Laboratory Treated T Cells in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Non-Hodgkin Lymphoma, or Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To evaluate the feasibility and safety of adoptive T cell therapy using ex vivo expanded
autologous CD8 positive (+) and CD4+ CD19 chimeric antigen receptor (CAR)-T cells for
patients with advanced CD19+ B cell malignancies.

SECONDARY OBJECTIVES:

I. To determine the duration of in vivo persistence of adoptively transferred T cells, and
the phenotype of persisting T cells.

II. To determine if adoptively transferred T cells traffic to the bone marrow and function in
vivo.

III. To determine if the adoptive transfer of CD19 CAR-T cells results in depletion of CD19+
B cells in vivo as a surrogate for functional activity.

IV. To determine if the adoptive transfer of CD19 CAR-T cells has antitumor activity in
patients with measurable tumor burden prior to T cell transfer.

V. To determine if the adoptive transfer of CD19 CAR-T cells is associated with tumor lysis
syndrome.

OUTLINE: This is a phase I, dose-escalation study of autologous CD19 CAR T-cells followed by
a phase II study.

Patients receive anti-CD19-CAR lentiviral vector-transduced autologous T cells intravenously
(IV) over 20-30 minutes on day 0. Treatment may be repeated in no less than 21 days with or
without additional lymphodepleting chemotherapy if there is persistent disease in the absence
of unacceptable toxicity.

DOSE DENSE EXPANSION COHORT: An additional cohort will receive a second anti-CD19-CAR
lentiviral vector-transduced autologous T cell infusion without additional lymphodepleting
chemotherapy 10-21 days after the first infusion if adequate CD19 CAR-T cells can be produced
and appropriate criteria are met.

After completion of study treatment, patients are followed up for at least 15 years.

Inclusion Criteria:

INCLUSIONS FOR SCREENING AND LEUKAPHERESIS

- Patients with CD19 expressing acute lymphoblastic leukemia (ALL), chronic lymphocytic
leukemia (CLL) or non-Hodgkin lymphoma (NHL)

- Ability to understand and provide informed consent

- Not human immunodeficiency virus (HIV) infected

INCLUSIONS FOR CAR-T CELL THERAPY

- Patients with:

- CLL who are beyond first remission and who have failed combination
chemoimmunotherapy with regimens containing a purine analogue and anti-CD20
antibody or who were not eligible for such therapy; patients with CLL for whom
ibrutinib is now standard first line therapy, must have progressed on ibrutinib;
patients with fludarabine refractory disease are eligible; patients may be
treated following allogeneic hematopoietic cell transplant (HCT); for the
concurrent ibrutinib cohort, patients must agree to continue on or be restarted
on ibrutinib and must not have had prior intolerance to ibrutinib that would
prevent this; patients managed with prior dose reductions for toxicity will
continue at the reduced dose for the remainder of this study

- Indolent NHL or mantle cell NHL who are beyond first remission and previously
treated with chemoimmunotherapy or who were not eligible for such therapy;
patients who have relapsed following autologous or allogeneic HCT are eligible

- Aggressive NHL such as diffuse large B-cell lymphoma (DLBCL), who have relapsed
or have residual disease following treatment with curative intent; patients
should have relapsed following, or not be eligible for high-dose therapy and
autologous HCT; patients with chemotherapy refractory disease or marrow
involvement or comorbidities precluding successful autologous HCT are eligible;
patients may be treated following allogeneic HCT

- Patients with CD19 expressing, relapsed or refractory ALL

- Patients with one of the above diagnoses whose disease state does not qualify but
who have prognostic indicators that suggest a high risk of progression of disease
may be screened and undergo leukapheresis; enrollment for T cell therapy would
require meeting the full disease state eligibility

- Confirmation of diagnosis

- Evidence of CD19 expression by immunohistochemistry or flow cytometry on any prior or
current tumor specimen or high likelihood of CD19 expression based on disease
histology

- Karnofsky performance status >= 60%

- All patients of childbearing potential must be willing to use a contraceptive method
before, during, and for at least two months after the T cell infusion

- Ability to understand and provide informed consent

Exclusion Criteria:

EXCLUSIONS FOR CAR-T CELL THERAPY

- Patients requiring ongoing daily corticosteroid therapy at a dose of > 15 mg of
prednisone per day (or equivalent); pulsed corticosteroid use for disease control is
acceptable

- Active autoimmune disease requiring immunosuppressive therapy is excluded unless
discussed with the Principal Investigator (PI)

- Serum creatinine > 2.5 mg/dL

- Serum glutamic oxaloacetic transaminase (SGOT) > 5 x upper limit of normal

- Bilirubin > 3.0 mg/dL

- Patients with clinically significant pulmonary dysfunction, as determined by medical
history and physical exam should undergo pulmonary function testing; those with a
forced expiratory volume in one second (FEV1) of < 50 % of predicted will be excluded

- Diffusing capacity of the lung for carbon monoxide (DLCO) (corrected) < 40% will be
excluded

- Significant cardiovascular abnormalities as defined by any one of the following: New
York Heart Association (NYHA) class III or IV congestive heart failure, clinically
significant hypotension, uncontrolled symptomatic coronary artery disease, or a
documented ejection fraction of < 35%

- Uncontrolled active infection