CAR T-Cell Therapy in Hematological Malignancies: Mechanisms, Innovations, and Challenges

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed or refractory hematological malignancies, producing deep and durable responses in B-cell acute lymphoblastic leukemia, aggressive B-cell non-Hodgkin lymphomas, and multiple myeloma. Nevertheless, antigen escape, limited in vivo persistence, T-cell exhaustion, and toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) limit broader application. This review synthesizes the mechanistic basis and clinical evidence for the currently approved CAR T-cell products and examines engineering strategies designed to overcome these barriers, including “armored” CAR T cells, multitargeted and logic-gated constructs, and modular or universal platforms intended to extend this approach beyond CD19-positive disease. Combination strategies with immune checkpoint inhibitors, radiotherapy, and other immunotherapies are discussed, together with emerging biomarkers of response and toxicity. Continued optimization of CAR design, toxicity management, and manufacturing scalability will be essential for CAR T-cell therapy to become a foundational pillar of precision oncology.