Phase I/IIA Study of CART19 Cells for Patients With Chemotherapy Resistant or Refractory CD19+ Leukemia and Lymphoma

At entry subjects will be staged and the suitability of their T cells for CART-19
manufacturing will be determined. Subjects who have adequate T cells will be leukapheresed to
obtain large numbers of peripheral blood mononuclear cells (PBMC) for CART-19 manufacturing.
The T cells will be purified from the PBMC, transduced with CART-19 lentiviral vector,
expanded in vitro and then frozen for future administration. Chemotherapy will then be given.
Following tumor burden reassessment, CART-19 cells will be thawed and infused.

Subjects will have blood tests to assess safety, and engraftment and persistence of the
CART-19 cells at regular intervals through four weeks after their last infusion of the study.
Following the 6 months of intensive follow-up, subjects will be evaluated quarterly for two
years with a medical history, a physical examination, and blood tests. Following this
evaluation, subjects will enter a roll-over study for annual follow-up by phone and
questionnaire for an additional thirteen years to assess for the diagnosis of long-term
health problems, such as development of new malignancy.

Primary objectives:

1. Determine the safety and feasibility of administration of chimeric antigen receptor T
cells transduced with the anti-CD 19 lentiviral vector (referred to as "CART-19" cells).

2. Determine duration of in vivio survival of CART-19 cells. Real Time polymerase chain
receptor (RT-PCR) analysis of whole blood will be used to detect and quantify survival
of CART-19 TCR:4-1BB and TCR cells over time.

Secondary objectives:

1. For patients with detectable disease, measure anti-tumor response due to CART-19 cell
infusions.

2. To determine if the 4-1BB transgene is superior to the TCR only transgene as measured by
the relative engraftment levels of CART-19 TCR:4-1BB and TCR cells over time.

3. For patients with stored or accessible tumor cells (such as patients with active chronic
lymphocytic leukemia (CLL), acute lymphoblastic leukema (ALL), etc) determine tumor cell
killing by CART-19 cells in vitro.

4. Determine if cellular or humoral host immunity develops against the murine anti-CD19,
and assess correlation with loss of detectable CART-19 (loss of engraftment).

5. Determine the relative subsets of CART-19 T cells (Tcm, Tem, and Treg)

Inclusion Criteria:

Male and female subjects with CD 19+ B cell malignancies in patients with no available
curative treatment options (such as autologous or allogeneic SCT) who have limited
prognosis (several months to <2 year survival) with currently available therapies will be
enrolled:

1. Eligible diseases: CD 19+ leukemia or lymphoma

1. ALL without curative options for therapy, including those not eligible for
allogeneic

SCT because of:

- age

- co-morbid disease

- other contraindications to TBI-based conditioning (required for ALL SCT)

- lack of suitable donor

- prior SCT

- Declines allo SCT (in CR3) as a therapeutic option after documented
discussion about the role of SCT with a BMT physician not part of the study
team. Note: Patient may be in any complete response, or patient may have
active disease but responding or stable after most recent therapy. The
intent is not to enroll patients with no degree of disease control, or
rapidly increasing disease burden between enrollment and cell infusion.

2. Follicular lymphoma, previously identified as CD19+

- At least 2 prior combination chemotherapy regimens (not including single
agent monoclonal antibody (Rituxan) therapy.

- Stage III-IV disease.

- Less than 1 year between last chemotherapy and progression (i.e. most recent
progression free interval <1 year).

- Disease responding or stable after most recent therapy (chemotherapy, MoAb).

3. CLL

- At least 2 prior chemotherapy regimens (not including single agent
monoclonal antibody (Rituxan) therapy.

- Less than 1 year between last chemotherapy and progression (i.e. most recent
progression free interval <1 year).

- Not eligible or appropriate for conventional allogeneic SCT

- Disease responding or stable after most recent therapy (chemotherapy, MoAb)

4. Mantle cell lymphoma

- Beyond 1st CR with relapsed or persistent disease and not eligible or
appropriate for conventional allogeneic or autologous SCT

- Disease responding or stable after most recent therapy (chemotherapy, MoAb)

- Relapsed after prior autologous SCT

5. B-cell prolymphocytic leukemia (PLL) with relapsed or residual disease after at
least 1 prior therapy and not eligible for allogeneic SCT.

6. Diffuse large cell lymphoma or other high-grade NHL, previously identified as
CD19+

- Residual disease after primary therapy and not eligible for autologous SCT

- Relapsed after prior autologous SCT

- Beyond 1st CR with relapsed or persistent disease and not eligible or
appropriate for conventional allogeneic or autologous SCT

2. Age 1 to 24 years. Patients ages 22-24 will only be enrolled if they are currently
being treated at CHOP or another pediatric facility/oncologist

3. Expected survival > 12 weeks

4. Creatinine < 2.5 mg/dl and less than 2.5x normal for age

5. ALT ≤ 5x normal

6. Bilirubin <2.0 mg/dl

7. Any relapse after prior SCT will make patient eligible regardless of other prior
therapy

8. 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 4 months from transplant

9. For those patients who require leukapheresis for T cell collection (i.e. no previously
collected product exists), adequate venous access for apheresis or eligible for
appropriate catheter placement, and no other contraindications for leukapheresis

10. Voluntary informed consent is given

11. Patients with CNS3 disease will be eligible if CNS disease is responsive to therapy
(at infusion)

Exclusion Criteria:

1. 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
or urine pregnancy test performed within 48 hours before infusion

2. Uncontrolled active infection

3. Active hepatitis B or hepatitis C infection

4. Concurrent use of systemic steroids at the time of cell infusion or cell collection,
or a condition, in the treating physician's opinion, that is likely to require steroid
therapy during collection or after infusion. Steroids for disease treatment at times
other than cell collection or at the time of infusion are permitted. Use of inhaled
steroids, or hydrocortisone for physiological replacement in patients with adrenal
insufficiency are permitted as well

5. Presence of grade 2-4 acute or extensive chronic GVHD

6. Under treatment for GVHD

7. Previous treatment with any gene therapy products

8. Any uncontrolled active medical disorder that would preclude participation as
outlined.

9. HIV infection.

10. CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that
might increase the risk of CNS toxicity