Chimeric Antigen Receptor T-Cell Therapy: Current Perspective on T Cell-Intrinsic, T Cell-Extrinsic, and Therapeutic Limitations

Abstract

Genetically engineered chimeric antigen receptor (CAR) T-cell therapy leverages the ability of the immune system to eliminate tumors and redirects cytotoxic functions toward cells expressing specified tumor-restricted antigens. Although 6 CAR T-cell therapies have received Food and Drug Administration (FDA) approval for the treatment of many hematological malignancies, limitations involving T cell-intrinsic, T cell-extrinsic, and therapeutic factors remain in the treatment of both liquid and solid tumors. Chimeric antigen receptor design, signals from the tumor microenvironment, tumor antigen escape mechanisms, and systemic inflammatory consequences of CAR T-cell infusion all influence the efficacy and feasibility of CAR T-cell therapy in different malignancies. Here, we review the core structure of the CAR, the evolution of different CAR generations, CAR T-cell therapy limitations, and current strategies being investigated to overcome the T cell-intrinsic, T cell-independent, and therapeutic barriers to successful CAR T-cell therapy.