Human CART22.19 Therapy in Refractory Pediatric B-ALL: Insights from a Named-Patient Cohort

Abstract

BACKGROUND: CD19-directed chimeric antigen receptor (CAR) T-cell therapies have transformed the treatment landscape for pediatric B-cell acute lymphoblastic leukemia (B-ALL), yet relapses driven by antigen escape remain a major limitation. Dual-targeting CAR approaches recognizing CD19 and CD22 have shown promising clinical activity, but sustained remissions are limited by insufficient CAR T-cell persistence. METHODS: CAR22.19, a fully human tandem CD19/CD22 CAR, was developed and administered under a named-patient program to nine heavily pretreated pediatric patients with relapsed or refractory B-ALL. Treatment indications were CD19-negative blast population (n=5), relapse after CD19 CAR T (n=3) and/or restricted access to approved CAR T-cell products (n=3). Autologous and donor-derived CAR22.19 T-cells (CART22.19) were manufactured using a good manufacturing practice-compliant, semiautomated fresh-in-fresh-out process. Safety and efficacy were assessed through standardized clinical monitoring, measurable residual disease analysis, and CAR T-cell kinetics. RESULTS: Preclinical validation demonstrated antigen-specific cytotoxicity and dual antigen activity. Clinically, CART22.19 were well tolerated, with no treatment-related deaths and no grade ≥3 neurotoxicity, while grade ≥3 cytokine release syndrome occurred in 38.5% (5/13) of infusions and resolved with standard interventions. An initial complete molecular remission was achieved in 78% (7/9) of patients, with a 12-month overall survival rate of 55.6% (95% CI, 20.4-80.5%). Complete remission in CD19⁻CD22⁺ disease underscores the functional contribution of the CD22-targeting domain, whereas all patients refractory to prior CD19 CAR T-cell therapy relapsed early despite retained CD19⁺CD22⁺ expression. Limited in vivo persistence may represent a contributing factor to treament failure. Notably, durable remission and sustained functional persistence of CART22.19 was achieved in one patient refractory to autologous CART22.19 following infusion of donor-derived CART22.19 after reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (alloHSCT) in nonremission. CONCLUSIONS: CART22.19 therapy demonstrated a favorable safety profile and promising clinical activity in a high-risk pediatric population, with dual targeting enabling disease control in CD19-negative leukemia. Nonetheless, limited CAR T-cell persistence may represent an important obstacle to sustained remission. Our findings support further clinical development of CART22.19 and indicate that donor-derived CAR T-cells following RIC alloHSCT may represent a potential therapeutic strategy to enhance persistence and improve outcomes in heavily pretreated pediatric patients.