Innate and Innate-Like Cells: The Future of Chimeric Antigen Receptor (CAR) Cell Therapy

Conventional αβ CAR-T cell-based approaches have revolutionized the field of cancer immunotherapy, but hurdles remain, especially for solid tumors. Novel strategies in conjunction with alternative cell types are therefore required for effective CAR-based therapies. In this respect, innate and innate-like cells with unique immune properties, such as natural killer (NK) cells, NKT cells, γδ T cells, and macrophages, are promising alternatives to αβ CAR-T adoptive therapy. We review the applicability of these cells in the context of CAR therapy, focusing on therapies under development, the advantages of these approaches relative to conventional CAR-T cells, and their potential in allogeneic therapies. We also discuss the inherent limitations of these cell types and approaches, and outline numerous strategies to overcome the associated obstacles. Innate and innate-like cells exert potent antitumor effects and present several advantages as platforms for CAR development, especially for the treatment of solid tumors.Innate and innate-like cells offer new opportunities for allogeneic 'off-the-shelf' innate and innate-like CAR-based therapy in the treatment of cancer.Innate and innate-like cells show solid potential as vehicles for CARs, but the reduced survival and durability of these cells may limit their potential in the clinic.Arming innate and innate-like cells with refined next-generation CAR designs and novel gene-editing approaches can help to eliminate the associated roadblocks and permit fine-tuning of antitumor immunity.