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

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. 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. 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. the donor of transplanted cells or tissues is from the same species but is genetically non-identical. the ability of T cells to recognize peptide–allogeneic MHC complexes (that were not encountered during thymic development) as foreign, thus driving a strong response and subsequent transplant rejection. engineered cells that are often armed with various stimulatory signals that facilitate T cell stimulation, activation, and expansion. the donor of transplanted cells or tissues is the same individual. pluripotent stem cells derived from the blastocyst stage the embryo that have the ability to differentiate and propagate indefinitely in the undifferentiated state. cells derived from a somatic cell source that have been programmed into an embryonic-like pluripotent state. engineered antibodies in which the variable regions of the heavy and light chains of an immunoglobulin are attached together by a short peptide sequence (linker) of ~10–25 amino acids. a molecular structure that is relatively unique to specific tumor cells and is targeted by the CAR single-chain fragment. the environment surrounding a tumor; it comprises heterogeneous cell populations (such as immune cells, blood cells, and stromal cells), signaling factors (e.g., cytokines and chemokines), and other physical components (e.g., extracellular matrix and blood vessels).