Advances in chimeric antigen receptor-T therapies to target tumor resistance in B-cell malignancies

Purpose of review Chimeric Antigen Receptor T cell (CAR-T) has transformed B-cell malignancies treatment, with seven FDA-approved therapies to date. Despite remarkable success, a substantial fraction of patients relapse, primarily due to limited CAR-T persistence or tumor escape driven by target-antigen loss. Here, we highlight preclinical and clinical advances in programming T cells to address these challenges and are poised to drive next-generation CAR-T development. Recent findings Building on FDA-approved CAR designs, innovations in tailoring CAR signaling, cytokine armoring, and multiantigen targeting are paving the way toward more effective and safer treatments. Satisfyingly, these new approaches have demonstrated feasibility, safety, and promising clinical activity, including in patients relapsing after prior CAR treatment. In parallel, CARs with enhanced sensitivity to low-antigen tumors are advancing from preclinical to clinical development. These innovations aiming to enhance T cell persistence and counter tumor escape are defining the next wave of CAR therapies. Summary Here, we outline key advances in CAR-T programming to improve persistence, broaden antigen targeting, and enhance efficacy in B-cell malignancies. While challenges such as toxicities or identifying optimal and standardized approaches across trials remain to be addressed, these approaches provide a foundation for translating innovations into effective and potentially curative CAR immunotherapies.