Outsmarting Antigen Escape: Next‐Generation CAR T Cell Engineering Strategies for Durable Remissions in Hematologic Malignancies

ABSTRACT

Chimeric antigen receptor (CAR) T‐cell therapy has revolutionized the treatment of hematologic malignancies, producing unprecedented clinical responses in relapsed or refractory B‐cell acute lymphoblastic leukemia (B‐ALL), diffuse large B‐cell lymphoma, and multiple myeloma. Despite these advances, durable remission remains limited by disease relapse, with antigen escape emerging as one of the principal mechanisms of therapeutic resistance. This review comprehensively summarizes the biologic mechanisms underlying antigen escape and highlights emerging engineering strategies designed to overcome immune evasion and improve long‐term CAR T‐cell efficacy. We discuss both irreversible and reversible resistance pathways, including genetic alterations, alternative splicing, lineage plasticity, trogocytosis, epigenetic repression, and tumor microenvironment‐mediated antigen modulation. Particular emphasis is placed on clinically relevant examples such as CD19 loss in B‐ALL and BCMA dysregulation in multiple myeloma. The review further examines next‐generation approaches developed to prevent antigen‐negative relapse, including dual‐ and multi‐target CAR constructs, logic‐gated systems, pharmacologic enhancement of antigen density, epitope spreading, and TCR‐mimic CAR platforms targeting intracellular antigens. In addition, we evaluate the major translational and biologic challenges associated with these advanced strategies, including structural complexity, manufacturing barriers, toxicity control, tumor heterogeneity, and limited long‐term clinical validation. Finally, we discuss future perspectives involving single‐cell and multi‐omic technologies, computational modeling, and universal modular CAR systems that may enable the development of safer, more adaptable, and precision‐guided cellular immunotherapies for hematologic malignancies.