Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy

Abstract

Natural killer (NK) cells are potential effector cells in cell-based cancer immunotherapy, particularly in the control of hematological malignancies. The chimeric antigen receptor (CAR) is an artificially modified fusion protein that consists of an extracellular antigen recognition domain fused to an intracellular signaling domain. T cells genetically modified with a CAR have demonstrated remarkable success in the treatment of hematological cancers. Compared to T cells, CAR-transduced NK cells (CAR-NK) exhibit several advantages, such as safety in clinical use, the mechanisms by which they recognize cancer cells, and their abundance in clinical samples. Human primary NK cells and the NK-92 cell line have been successfully transduced to express CARs against both hematological cancers and solid tumors in pre-clinical and clinical trials. However, many challenges and obstacles remain, such as the ex vivo expansion of CAR-modified primary NK cells and the low transduction efficiency of NK cells. Many strategies and technologies have been developed to improve the safety and therapeutic efficacy in CAR-based immunotherapy. Moreover, NK cells express a variety of activating receptors (NKRs), such as CD16, NKG2D, CD226 and NKp30, which might specifically recognize the ligands expressed on tumor cells. Based on the principle of NKR recognition, a strategy that targets NKRs is rapidly emerging. Given the promising clinical progress described in this review, CAR- and NKR-NK cell-based immunotherapy are likely promising new strategies for cancer therapy.

Figure 1

Basic principle of CAR-NK cells. Chimeric antigen receptors contain an antigen-recognition domain (eg, ScFv or NKG2D), a transmembrane domain and a signaling domain that provides a signal to activate NK cells. First-generation CARs only contain CD3ζ or DAP12 as the signaling domain, and CD3ζ appears to be a better signaling domain than DAP10, whereas DAP12 may activate NK cells better than CD3ζ. In contrast, second-generation CARs express a second signaling domain (eg, CD28 or 4-1BB) in conjunction with CD3ζ. Third-generation CARs contain two co-stimulatory signaling domains. Based on the mechanisms by which NKG2D activates NK cells, a unique CAR construct containing NKG2D as the ectodomain that links DAP10 and CD3ζ as key signaling molecules was developed. The clustering of CARs induced by antigen binding or NKG2D and its ligand ligation initiates signal transduction that leads to NK cell activation, cytotoxicity against cancer cells, cytokine production, survival and proliferation.