CAR-NK cell in cancer immunotherapy; A promising frontier.

Chimeric antigen receptors (CARs) have a unique facet of synthetic biology and offer a paradigm shift in personalized medicine as they can use and redirect the patient's immune cells to attack cancer cells. CAR-natural killer (NK) cells combine the targeted specificity of antigens with the subsequent intracellular signaling ability of the receptors to increase their anti-cancer functions. Importantly, CAR-NK cells can be utilized as universal cell-based therapy without requiring human leukocyte antigen (HLA) matching or earlier contact with tumor-associated antigens (TAAs). Indeed, CAR-NK cells can be adapted to recognize various antigens, hold higher proliferation capacity, and in vivo persistence, show improved infiltration into the tumors, and the ability to overcome the resistant tumor microenvironment leading to sustained cytotoxicity against tumors. Accumulating evidence from recent in vivo studies rendering CAR-NK cell anti-cancer competencies renewed the attention in the context of cancer immunotherapy, as these redirected effector cells can be used in the development of the "off-the-shelf" anti-cancer immunotherapeutic products. In the current review, we focus on the therapeutic efficacy of CAR-NK cell therapies for treating various human malignancies, including hematological malignancies and solid tumors, and will discuss the recent findings in this regard, with a special focus on animal studies.

Marofi F ，Abdul-Rasheed OF ，Rahman HS ，Budi HS ，Jalil AT ，Yumashev AV ，Hassanzadeh A ，Yazdanifar M ，Motavalli R ，Chartrand MS ，Ahmadi M ，Cid-Arreguid A ，Jarahian M ... -  《-》

CAR-NK cells: A promising cellular immunotherapy for cancer.

Natural Killer (NK) cells and CD8+ cytotoxic T cells are two types of immune cells that can kill target cells through similar cytotoxic mechanisms. With the remarkable success of chimeric antigen receptor (CAR)-engineered T (CAR-T) cells for treating haematological malignancies, there is a rapid growing interest in developing CAR-engineered NK (CAR-NK) cells for cancer therapy. Compared to CAR-T cells, CAR-NK cells could offer some significant advantages, including: (1) better safety, such as a lack or minimal cytokine release syndrome and neurotoxicity in autologous setting and graft-versus-host disease in allogenic setting, (2) multiple mechanisms for activating cytotoxic activity, and (3) high feasibility for 'off-the-shelf' manufacturing. CAR-NK cells could be engineered to target diverse antigens, enhance proliferation and persistence in vivo, increase infiltration into solid tumours, overcome resistant tumour microenvironment, and ultimately achieve an effective anti-tumour response. In this review, we focus on recent progress in genetic engineering and clinical application of CAR-NK cells, and discuss current challenges and future promise of CAR-NK cells as a novel cellular immunotherapy in cancer.

Xie G ，Dong H ，Liang Y ，Ham JD ，Rizwan R ，Chen J ... -  《EBioMedicine》

CAR-NK Cells: From Natural Basis to Design for Kill.

Chimeric antigen receptors (CARs) are fusion proteins with an extracellular antigen recognition domain and numerous intracellular signaling domains that have been genetically modified. CAR-engineered T lymphocyte-based therapies have shown great success against blood cancers; however, potential fatal toxicity, such as in cytokine release syndrome, and high costs are some shortcomings that limit the clinical application of CAR-engineered T lymphocytes and remain to overcome. Natural killer (NK) cells are the focal point of current immunological research owing to their receptors that prove to be promising immunotherapeutic candidates for treating cancer. However, to date, manipulation of NK cells to treat malignancies has been moderately successful. Recent progress in the biology of NK cell receptors has greatly transformed our understanding of how NK cells recognize and kill tumor and infected cells. CAR-NK cells may serve as an alternative candidate for retargeting cancer because of their unique recognition mechanisms, powerful cytotoxic effects especially on cancer cells in both CAR-dependent and CAR-independent manners and clinical safety. Moreover, NK cells can serve as an 'off-the-shelf product' because NK cells from allogeneic sources can also be used in immunotherapies owing to their reduced risk of alloreactivity. Although ongoing fundamental research is in the beginning stages, this review provides an overview of recent developments implemented to design CAR constructs to stimulate NK activation and manipulate NK receptors for improving the efficiency of immunotherapy against cancer, summarizes the preclinical and clinical advances of CAR-NK cells against both hematological malignancies and solid tumors and confronts current challenges and obstacles of their applications. In addition, this review provides insights into prospective novel approaches that further enhance the efficiency of CAR-NK therapies and highlights potential questions that require to be addressed in the future.

Khawar MB ，Sun H 《Frontiers in Immunology》

Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy.

Yilmaz A ，Cui H ，Caligiuri MA ，Yu J ... -  《Journal of Hematology & Oncology》

Engineering Natural Killer Cells for Cancer Immunotherapy.

The past several years have seen tremendous advances in the engineering of immune effector cells as therapy for cancer. While chimeric antigen receptors (CARs) have been used extensively to redirect the specificity of autologous T cells against hematological malignancies with striking clinical results, studies of CAR-modified natural killer (NK) cells have been largely preclinical. In this review, we focus on recent advances in NK cell engineering, particularly on preclinical evidence suggesting that NK cells may be as effective as T cells in recognizing and killing targets after genetic modification. We will discuss strategies to introduce CARs into both primary NK cells and NK cell lines in an effort to provide antigen specificity, the challenges of manufacturing engineered NK cells, and evidence supporting the effectiveness of this approach from preclinical and early-phase clinical studies using CAR-engineered NK cells. CAR-NK cells hold great promise as a novel cellular immunotherapy against refractory malignancies. Notably, NK cells can provide an "off-the-shelf" product, eliminating the need for a personalized and patient-specific product that plagues current CAR-T cell therapies. The ability to more potently direct NK cell-mediated cytotoxicity against refractory tumors through the expression of CAR is likely to contribute to the recent paradigm shift in cancer treatment.

Rezvani K ，Rouce R ，Liu E ，Shpall E ... -  《-》