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Antigen downregulation and early chimeric antigen receptor (CAR) T-cell loss have emerged as two major challenges threatening outcomes following CD19-specific CAR T-cell therapy for children and young adults with B-cell acute lymphoblastic leukemia (B-ALL). In addressing the future of CAR T-cell therapy for B-ALL, innovative strategies to avert antigen downregulation and enhance CAR persistence warrant prioritized focus. We describe promising engineering strategies to refine CAR constructs to reverse exhaustion, develop regulatable CARs, optimize manufacturing, enrich for immune memory, and disrupt immune inhibition. We additionally focus on alternative targeting to CD19-monospecific targeting and contextualize possibilities for expanded CAR utilization. We describe research advances as they are independently reported, however, anticipate an integrative strategy incorporating complementary modifications will be required to effectively address CAR loss, overcome antigen downregulation, and enhance reliability and durability of CAR T-cell responses for B-ALL.

The future of CAR T-cell therapy for B-cell acute lymphoblastic leukemia in pediatrics and adolescents