Treatment of Relapsed or Chemotherapy Refractory Chronic Lymphocytic Leukemia or Indolent B Cell Lymphoma Using Autologous T Cells Genetically Targeted to the B Cell Specific Antigen CD19

• Safety (phase I) [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
• efficacy of the two CD19-targeted T cell methods (phase II) [ Time Frame: 1 year ] [ Designated as safety issue: No ]

• Antileukemic effect [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• Comparison of in vivo survival of patients receiving genetically modified anti-CD19 T cells after T-cell infusion with vs without lymphodepleting therapy [ Time Frame: 1 year ] [ Designated as safety issue: No ]

• Antileukemic effect
• Comparison of in vivo survival of patients receiving genetically modified anti-CD19 T cells after T cell infusion with vs without prior lymphodepleting therapy

RATIONALE: Using T cells from the patient that have been treated in the laboratory may help the body build an effective immune response to kill cancer cells. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving laboratory-treated T cells together with cyclophosphamide may kill more cancer cells.

PURPOSE: This is a two-stage protocol, consisting of a single-institution phase I safety study and multi-institution phase IIa extension study.

OBJECTIVES:

Phase 1: The primary objective is to assess the safety of autologous T cells genetically modified to express chimeric antigen receptor (CAR) targeting CD19 antigen (19-28z) with or without conditioning chemotherapy.

• Phase IIa: The primary objective is to compare the relative engraftment and persistence of the two CAR modified CD19-targeted T cells expressing different co-stimulatory signaling domain CD28 (19-28z) and 4-1BB (CART-19:CD3z-4-1BB) in the CAR construct.

To compare the in vivo survival of genetically modified 19-28z CAR+ T cells after T cell infusion alone or in combination with conditioning chemotherapy.

• To compare the gene transfer/expression efficiency of the two viral vectors (retrovirus vs. lentivirus).
• To assess the anti-leukemic activity of adoptively transferred CD19-targeted modified T cells linked to the CD28 (19-28z) and 4-1BB signaling domains (CART-19:CD3z-4-1BB).

OUTLINE:

The first stage is a standard 3-step phase I dose escalation trial to assess the safety of 19-28z CAR expressing autologous T cells with or without prior conditioning chemotherapy. In Step 1, a cohort of patients will receive the lowest planned dose of 19-28z+ modified T cells. In Step 2, a cohort of patients will receive cyclophosphamide conditioning chemotherapy followed by the lowest planned dose of 19-28z+ modified T cells. In Step 3, a cohort of patients will be treated with the investigator's choice conditioning chemotherapy followed by the higher dose of 19-28z+ modified T cells. In all cohorts, 3-6 patients will be treated at each dose level, and dose escalation will proceed (from step 3 to step 3) if less than 33% of patients in a cohort experience unanticipated dose-limiting toxicity.

In the Phase IIa extension part of the trial, 6 patients from MSKCC will be enrolled, and will be treated with co-infusion of 19-28z and CART-19:CD3z-4-1BB+ modified T cells mixed at 1:1 ratio at the MTD of T cells determined from the phase I trial.

• Biological: therapeutic autologous lymphocytes
• Drug: cyclophosphamide

Inclusion:

• Patients must have the following CD19+ B cell leukemia or lymphoma either with relapsed or chemotherapy-refractory disease or with evidence of residual disease following therapy.

In all cases, patient's disease must be confirmed at MSKCC.

• CLL: Patients must have a diagnosis of CLL as evidenced by flow cytometry, bone marrow histology, and/or cytogenetics.
• Other low grade B-cell neoplasms are eligible for study, such as small lymphocytic lymphoma (SLL), follicular lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphomas, and mantle cell lymphomas.
• Creatinine ≤2.0 mg/100 ml, bilirubin ≤2.0 mg/100 ml, AST and ALT ≤3.0x normal, PT and PTT ≤ 2x normal outside the setting of stable chronic anticoagulation therapy, granulocytes ≥1,000/mm3, platelets ≥50,000/mm3, hemoglobin ≥8.0g/dl with transfusion support
• Adequate cardiac function (LVEF ≥40%) as assessed by ECHO or MUGA scan performed within 1 month of treatment.
• Adequate pulmonary function as assessed by ≥92% oxygen saturation on room air by pulse oximetry.
• Life expectancy of > 3 months.

Exclusion:

Karnofsky performance status <70.

• Patients previously treated with allogeneic bone marrow or stem cell transplantation are ineligible.
• Patients who are immediate candidates for allogeneic bone marrow or stem cell transplantation. Patient who refuse this option remain eligible.
• CLL patients with transformed disease (Richter's transformation) are ineligible for enrollment on this study.
• Patients with HIV, hepatitis B or hepatitis C infection are ineligible.
• Patients with any concurrent active malignancies as defined by malignancies requiring any therapy other than expectant observation.