft-Gault equation) ANC ≤ 1000/uL Platelets ≤75,000/uL PR or INR \>1.5 x ULN aPTT\> 1.5 x ULN
3. Active uncontrolled bleeding or a known bleeding diathesis
4. Inadequate pulmonary function defined as pulse oximetry \< 90% on room air
5. Ongoing treatment with immunosuppressive drugs including calcineurin inhibitions, TNFalpha, mTOR, etc or chronic systemic corticosteroids (\>10 mg/day prednisone or equivalent for \>48 hours)
6. Received prior therapy of:

   Anti-CD30 Ab based therapy within the previous 8 weeks Previous CD30.CAR-T investigational product Bi-specific CD30 Ab within the previous 8 weeks Allogenic HSCT in the last 180 days Autologous HSCT within 90 days
7. Active GVHD requiring immune suppression regardless of grade
8. HIV positive
9. Active HBV and/or HCV
D: Inclusion Criteria

* Male or female subjects with CD19+ B cell lymphomas with no available curative treatment options (such as autologous or allogeneic SCT) who have a limited prognosis (several months to \<2 year survival) with currently available therapies will be enrolled. The study will enroll 51 evaluable subjects as follows:
* CD19+ Lymphoma

Cohort A Subjects:

a. Follicular lymphoma, previously identified as CD19+ i. At least 2 prior chemotherapy or immunochemotherapy regimens (not including single agent monoclonal antibody therapy) ii. Patients who progress within 2 years after second or higher line of therapy will be eligible. For instance, patients who have progression of lymphoma \< 2 years after second or greater line therapy, but who have responded to their most recent treatment (3rd line or higher) will be eligible. Patients may have progression, stable disease or responding disease at the time of enrollment.

iii. Patients with a history of large cell transformation are eligible. b. Mantle cell lymphoma, previously identified as CD19+ i. Beyond 1st CR with relapsed disease, progressive disease during first line rituximab-chemotherapy combination, or persistent disease after first line rituximab-chemotherapy combination and not eligible or appropriate for conventional allogeneic or autologous SCT.

ii. Relapsed after prior autologous SCT. c. Diffuse large B cell lymphoma, previously identified as CD19+ i. Residual disease after primary therapy and not eligible for autologous SCT ii. Relapsed or persistent disease after prior autologous SCT iii. Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for conventional allogeneic or autologous SCT iv. Patients with an antecedent history of follicular lymphoma or CLL/SLL are eligible.

Cohort B Subjects:

a. Diffuse large B cell lymphoma, previously identified as CD19+ CD19 i. Residual disease after primary therapy and not eligible for autologous SCT ii. Relapsed or persistent disease after prior autologous SCT iii. Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for conventional allogeneic or autologous SCT iv. Patients with an antecedent history of follicular lymphoma or CLL/SLL are eligible.

v. Patients with T cell/histiocyte-rich disease as confirmed by surgical pathology report

Cohort C Subjects:

a. Diffuse large B cell lymphoma, previously identified as CD19+ i. Residual disease after primary therapy and not eligible for autologous SCT ii. Relapsed or persistent disease after prior autologous SCT iii. Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for conventional allogeneic or autologous SCT iv. Patients with an antecedent history of follicular lymphoma or CLL/SLL are eligible.

* Age ≥18 years
* Creatinine \< 1.6 mg/dL
* ALT/AST \< 3x upper limit of normal
* Bilirubin \<2.0 mg/dL, unless subject has Gilbert's Syndrome (\<3.0 mg/dL)
* Any relapse after prior autologous SCT will make patient eligible regardless of other prior therapy.
* Patients with relapsed disease after prior allogeneic SCT (myeloablative or non-myeloablative) will be eligible if they meet all other inclusion criteria and:

  1. Have no active GVHD and require no immunosuppression
  2. Are more than 6 months from transplant
* Measurable or assessable disease according to the "Revised Response Criteria for Malignant Lymphoma" (Cheson et al., J. Clin. Onc., 1999)108. Patients in complete remission with no evidence of disease are not eligible.
* Performance status (ECOG) 0 or 1.
* Left Ventricle Ejection Fraction (LVEF) \> 40% confirmed by ECHO/MUGA
* Written informed consent is given. Successful T cell test expansion (first 10 subjects).

Exclusion Criteria

* Pregnant or lactating women. The safety of this therapy on unborn children is not known. Female study participants of reproductive potential must have a negative serum pregnancy test at enrollment. A urine pregnancy test will be performed within 48 hours before infusion.
* Uncontrolled active infection.
* Active hepatitis B or hepatitis C infection.
* Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary. For additional details regarding use of steroids
* Any uncontrolled active medical disorder that would preclude participation as outlined.
* Class III/IV cardiovascular disability according to the New York Heart Association Classification (see Appendix 1).
* HIV infection.
* Patients with active CNS involvement by malignancy. Patients with prior CNS disease that has been effectively treated will be eligible providing treatment was \>4 weeks before enrollment
* Patients in complete remission with no assessable disease.
* Patients with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system.

Answer: D