Expanding the Horizon of CAR-T Cell Therapy: Present Obstacles and New Strategies for Future CARs in Solid Tumors.

Abstract

Chimeric antigen receptor (CAR)-T cells are synthetic receptors used for the recognition of specific antigens expressed by reprogrammed T cells for targeting tumors. CAR-T cell therapy has gained remarkable clinical success for the treatment of hematological malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL), and primary intraocular lymphoma (PIL). The increasing number of preclinical investigations and clinical trials is focusing on extending CAR-T cell therapy to solid tumors due to its remarkable success in leukemia and lymphoma cancers. However, some limitations of CAR-T therapy still exist, including a lack of targetable antigen diversity, heterogeneous antigen expression, insufficient T-cell trafficking efficiency, and an immunosuppressive tumor microenvironment. This review explores the role of CAR-T cell therapy, current challenges, and emerging solutions for solid tumor malignancies. To overcome the existing limitations of CAR-T cell therapy, innovative strategies, including the optimization of novel CAR vectors with checkpoint inhibitors, have been designed to enhance the antitumor activity of CAR-T cells against solid tumors. It also explores the design of novel CAR-T cells and strategies for improving antitumor activity against solid tumors. Among the emerging strategies, universal CARs and combination approaches with checkpoint inhibitors are especially promising for extending CAR-T therapy to solid tumors.