A Pediatric and Young Adult Trial of Genetically Modified T Cells Directed Against CD19 for Relapsed/Refractory CD19+ Leukemia

Upon meeting the eligibility requirements and enrolling on study, subjects will undergo
apheresis to obtain the T cells for the generation of the CD19 CAR+ T cells. In patients with
a prior history of allogeneic HCT, the T cells obtained are of donor origin. The T cells are
isolated from the apheresis product, the CD4 and CD8 T cells are then selected and grown
separately, transduced with a lentivirus to express the CD19 CAR as well as a truncated EGFR
that has no signaling capacity (noted EGFRt) and expanded in culture over a three week
period. During the process of cell generation, subjects will continue to be cared for by
their primary oncologist and may undergo additional treatment directed at the leukemia during
this time.

After the CAR+ T cells have been generated, the subject undergoes a disease assessment and
determination if lymphodepletion is necessary. A variety of lymphodepletion strategies are
acceptable and determined on a case by case basis. At least 48 hours after the completion of
lymphodepletion, the subject will receive and infusion of CAR+ T cells at an approximate 1:1
ratio of CD4 to CD8 CAR+ T cells.

Following treatment with the CAR+ T cells, subjects will be followed intensely for 2 months
with serial blood testing and re-evaluation of disease status with bone marrow aspirates.
After 2 months, the subjects clinical care will be resumed by their primary oncologist, and
it is possible that they would receive additional chemotherapy or HCT.

Some subjects will receive cetuximab for ablation of the genetically modified T cells.
Criteria to receive cetuximab include acute toxicities that are life threatening, as well as
an ongoing remission with continued B cell aplasia.

Upon completion of the study, subjects will be followed bi-annually for 5 years, and then
annually for 10 additional years with either a medical history, physical exam and blood tests
or a phone call/questionnaire. This follow up will help to determine if the subject develops
any long-term health problems related to the CAR+ T cells including a new cancer.

Inclusion Criteria:

Patients must be ≥12 months of age and <27 years of age at the time of study enrollment.

Must be ≥10kg

Confirmed CD19+ leukemia recurrence defined as ≥0.01% disease in the marrow or isolated
extramedullary disease following allogeneic HCT.

OR

No prior history of allogeneic HCT (one of the following)

- 2nd or greater relapse, with or without extramedullary disease (isolated
extramedullary disease is eligible)

- 1st marrow relapse at end of 1st month of re-induction with marrow having ≥0.01% blast
disease, with or without extramedullary disease

- Primary Refractory as defined as having M2 or M3 marrow after induction

- Subject has indication for HCT but has been deemed ineligible

OR

CD19+ Non-Hodgkin Lymphoma (NHL) refractory or relapsed with no known curative therapies
available

Patients with CNS involvement are eligible provided that they are asymptomatic and in the
opinion of the study PI have a reasonable expectation that disease burden can be controlled
in the interval between enrollment and T cell infusion. Patients that have a significant
neurologic deterioration will be not be eligible for T cell infusion until alternate
therapies result in neurological stabilization.

Patients must have a Lansky performance status score of ≥50 or a Karnofsky score of ≥ 50
for patients ≥16 years of age.

Life Expectancy of >8 weeks

Patients must be free from active GVHD and off immunosuppressive GVHD therapy for 4 weeks
prior to enrollment.

Recovered from acute toxic effects of all prior chemotherapy, immunotherapy, or
radiotherapy

It must be at least 7 days since last chemotherapy was administered (this does not include
intrathecal chemotherapy or maintenance chemotherapy)

No systemic corticosteroids (unless physiologic replacement dosing) within 7 days of
enrollment.

No prior genetically modified cell therapy that is still detectable or virotherapy allowed.

- Normal serum creatinine based on age/gender

- Total bilirubin
- ALT
- SF of >28% by ECHO or EF >50% by MUGA

- ALC of >/= 100 cells/ul

- Pulse ox >/= 90% on room air

Patient must have documented negative HIV antigen and antibody, Hepatitis B surface
antigen, and Hepatitis C antibody within 3 months prior to enrollment. For patient with
positive Hepatitis C Ab, negative PCR testing must be documented in order to be eligible.

Patients must NOT have active clinically significant CNS dysfunction (including but not
limited to such as uncontrolled seizure disorder, paresis, aphasia, cerebrovascular
ischemia/hemorrhage, severe brain injuries, dementia, cerebellar disease, organic brain
syndrome, psychosis, coordination or movement disorder)

Must agree to highly effective contraception during and for 12 months after T cell
infusion.

Patients must be able to tolerate apheresis procedure, including placement of temporary
apheresis line if required.

Patients must NOT have an active malignancy other than CD19+ leukemia.

Patients must NOT have an active severe infection defined as:

- A positive blood culture within 48 hours of study enrollment

- A fever above 38.2 C AND clinical signs of infection within 48 hours of study
enrollment

Patients must NOT have any concurrent medical condition that, in the opinion of the PI or
designee, would prevent the patient from undergoing protocol-based therapy. Patients with a
primary immunodeficiency/ bone marrow failure syndrome are excluded from this trial.

Research participant or parent/legal guardian must agree to participate in long-term
follow-up for up to 15 years, if they are enrolled in the study and receive T-cell
infusion.