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

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. If less than
33% of patients in the cohort (Step 2) experience unanticipated dose-limiting toxicity. 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. If less than 33% of
patients in the initial cohort (Step 3) experience unanticipated dose-limiting toxicity, the
cohort in Step 3 may be be expanded to include up to 15 patients. In Step 3, an additional
cohort of Waldenstrom's Macroglobulinemia (WM) patients will be treated with the
investigator's choice conditioning chemotherapy followed by 19-28z+ T cells. However, to
maximize safety for WM patients, they will be treated at the lower dose of modified T cells
(1x106 19-28z+ T cells/kg). If no toxicity is observed in the initial cohort, the dose may be
increased in a standard 3-step dose-escalation scheme as described above.

In the Phase IIa extension part of the trial, 12 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.

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, hairy cell
leukemia, 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.

- CLL patients with active transformed disease (Richter's transformation) are ineligible
for enrollment on this study.

- Patients with 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

- History of severe non-ischemic cardiomyopathy with EF ≤20%

- 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.