Current Progress of CAR-NK Therapy in Cancer Treatment

Abstract

CD8+ T cells and natural killer (NK) cells eliminate target cells through the release of lytic granules and Fas ligand (FasL)-induced target cell apoptosis. The introduction of chimeric antigen receptor (CAR) makes these two types of cells selective and effective in killing cancer cells. The success of CAR-T therapy in the treatment of acute lymphoblastic leukemia (ALL) and other types of blood cancers proved that the immunotherapy is an effective approach in fighting against cancers, yet adverse effects, such as graft versus host disease (GvHD) and cytokine release syndrome (CRS), cannot be ignored for the CAR-T therapy. CAR-NK therapy, then, has its advantage in lacking these adverse effects and works as effective as CAR-T in terms of killing. Despite these, NK cells are known to be hard to transduce, expand in vitro, and sustain shorter in vivo comparing to infiltrated T cells. Moreover, CAR-NK therapy faces challenges as CAR-T therapy does, e.g., the time, the cost, and the potential biohazard due to the use of animal-derived products. Thus, enormous efforts are needed to develop safe, effective, and large-scalable protocols for obtaining CAR-NK cells. Here, we reviewed current progress of CAR-NK therapy, including its biological properties, CAR compositions, preparation of CAR-NK cells, and clinical progresses. We also discussed safety issues raised from genetic engineering. We hope this review is instructive to the research community and a broad range of readers.

Retinoic acid receptor activation reprograms senescence response and enhances anti-tumor activity of natural killer cells

“…Various strategies are being employed to overcome these challenges, such as ex vivo pre-conditioning with cytokines, treatment with small molecules, NK cells engineering, or iPSC differentiation in NK cells. 47 , 63 , 65 In this respect, we envision that the combination of adapalene and docetaxel may be used as an alternative strategy to enhance the efficacy of allogenic infusion of NK cells or CAR-NK cell treatment in metastatic PCa patients. This combination of compounds could promote an increased migration of NK cells in the tumors, ultimately enhancing their antitumor activity in this cold tumor model.…”

Bispecific immune cell engager enhances the anticancer activity of CD16+ NK cells and macrophages in vitro, and eliminates cancer metastasis in NK humanized NOG mice

“… 32 Moreover, it is well understood that CAR-NK cells present significant challenges in genetic manipulation, and their antitumor efficacy is limited by the short life of NK cells. 33 While earlier reports indicated that NK therapy had no significant side effects, such as cytokine release syndrome (CRS), Zhang et al recently published clinical data on the use of the third generation of CAR-NK cells (referred to as CCCR-NK92) and observed CRS in one patient. 34 Another class of immunotherapeutic modalities harnessing NK cells, known as NK cell engagers (NKCEs), has recently emerged and exhibited several advantages over the abovementioned strategies.…”

Chimeric antigen receptor (CAR) modified T Cells in acute myeloid leukemia: limitations and expectations

“…This feature of NK cells can be used as an anti-tumor strategy, particularly because tumor cells frequently exhibit downregulation or loss of HLA-I molecules ( Mehta and Rezvani, 2018 ). They also induce less CRS and ICANS than CAR-T therapy ( Pang et al, 2022 ). However, their lifespan is low so this therapy will require various doses of treatment to achieve maintained CR ( Khawar and Sun, 2021 ) and CAR-NK manufacturing is more challenging than CAR-T cell expansion.…”