Approaches for refining and furthering the development of CAR-based T cell therapies for solid malignancies.

: Chimeric antigen receptor-engineered T-cells typically use the binding domains of antibodies to target cytotoxicity toward tumors. This approach has produced great efficacy against selected hematological cancers, but benefit in solid tumors has been limited. Characteristically, the microenvironment in solid tumors restricts CAR T cell function, thereby limiting success. Enhancing efficacy will depend on novel target discovery to refine specificity and reduce toxicity. Additionally, overcoming immunosuppressive mechanisms may be achieved by altering the structure of the CAR itself, together with ancillary gene expression or additional therapeutic interventions.: Herein, the authors discuss approaches for refining and further developing CAR T cell therapies specifically for use with solid malignancies. The authors survey the existing literature and provide perspectives for the future.: Pronounced efficacy in solid tumors will likely require combination therapies, targeting both the tumor itself and associated immunosuppressive mechanisms. Future exploration of CAR T cell therapies for solid tumors is likely to incorporate next-generation designs that couple more precise targeting of cancer-associated targets with enhanced potency and resistance to exhaustion.