CD19t T-APC, CAR T-cells, and Chemotherapy in Treating Patients with CD19 Positive Acute Lymphoblastic Leukemia

Inclusion Criteria

• The first 3 subjects enrolled on this study must be 18 years of age or older (as of 27 Jun 2018 this requirement has been met); subsequent subjects must be >= 12 months of age and < 30 years of age
• Diagnosis of CD19 positive (+) leukemia
• Disease status meeting one of the criteria below: * Subject status post allogeneic hematopoietic cell transplantation (HCT): ** Recurrent CD19+ leukemia defined as >= 0.01% disease in the marrow or isolated extramedullary disease following allogeneic HCT * Subject with 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
• Subjects with central nervous system (CNS) involvement are eligible provided they are asymptomatic and in the opinion of the study investigator have a reasonable expectation that disease burden can be controlled in the interval between enrollment and T cell infusion. Subjects who have a significant neurologic deterioration during this time will be not be eligible for CAR T cell infusion until alternate therapies result in neurologic stabilization
• Life expectancy of > 8 weeks
• Lansky or Karnofsky performance status score >= 50; subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• All subjects must discontinue all anti-cancer agents and radiotherapy, and, in the opinion of the study investigator, have sufficiently recovered from significant acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study * Chemotherapy: Must be at least 7 days since last chemotherapy was administered (this does not include intrathecal chemotherapy which can be administered at any given time pre study or upon enrollment nor does it include maintenance chemotherapy for the subset of subjects who relapse during maintenance); for subjects who already have a usable apheresis product, the duration and chemotherapy agents used is not restricted * Steroids: All systemically administered (i.e. oral [PO] or IV) corticosteroids therapy (unless physiologic replacement dosing) within 7 days of enrollment; for subjects who already have a usable apheresis product, the duration and steroid agents used is not restricted * Gene-modified cells: No prior genetically modified cell therapy that is still detectable or virotherapy allowed
• A serum creatinine =< upper limit of normal (ULN) based on age/gender as listed below: * 1 to < 2 years: Male & Female: 0.6 mg/dL * 2 years < 6 years: Male & Female: 0.8 mg/dL * 6 years < 10 years: Male & Female: 1.0 mg/dL * 10 years < 13 years: Male & Female: 1.2 mg/dL * 13 years < 16 years: Male: 1.5 mg/dL; Female: 1.4 mg/dL * > 16 years: Male: 1.7 mg/dL; Female: 1.4 mg/dL
• Total bilirubin: =< 3 x upper limit of normal (ULN) for age OR direct bilirubin =< 2 mg/dl
• Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]): =< 5 x the ULN
• Subject does not require supplemental oxygen or mechanical ventilation
• Oxygen saturation >= 90% on room air
• Echocardiogram (ECHO): shortening fraction >= 28% OR ejection fraction >= 50%, OR
• Multigated acquisition scan (MUGA): ejection fraction of >= 50%
• Adequate absolute lymphocyte count (ALC) defined as ALC >= 100 cells/ul (not required if subject has adequate apheresis product already available)
• Documented negative human immunodeficiency virus (HIV) antigen and antibody, hepatitis B surface antigen, and hepatitis C antibody within 3 months prior to enrollment; for subjects with positive hepatitis C antibody (Ab), negative polymerase chain reaction (PCR) testing must be documented in order to be eligible
• Able to tolerate apheresis, including placement of temporary apheresis line if required (not required if subject has adequate apheresis product already available)
• Willing to participate in long-term follow-up for up to 15 years if enrolled in the study and receive T-cell infusion
• Subjects of childbearing/fathering potential agree to use highly effective contraception from the time of initial CAR T cell infusion through 12 months following the last infusion of investigational product
• COHORT A: Prior to lymphodepletion, the subject’s total CD19 antigen load in the bone marrow is < 15% of cells analyzed by flow cytometry (CD19 antigen load includes both CD19+ leukemia cells and non-malignant CD19+ B cells)
• COHORT A: Subject has available apheresis product for T-APC manufacture
• COHORT A: Cohort A remains open to accrual
• COHORT B: Following CAR T cell infusion, the ratio of the % CAR T cells in peripheral blood on day 10 (as measured by flow cytometry) compared to the % CAR T cells in peripheral blood on day 14 is >= 1.5
• COHORT B: Subject has available apheresis product for T-APC manufacture
• COHORT B: Subjects must demonstrate evidence of ongoing B cell aplasia (BCA) in the bone marrow within 7 days prior to planned T-APC test dose, in order to remain on Cohort B. BCA in the bone marrow is defined as < 1% CD19+ cells, as measured by flow cytometry. Subjects not demonstrating ongoing BCA may be considered for crossover to Cohort C of this study
• COHORT B: Cohort B remains open to accrual
• COHORT C: Following initial CAR T cell infusion subject initially achieved BCA, but subsequently lost BCA in the bone marrow or peripheral blood on or prior to the 6 month follow up time point following the initial CAR T cell infusion. BCA is defined as < 1% CD19+ cells by lymphocyte subset testing, as measured by flow cytometry * If subject has disease relapse in this setting, disease must remain CD19+
• COHORT C: Subject has an CD19-targeting CAR T cell product available for re-infusion
• COHORT C: Subject has available apheresis product for T-APC manufacture
• COHORT C: Subject tolerated prior CD19-targeting CAR T cell infusion without experiencing a severe toxicity or if subject did experience a severe toxicity, they have recovered to baseline
• COHORT D: Subjects who do not meet cohort assignment rules for Cohorts A, B or C, elect not to proceed with T-APC infusions on Cohorts A or B, or elect not to proceed with CAR T reinfusion on cohort C will be assigned to Cohort D and will continue to be followed post CAR T cell infusion on this study

Exclusion Criteria

• Presence of 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)
• Pregnant or breast-feeding
• If status post allogeneic HCT, presence of active graft versus host disease (GVHD) or receiving immunosuppressive GVHD therapy within 4 weeks prior to enrollment
• Presence of an active malignancy other than CD19+ malignancy
• Presence of an active severe infection defined as: * A positive blood culture within 48 hours of study enrollment AND/OR * A fever above 38.2 Celsius (C) AND clinical signs of infection within 48 hours of study enrollment
• Presence of any concurrent medical condition that, in the opinion of the study investigator, would prevent the subject from undergoing protocol-based therapy; subjects with a primary immunodeficiency/ bone marrow failure syndrome are excluded from this trial