CAR-NK cell in cancer immunotherapy; A promising frontier

Abstract

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.

Keywords: CAR-NK; cancer; chimeric antigen receptors; immunotherapy; natural killer cells.

FIGURE 1

NK cell dysfunction in the tumor microenvironment (TME). Varied immunosuppressive molecules secreted by tumor cells, tumor‐associated macrophages (TAM), myeloid‐derived suppressor cells (MDSC), regulatory T‐cells (Treg), dendritic cells (DC), and T cells and also other types of cells presented in TME can stimulate suppressive effects on NK cell functions and proliferation. Nonetheless, using chimeric antigen receptor‐natural killer (CAR‐NK) cells can result in overcoming the NK cell dysfunction in TME. Moreover, engineered CAR‐NK cells to overexpress specific chemokine receptors can support the CAR‐NK cell more proficient homing to tumor tissue and accordingly may lead to more reliable therapeutic outcomes

FIGURE 2

Generation process of CAR‐NK cells. Isolated or established NK cells from diverse sources can be modified with CAR‐expressing vectors (eg, lentivirus or retrovirus) and then expanded in NK cell‐specific expansion media. The established CAR‐NK cells are commonly injected via an intravenous route to selectively kill tumor cells. Umbilical cord blood (UCB), peripheral blood (PB), human induced pluripotent stem cell (hiPSCs), human embryonic stem cell (hESC), hematopoietic stem cell (HSC), chimeric antigen receptor‐natural killer (CAR‐NK) cells