t-cells expressing anti-cd19 car in pediatric and young adults with b-cell malignancies

Conditions: Acute Lymphoblastic Leukemia, B-precursor; Non-Hodgkin Lymphoma, B-cell

Summary: 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).

Eligibility criteria:
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