Genetically Engineered Immune Cells (TriCAR-ALL T-Cells) for the Treatment of Recurrent or Refractory CD19, CD20, and/or CD22 Positive B-Cell Acute Lymphoblastic Leukemia

Inclusion Criteria

• PROCUREMENT: Diagnosis of refractory or recurrent B cell acute lymphoblastic leukemia (B-ALL) with expression of CD19, CD20 and/or CD22
• PROCUREMENT: Projected age >= 12 months and =< 21 years at the time of TriCAR-ALL T cell infusion. To obtain the necessary safety data, the projected age of the first three patients enrolled on dose level 1 of the study will be 16 years and older
• PROCUREMENT: Life expectancy of >= 8 weeks
• PROCUREMENT: Weight >= 10 kg
• PROCUREMENT: Subjects >= 18 years of age must have the ability to give informed consent according to applicable regulatory and local institutional requirements. Legal guardian’s consent must be obtained for subjects < 18 years of age. Assent will be obtained from pediatric subjects and according to applicable regulatory and local institutional requirements. Adults with cognitive impairment who are unable to consent and those with Down’s syndrome are also eligible for this protocol with consent/assent according to applicable regulatory and local institutional requirements
• PROCUREMENT: Unless a subject has a previously obtained apheresis/phlebotomy product that is acceptable and available for manufacturing of CAR-T cells, the subject must discontinue all anti-cancer agents and, in the opinion of the investigator, have recovered from significant acute toxic effects of: * Chemotherapy and biologic agents: All chemotherapy and biologic therapy not specifically mentioned below must be discontinued >= 7 days prior to collection, with the exception of intrathecal chemotherapy and maintenance chemotherapy but >= 72 hours prior to collection (for the subset of subjects who relapse during maintenance); both of which may be administered at any point pre-study or upon enrollment * Steroid use: All systemic corticosteroid therapy (unless physiologic replacement dosing of =< 12mg/m^2/day hydrocortisone or equivalent) must be discontinued >= 7 days prior to collection * Tyrosine Kinase Inhibitor (TKI) use: All TKIs must be discontinued >= 3 days prior to collection * Hydroxyurea: must be discontinued >= 1 day prior to collection * Prior CAR-T cell therapy: must be at least 30 days from most recent CAR-T cell infusion prior to collection * Immunotherapy directed at leukemia: No antibodies within three (3) half-lives prior to collection (or within 4 weeks) whichever is shorter. This includes Antithymocyte globulin (ATG) formulations * Anti T-cell Antibodies, Alemtuzumab: must be discontinued >= 8 weeks prior to collection
• PROCUREMENT: Absolute lymphocyte count (ALC) >= 100 cells/uL
• PROCUREMENT: Subject willing to participate in long-term follow-up for up to 15 years if enrolled in the study
• T-CELL THERAPY: Age >= 12 months and =< 22 years. To obtain the necessary safety data, the first three patients enrolled on dose level 1 of the study will be patients 16 years and older
• T-CELL THERAPY: Weight >= 10.0 Kg
• T-CELL THERAPY: Life expectancy of >= 6 weeks
• T-CELL THERAPY: * B-ALL with no prior history of allo-HCT with one of the following: ** Second or subsequent marrow relapse with or without extramedullary disease ** First marrow relapse at the end of re-induction with marrow having >= 0.01% blasts by morphology &/or flow cytometry with or without extramedullary disease ** Primary refractory disease defined by having >= 5% blasts in the marrow by morphology and/or minimal residual (MRD) testing after 2 or more separate induction regimens ** Subject has an indication for allo-HCT but deemed ineligible (including subjects who have persistent MRD prior to allo-HCT) ** CD19(+) or CD19(-) relapse or refractory ALL after infusion of CD19-targeted immunotherapy including CAR-T cells or blinatumomab (CD20 or CD22 expression is required for CD19- B-ALL) OR * B-ALL recurrent after allo-HCT defined as having >= 0.01% marrow disease
• T-CELL THERAPY: Available transduced T-cells with >= 15% expression of CD19, CD20 or CD22 CAR by flow cytometry
• T-CELL THERAPY: Prohibited medications: * Treatment - Washout Period (prior to CAR-T cell product infusion) ** Cranial radiation therapy (inclusive of total body irradiation [TBI]) - >= 4 weeks ** Cytotoxic chemotherapy - >= 2 days ** Tyrosine Kinase Inhibitors - >= 7 days
• T-CELL THERAPY: Total bilirubin: =< 3X upper limit of normal (ULN) for age OR conjugated bilirubin =< 2 mg/dl, except in subjects with Gilbert’s syndrome where a total bilirubin level of up to 5.3 mg/dL will be acceptable
• T-CELL THERAPY: Alanine aminotransferase (ALT) =< 5 times upper limit of normal
• T-CELL THERAPY: Adequate renal function defined as serum creatinine that is =< maximum based on age/gender below or creatinine clearance or glomerular filtration rate (GFR) (as measured or estimated by Cockcroft Gault or Schwartz) >= 50 mL/min/1.73m^2 * Age - Maximum serum creatinine (mg/dL) ** 1 to < 2 years - Male (0.6); Female (0.6) ** 2 to < 6 years - Male (0.8); Female (0.8) ** 6 to < 10 years - Male (1.0); Female (1.0) ** 10 to < 13 years - Male (1.2); Female (1.2) ** 13 to <16 years - Male (1.5); Female (1.4) ** >= 16 years - Male (1.7); Female (1.4)
• T-CELL THERAPY: Pulse oximetry of >= 90% on room air
• T-CELL THERAPY: Left ventricular fractional shortening (LVFS) >= 28% confirmed by echocardiogram or left ventricular ejection fraction (LVEF) >= 45% confirmed by echocardiogram (multi-gated acquisition scan [MUGA] or MRI heart may replace echocardiogram)
• T-CELL THERAPY: Lansky score of >= 50% (age >= 1 and < 16 years) or Karnofsky score of >= 50% (age ≥ 16 years)
• T-CELL THERAPY: Donor lymphocyte infusions (DLI) completed > 6 weeks prior to CAR-T cell infusion
• T-CELL THERAPY: Subjects of childbearing/fathering potential must agree to use highly effective contraception from the time of initial T cell infusion through 12 months following the last T cell infusion
• T-CELL THERAPY: Subjects > 18 years of age must have the ability to give informed consent according to applicable regulatory and local institutional requirements. Legal guardian’s consent must be obtained for subjects < 18 years of age. Assent will be obtained from pediatric subjects and according to applicable regulatory and local institutional requirements. Adults with cognitive impairment who are unable to consent and those with Down’s Syndrome are also eligible for this protocol with consent/assent according to applicable regulatory and local institutional requirements

Exclusion Criteria

• PROCUREMENT: Active malignancy other than disease under study
• PROCUREMENT: Central nervous system (CNS) 3 involvement with leukemia that, in the opinion of the investigator, cannot be controlled (to CNS 2 or 1) during the interval between enrollment and CAR-T cell infusion
• PROCUREMENT: If history of allogeneic hematopoietic cell transplant (allo-HCT): active GVHD, or receiving immunosuppressive therapy for treatment or prevention of GVHD within 4 weeks prior to enrollment
• Presence of active severe infection, defined as: * Positive blood culture within 48 hours of collection, OR * Fever above 38.2° Celsius (C), AND clinical signs of infection within 48 hours of collection (unless fever is attributed to leukemia) * Active viral infections including infection with human immunodeficiency virus (HIV), hepatitis B, hepatitis C or human T-cell lymphotropic virus (HTLV)
• PROCUREMENT: Primary immunodeficiency syndrome
• PROCUREMENT: Pregnant or breastfeeding
• PROCUREMENT: Presence of any condition that, in the opinion of the investigator, would prohibit the subject from undergoing treatment under this protocol
• PROCUREMENT: History of symptomatic CNS pathology or ongoing symptomatic CNS pathology requiring medical intervention, including paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injury, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder (subjects with nonfebrile seizure disorder controlled on anti-epileptic medication and without seizure activity within 3 months are eligible)
• T-CELL THERAPY: Pregnant or lactating
• T-CELL THERAPY: Presence of any condition that, in the opinion of the principal investigator (PI) or designee, would prevent the patient from undergoing protocol-based therapy
• T-CELL THERAPY: Active CNS involvement by ALL, defined as CNS-3 or symptomatic CNS 2. Note: Asymptomatic CNS2 or patients with history of CNS disease that has been effectively treated will be eligible. Patients that have a significant neurologic deterioration will not be eligible for T cell infusion until alternate therapies result in neurological stabilization