Engineering strategies for broad application of TCR-T- and CAR-T-cell therapies

Abstract Adoptive-cell therapy, including the transfer of tumor-infiltrating T lymphocytes after in vitro expansion or T cells redirected to tumor antigens using antigen-specific transgenic T-cell receptor T cells (TCR-T cells) or chimeric antigen receptor T cells (CAR-T cells), has shown a significant clinical impact. Particularly, several types of CAR-T-cell therapies have been approved for the treatment of hematological malignancies. The striking success of CAR-T-cell therapies in hematological malignancies motivates their further expansion to a wide range of solid tumors, yet multiple obstacles, including the lack of proper target antigens exhibiting a tumor-specific expression pattern and the immunosuppressive tumor microenvironment (TME) impairing the effector functions of adoptively transferred T cells, have prevented clinical application. Gene engineering technologies such as the CRISPR/Cas9 system have enabled flexible reprogramming of TCR/CAR-T-cell signaling or loading genes that are targets of the tumor immunosuppression as a payload to overcome the difficulties. Here, we discuss recent advances in TCR/CAR-T-cell engineering: various promising approaches to enhance the anti-tumor activity of adoptively transferred T cells in the TME for maximizing the efficacy and the safety of adoptive-cell therapy are now being tested in the clinic, especially targeting solid tumors. Engineering new TCR-T and CAR-T cells for immunotherapy