T-cells Expressing Anti-CD19 CAR in Pediatric and Young Adults With B-cell Malignancies

A Phase 1 / 2 Single Arm Study of T-cells Expressing Anti-CD19 Chimeric Antigen Receptor in Pediatric and Young Adult Patients With B-cell Malignancies

This phase 1 / 2 study will evaluate the response of B-cell malignancies expressing CD19 to autologous T cells transduced with a second generation anti-CD19 chimeric antigen receptor in children and young adults.

Autologous T cells transduced with chimeric antigen receptors (CAR) that recognize the CD19 antigen (CD19-CAR T cells) have been used in multiple clinical trials at several institutions worldwide. We established an in-house manufacturing process for CD19-CAR T cells with a CD28 (cluster of differentiation 28) costimulatory domain.

Primary Objectives:

1. To study the safety of administration of CAR T cell at the Sheba Medical Center
2. To determine the feasibility and efficacy of administering anti-CD19-CAR T cells in children and young adults with B cell malignancies.

Secondary Objectives

1. To study in vivo and in vitro behavior of CAR T cell in patients, including persistence, expansion, cytotoxic potential and exhaustion.
2. To study the cytokine milieu in CAR treated patients.

Eligibility Patients 1-50 years of age, with a CD19-expressing B-cell malignancy that has recurred after, or not responded to, one or more standard chemotherapy-containing regimens.

Design Peripheral blood mononuclear cells (PBMCs)will be obtained by leukapheresis. Anti-CD19 CAR T cells will be manufactured from fresh autologous PBMCs. PBMC will be cultured in the presence of anti-CD3 (cluster of differentiation 3) antibody and interleukin-2 followed by retroviral vector supernatant containing the anti-CD19 CAR. Total culture time is between 7-10 days. Patients will receive lymphodepleting chemotherapy composed of cyclophosphamide and fludarabine prior to cell infusion, and on day 0 will receive one million CAR T cells per kilogram. Patients will be monitored for toxicity including cytokine release syndrome, hematologic toxicities and B-cell aplasia; for response of their underlying malignancy; and for CAR-T cell persistence in the blood, marrow and cerebral spinal fluid (CSF).

Inclusion Criteria:

• Patient with relapsed or refractory B-cell malignancy
• Age 1-50 years
• CD19 expression shown by flow cytometry or immunohistochemistry on at least 70% of leukemic blasts / lymphoma cells
• Adequate CD3 count (above 250 CD3+ cells per microliter blood)
• Clinical performance status: Patients > 10 years of age: Karnofsky ≥ 50%; Patients ≤ 10 years of age: Lansky scale ≥ 50%. Exception for neurologic symptoms (e.g. paralysis) that are explained by the malignancy.
• Females of child-bearing potential must have a negative pregnancy test
• Cardiac function: Left ventricular ejection fraction >45% or shortening fraction >28%
• For patients following allogeneic bone marrow transplantation - at least 100 days post BMT with no signs or symptoms of active graft-versus-host disease.

Key Exclusion Criteria:

• Hyperleukocytosis (WBC>50,000) or rapidly progressive disease
• Pregnant or breast-feeding females
• Hepatic dysfunction, defined as bilirubin > x2 upper normal limit (except when explained by hemolysis or Gilbert) or serum glutamate oxaloacetate transaminase > x25 upper normal limit.
• Hepatitis B, Hepatitis C or HIV infection.
• Anti-neoplastic treatment given in the 2 weeks prior to apheresis, with the exception of intrathecal chemotherapy.
• Active immunosuppressive therapy