This is a single center, open-label, phase 1 study to determine the safety and feasibility of infusing CART22-65s with or without huCART19 after administration of lymphodepleting chemotherapy in adult patients with relapsed or refractory B-ALL.

Inclusion Criteria:

- 1. Patients with relapsed or refractory B cell ALL:

a. Patients with 2nd or greater relapse or refractory to 1st salvage as defined by: i. Recurrent disease in the bone marrow identified morphologically, by immunohistochemistry or by Flow cytometry.

ii. Patients with extramedullary relapse only (no bone marrow involvement) will be eligible if disease response can be assessed radiographically b. Patients with refractory disease as defined by: i. Failure to achieve remission (<5% bone marrow blasts) after 2 cycles of induction chemotherapy ii. Patients that achieve remission but remain MRD+ after ≥2 cycles of induction chemotherapy.

c. Patients with Ph+ ALL are eligible provided they are intolerant to or have failed tyrosine kinase inhibitor therapy.

d. Patients with prior or current history of CNS3 disease* will be eligible only if CNS disease is responsive to therapy.

i. *CNS disease definitions:

1. CNS1 - no blasts seen on cytocentrifuge (CNS negative);

2. CNS2 - total nucleated cell count <5x106/L, but blasts seen on cytocentrifuge;

3. CNS3 - total nucleated cell count 5x106/L with blasts on cytocentrifuge and/or signs of CNS leukemia (i.e. cranial nerve palsy).

   • 2. For Cohort 1: Documentation of CD22 expression on malignant cells at relapse. For Cohort 2: Documentation of CD22 and/or CD19

   • 3. Adequate vital organ function defined as:

     1. Creatinine ≤ 1.6 mg/dl
     2. ALT/AST ≤ 3x upper limit of normal range
     3. Total or Direct bilirubin ≤ 2.0 mg/dl. If Total bilirubin is ≤2.0, Direct bilirubin does not need to be assessed.
     4. Left Ventricle Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA

   • 4. Male or female age ≥ 18 years.

   • 5. ECOG Performance Status that is either 0 or 1.

   • 6. No contraindications for leukapheresis.

   • 7. Subjects of reproductive potential must agree to use acceptable birth control methods.

Exclusion Criteria:

• 1. Active hepatitis B or active hepatitis C.
• 2. HIV Infection.
• 3. Class III/IV cardiovascular disability according to the New York Heart Association Classification.
• 4. Subjects with clinically apparent arrhythmia or arrhythmias who are not stable on medical management within two weeks of eligibility confirmation by physician-investigator.
• 5. Active acute or chronic graft-versus-host disease (GVHD) requiring systemic therapy.
• 6. Planned concurrent treatment with systemic steroids or immunosuppressant medications. Patients may be on a stable low dose of steroids (<10mg equivalent of prednisone) for chronic respiratory conditions or adrenal insufficiency. For additional details regarding use of steroid and immunosuppressant medications.
• 7. CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity.
• 8. Pregnant or nursing (lactating) women.
• 10. Patients with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system.