CAR-T AND CAR-NK CELL THERAPIES FOR HEMATOLOGIC MALIGNANCIES AND SOLID TUMORS: OVERCOMING RESISTANCE AND TOXICITY

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed or refractory hematologic malignancies, with durable remissions observed in B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, multiple myeloma, and other B-cell malignancies. However, significant challenges persist, including antigen escape, limited persistence, immunosuppressive tumor microenvironments, and potentially life-threatening toxicities such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Moreover, efficacy in solid tumors remains limited due to heterogeneous antigen expression, poor trafficking, and immunosuppressive barriers. CAR-natural killer (NK) cells have emerged as a promising alternative or complement to CAR-T cells, offering potential advantages including lower risk of graft-versus-host disease, reduced cytokine release syndrome, and the possibility of allogeneic off-the-shelf products. This review critically examines recent clinical progress in CAR-T and CAR-NK cell therapies through early 2024, focusing on mechanisms of resistance and strategies to overcome them, as well as toxicity management. It discusses innovations such as dual-targeting CARs, armored CARs, logic-gated CARs, and allogeneic platforms. While CAR-T therapy has achieved remarkable success in hematologic cancers, extending these benefits to solid tumors and broader patient populations will require continued advances in cell engineering, combination therapies, and a deeper understanding of the tumor–immune interface.