Chimeric antigen receptors utilizing the binding capability of activating receptors expressed by natural killer cells

Abstract

Chimeric antigen receptor (CAR)-transduced T (CAR-T) cell therapy is an emerging cancer immunotherapy and has made remarkable progress in recent years. CAR-T cell therapy targeting CD19 (tisagenlecleucel) has shown remarkable efficacy in the treatment of recurrent and refractory B-cell leukemia and lymphoma and has been covered by the national health insurance in Japan since 2019. However, an effective CAR-T cell therapy against acute myeloid leukemia (AML) and solid tumors has not yet been established. One of the major issues is the difficulty in identifying appropriate antigens that are expressed specifically in tumors and can be attacked by CAR-T cells. Conventional CARs recognize antigens on the surface of target cells using single-chain variable fragments derived from monoclonal antibodies. On the other hand, the physiological binding of natural receptors to their ligands is also available for the antigen recognition of CAR. Natural killer (NK) cells are effector lymphocytes of the innate immune system, which can mediate spontaneous cytotoxicity against transformed cells. Various CARs utilizing the binding capability of activating receptors expressed by NK cells to ligands expressed on tumor cell surface have been reported. Among them, CAR-T cells endowed with the antigen recognition capability of natural killer group 2 member D (NKG2D) have been most actively developed, and several clinical trials for AML and solid tumors are underway. In this article, we will review the basics of CARs, followed by detailed explanation of CARs utilizing the activating receptors expressed by NK cells.