Harnessing the potential of gene editing technology for CAR-T cell therapy of solid tumors

Chimeric antigen receptor (CAR)-T cell therapy is now considered a mainstay treatment for certain hematologic malignancies, as evidenced by several products that have gained marketing authorization from regulatory authorities worldwide. Despite the undeniable successes of this treatment in certain blood cancers, its effectiveness in solid tumors remains unsatisfactory. This limited efficacy is attributed to several factors, including low trafficking and poor infiltration of CAR-T cells into the tumor bed, antigen heterogeneity, the risk of on-target off-tumor toxicities, immunosuppressive tumor microenvironment, and intrinsic resistance mechanisms in tumor cells. Advances in gene editing platforms, notably CRISPR/Cas9 and its derivative novel technologies, have created opportunities to overcome the existing hurdles of CAR-T cell therapy in solid tumors. Gene editing can be harnessed to disrupt, correct, activate, repress intended genes, and precisely integrate transgenes at predefined loci. Multiplex genome editing using the CRISPR system enables the simultaneous targeting of multiple genes to induce desired changes in cellular behavior, aiming to improve the efficacy and safety profile of CAR-T cell therapy. This review comprehensively examines how gene editing technology is leveraged to enhance CAR-T cell therapy against solid tumors. In this regard, after an overview of various applications of gene editing in CAR-T cell therapy of solid tumors, clinical trials of genome-edited CAR-T cells in solid tumors are discussed to provide a comprehensive perspective regarding the current state of genome-edited CAR-T cell therapy in solid tumors.