CD19x22 Chimeric Antigen Receptor T-cell Therapy (CAR T) in Pediatric B-ALL

This study will evaluate the safety and tolerability of administering a novel bispecific CD19/CD22-directed CAR T cell product (CD19x22) for the treatment of relapsed or refractory pediatric B-ALL.

Precursor B-Cell Acute Lymphoblastic Leukemia (B-ALL) is the most common type of hematologic malignancy in the pediatric population (ages 0-19). Despite favorable prognosis in pediatric B-ALL as a whole, outcomes remain poor for patients who have relapsed or are refractory (R/R) to standard therapies. The Federal and Drug Administration (FDA) approved CD19-directed chimeric antigen receptor T-cell therapy (CAR T cell) based on an 80+% remission induction rate thus expanding treatment options for this subtype of leukemia. However, despite the high remission rates induced by CD19-directed CAR T cell therapy, the current FDA-approved chimeric antigen receptor therapies (CARs) have limitations associated with the durability of response. Additionally, relapse due to loss of the targeted antigen (CD19 negative) is a frequent cause of resistance to CD19-targeted cell therapy. This study will investigate a novel bispecific CD19/CD22-directed CAR T cell product (CD19x22). This CAR T cell therapy can be used in patients with CD19-negative relapse after initial CD19-targeted cell therapy or in naive CAR T cell patients with the goal of reducing CD19-negative relapses.

Eligibility Criteria:
Inclusion Criteria:

1. Subjects must have a history of B precursor ALL with any of the following conditions:

   1. Relapsed two or more times.
   2. Relapsed at any time after allogeneic bone marrow transplant (BMT).
   3. Relapse or refractory after single antigen targeting CAR T cell therapy.

   i. 90 days must have elapsed post previous CAR infusion prior to apheresis. d. Refractory to standard therapy as determined by the treating physician. e. Patient and/or parents declining BMT options and would prefer CAR T Therapy.
2. CD19 and/or CD22 present on last relapsed/refractory disease evaluation.
3. Performance score (Lansky or Karnofsky ≥ 50%; or Eastern Cooperative Oncology Group (ECOG) must be ≤2).
4. Meets criteria for potential leukapheresis collection or has leukapheresis product previously collected and stored per recommended guidelines.
5. Males OR non-pregnant, non-lactating females.
6. Aged 3 months to 30 years (inclusive) at time of consent and enrollment.
7. Provision of a signed and dated consent form from parent or guardian (patients \< 18), the patient themselves (\> 18), or legally authorized representative (patient \> 18 who lack decision-making capacity) after standard of care (SOC) screening assessments are performed.
8. Stated willingness to comply with all study procedures and be available for the duration of the study.
9. Willingness to participate in long-term follow-up protocol.

Exclusion Criteria:

1. Active, uncontrolled central nervous system (CNS) leukemia as determined by the treating physician at eligibility, prior to lymphodepleting chemotherapy (LD chemo), and pre- CD19x22 CAR T cell infusion.
2. History of allogeneic stem cell transplantation prior to apheresis that meet the following criteria:

   1. Less than 100 days post-transplant;
   2. Evidence of active Graft-versus-Host Disease (GvHD) requiring systemic therapy;
   3. Less than 6 weeks post donor lymphocyte infusion (DLI).
3. Active, uncontrolled, life-threatening infection that at the determination of the treating physician would preclude safe apheresis or tolerance of lymphodepleting chemotherapy, cell infusion, or increased risk of cytokine release syndrome.
4. Evidence of severe organ dysfunction defined by:

   1. Baseline oxygen saturation of \< 90% on room air
   2. Myocardial dysfunction (based on age standards): Ejection fraction ≤\< 40% or shortening fraction ≤ 28%,, evidence of physiologically significant pericardial effusion as determined by an echocardiogram (ECHO), and clinically significant electrocardiogram (ECG) findings
   3. Transaminases \> 10x upper limit of normal (ULN) or bilirubin \> 5x the ULN, unless thought to be related to primary disease
   4. Estimated Creatinine (Cr) clearance \< 60 mL/min/1.73 m2 (if nuclear medicine GFR or other more specific testing exceeds this level than it can supersede the estimated clearance)
5. Post-pubertal females that are pregnant, planning to become pregnant, or unwilling to use birth control (includes abstinence) for the study duration.
6. Known HIV infection or active Hepatitis B or Hepatitis C infection.