Trivalent CAR-T Cell in Acute B-Lineage Leukemia (TRICAR-ALL)

INCLUSION CRITERIA FOR PROCUREMENT: * Diagnosis of refractory or recurrent B cell Acute Lymphoblastic Leukemia (B-ALL) with expression of CD19, CD20 and/or CD22 * Age between 1 and 25 years. * Life expectancy of ≥ 8 weeks * Weight ≥ 10 kg * 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. * The subject must discontinue all anti-cancer agents and, in the opinion of the investigator, has recovered from significant acute toxic effects of: a) 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 being discontinued ≥ 72 hours prior to collection (for the subset of subjects who relapse during maintenance); b) Steroid use: All systemic corticosteroid therapy (unless physiologic replacement dosing of ≤ 12mg/m2/day hydrocortisone or equivalent) must be discontinued ≥ 3 days prior to collection; c) Tyrosine Kinase Inhibitor (TKI) use: All TKIs must be discontinued ≥ 3 days prior to collection; d) Hydroxyurea: must be discontinued ≥ 1 day prior to collection; e) Prior CAR-T cell therapy: must be at least 30 days from most recent CAR-T cell infusion prior to collection; f) 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; g) Anti T-cell Antibodies, Alemtuzumab: must be discontinued ≥ 8 weeks prior to collection EXCLUSION CRITERIA FOR PROCUREMENT: * Active malignancy other than disease under study * Presence of active severe infection, defined as: a) positive blood culture within 48 hours of collection, OR; b) known history of active viral infections including infection with HIV, hepatitis B, hepatitis C or HTLV * Primary immunodeficiency syndrome * Pregnant or breastfeeding * Presence of any condition that, in the opinion of the investigator, would prohibit the subject from undergoing treatment under this protocol INCLUSION CRITERIA FOR T-CELL THERAPY * Diagnosis of refractory or recurrent B cell Acute Lymphoblastic Leukemia (B-ALL) with expression of CD19, CD20 and/or CD22 and meeting any of the following conditions: * B-ALL with no prior history of allo-HCT with one of the following: 1. Second or subsequent marrow relapse 2. First marrow relapse if, at the end of re-induction, bone marrow showing ≥ 0.01% blasts by morphology \&/or flow cytometry 3. 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 (which may include CD19-targeting therapies) 4. Subject has an indication for allo-HCT but deemed ineligible (including subjects who have persistent MRD prior to allo-HCT) 5. CD19(+) or CD19(-) relapse or refractory ALL after infusion of CD19- CAR-T cells or other CD19-targeting immunotherapies. CD20 or CD22 expression is required for CD19(-) B-ALL. Or * B-ALL recurrent after allo-HCT defined as having ≥ 0.01% marrow disease * Available transduced T-cells with ≥ 15% expression of CD19, CD20 or CD22 CAR by flow cytometry. * Prohibited medications - washout periods (prior to CAR-T cell product infusion): Radiation therapy including TBI and cranial radiation. Local/palliative radiation excluded: ≥ 4 weeks. Cytotoxic chemotherapy: ≥ 2 days. Tyrosine Kinase Inhibitors: ≥ 7 days * Total Bilirubin: ≤ 3X upper limit of normal (ULN) for age OR conjugated bilirubin ≤ 2mg/dl, except in subjects with Gilbert's syndrome where a total bilirubin level of up to 5.3 mg/dL will be acceptable * ALT ≤ 5 times upper limit of normal * Adequate renal function defined as serum creatinine that is ≤ maximum based on age/gender (as indicated below) or Creatinine clearance or GFR (as measured or estimated by Cockcroft Gaultor Schwartz) ≥ 50 mL/min/1.73m2 Maximum Serum Creatinine (mg/dL): Male and Female: Age 1 to \< 2 years: 0.6 Male and Female: Age 2 \< 6 years: 0.8 Male and Female: Age 6 to \< 10 years: 1.0 Male and Female: Age 10 to \< 13 years: 1.2 Male: Age 13 to \<16 years 1.5 Female: Age 13 to \<16 years 1.4 Male: Age equal to or \> 16 years 1.7 Female: Age equal to or \> 16 years 1.4 * Pulse oximetry of ≥ 90% on room air * Left ventricular fractional shortening (LVFS) ≥ 28% confirmed by echocardiogram or left ventricular ejection fraction (LVEF) ≥ 45% confirmed by echocardiogram (MUGA or MRI heart may replace echocardiogram). * Lansky score of ≥ 50% (age ≥1 and \< 16 years) or Karnofsky score of ≥ 50% (age ≥ 16 years). Refer to appendix IV * Donor lymphocyte infusions (DLI) completed \> 6 weeks prior to CAR-T cell infusion * Subjects of childbearing/fathering potential must agree to use highly effective contraception (see Appendix IIII for acceptable forms of contraception) from the time of initial T cell infusion through 12 months following the last T cell infusion * 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. Subject willing to participate in long term follow up for up to 15 years. EXCLUSION CRITERIA FOR T-CELL THERAPY * Pregnant or lactating * Presence of any condition that, in the opinion of the PI or designee, would prevent the patient from undergoing protocol-based therapy. * If history of allogeneic Hematopoietic Cell transplantation (allo-HCT): * active GVHD: acute GVHD \>/= Grade 2 or chronic GVHD, extensive global severity score, OR * actively taking corticosteroids for management of GVHD at a dose of \> 0.5 mg/kg/day of prednisone equivalent * receiving immunosuppressive therapy for treatment or prevention of GVHD within 4 weeks prior to T-cell infusion. * Acute symptomatic CNS pathology requiring active medical intervention, including paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injury, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder. Subjects with chronic, stable neurological conditions such as non-febrile seizure disorder controlled on anti-epileptic medication and without seizure activity within 3 months may be eligible. Subjects with a history of an isolated seizure episode of ≥ 4 weeks (including methotrexate neurotoxicity) without an underlying epileptic disorder are eligible.