Chimeric Antigen Receptor-Engineered Natural Killer (CAR NK) Cells in Cancer Treatment; Recent Advances and Future Prospects

Abstract

Natural Killer (NK) cells are critical members of the innate immunity lymphocytes and have a critical role in host defense against malignant cells. Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) redirects the specificity of the immune cell against a target-specific antigen. ACT has recently created an outstanding opportunity for cancer treatment. Unlike CAR-armored T cells which hadnsome shortcomings as the CAR-receiving construct, Major histocompatibility complex (MHC)-independency, shorter lifespan, the potential to produce an off-the-shelf immune product, and potent anti-tumor properties of the NK cells has introduced NK cells as a potent alternative target for expression of CAR. Here, we aim to provide an updated overview on the current improvements in CAR NK design and immunobiology and describe the potential of CAR-modified NK cells as an alternative "off-the-shelf" carrier of CAR. We also provide lists for the sources of NK cells in the process of CAR NK cell production, different methods for transduction of the CAR genetic sequence to NK cells, the differences between CAR T and CAR NK, and CAR NK-targeted tumor antigens in current studies. Additionally, we provide data on recently published preclinical and clinical studies of CAR NK therapy and a list of finished and ongoing clinical trials. For achieving CAR NK products with higher efficacy and safety, we discuss current challenges in transduction and expansion of CAR NK cells, CAR NK therapy side effects, and challenges that limit the optimal efficacy of CAR NK cells and recommend possible solutions to enhance the persistence, function, safety, and efficacy of CAR NK cells with a special focus on solid tumors.

Keywords: Cancer; Challenges; Chimeric antigen receptor; Immunotherapy; Natural killer cell.

Fig. 1

Structure of the natural killer cell receptors and diferent generations of CARs in NK cells. Created by Esmaeiladeh et al.

Fig. 2

Recent developments of CAR NK cells to increase the efficacy and safety of cancer treatment. Created by Esmaeiladeh et al. CAR: chimeric antigen receptor, NK: natural killer cell, TAA: tumor-associated antigen, IL-4: interleukin-4, IL-7: interleukin-7, TGF-ΒRII: transforming growth factor beta receptor II, IL-15: interleukin-15, KIR: killer inhibitory receptor, iC9: inducible caspase 9, ICR: inverted cytokine receptor, SynNotch: synthetic Notch, scFv: single-chain variable fragment