Dual CD19/CD22 CAR T Cells Show Feasibility in Pediatric/Young Adult B-ALL

The use of chimeric antigen receptor (CAR) T cells specific to CD19 or CD22 in the treatment of B-cell acute lymphoblastic leukemia (B-ALL) has shown remarkable promise, but relapse can occur due to antigen loss or downregulation. To address this issue, CAR T cells targeting both of these antigens have been developed, but the safety and efficacy of dual-targeting CAR T cells remain unclear. Cordoba, Onuoha, Thomas, and colleagues con-ducted a phase I clinical trial testing AUTO3, a dual-targeted CAR T cell–based therapy generated by transducing T cells with a bicistronic vector encoding CD19 and CD22 CARs, in 15 pediatric and young adult patients (1–24 years old) with relapsed or refractory B-ALL. The incidence of grade 3–5 toxicity and the frequency of dose-limiting toxicity were the primary endpoints for this study, with the secondary endpoints including the rate of morphologic remission, frequency of adverse events, expansion and persistence of AUTO3, duration of B-cell aplasia, and overall/event-free survival. The endpoints of this study were met with a favorable safety profile being observed, with 60% exhibiting grade 3–4 toxicities (fever, neutropenia, anemia, and thrombocytopenia were most common), but no dose-limiting toxicities were reported and only mild cases of cytokine release syndrome were observed. Expansion of these CAR T cells was noted in 66% of individuals, but persistence was reduced as compared to tisagenlecleucel, a CD19-directed CAR T-cell therapy. Remission rate at 1 month posttreatment—defined as complete response or complete response with incomplete bone marrow recovery—was 86%, and overall and event-free survival at 1 year were 60% and 32%, respectively, with relapses postulated to occur due to limited long-term CAR T-cell persistence. In summary, the results of this phase I trial show that AUTO3 use in pediatric or young adult relapsed or refractory B-ALL is both safe and feasible, but future studies on improving long-term persistence of these CAR T cells are still needed.

Cordoba S, Onuoha S, Thomas S, Pignataro DS, Hough R, Ghorashian S, et al. CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase I trial. Nat Med 2021;27:1797–805.

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