Abstract
Natural killer (NK) cells are a critical component of the innate immune system. Chimeric antigen receptors (CARs) re-direct NK cells toward tumor cells carrying corresponding antigens, creating major opportunities in the fight against cancer. CAR NK cells have the potential for use as universal CAR cells without the need for human leukocyte antigen matching or prior exposure to tumor-associated antigens. Exciting data from recent clinical trials have renewed interest in the field of cancer immunotherapy due to the potential of CAR NK cells in the production of “off-the-shelf” anti-cancer immunotherapeutic products. Here, we provide an up-to-date comprehensive overview of the recent advancements in key areas of CAR NK cell research and identify under-investigated research areas. We summarize improvements in CAR design and structure, advantages and disadvantages of using CAR NK cells as an alternative to CAR T cell therapy, and list sources to obtain NK cells. In addition, we provide a list of tumor-associated antigens targeted by CAR NK cells and detail challenges in expanding and transducing NK cells for CAR production. We additionally discuss barriers to effective treatment and suggest solutions to improve CAR NK cell function, proliferation, persistence, therapeutic effectiveness, and safety in solid and liquid tumors.
Highlights
Natural killer (NK) cells are large granular lymphocytes with surface markers CD3−CD56+NKp46+ in humans
Both NK cells and innate lymphoid cell 1 (ILC1) depend on the transcription factor T-bet for their proper function and development, and secrete interferon-γ (IFN-γ) rather than type 2 cytokines (IL-5 and IL-13), IL-17, or IL-22 [3]
We found that CS1CAR NK cells were able to target MM cells and eradicate MM both in vitro and in vivo [44]
Summary
Natural killer (NK) cells are large granular lymphocytes with surface markers CD3−CD56+NKp46+ in humans. ScFv is derived from a tumor-specific antibody and can target any antigen expressed on tumor cell surface [27]. The first-generation CARs contained only the CD3ζ chain, the common signal transducing subunit of TCR, or FcRγ subunits as the intracellular signaling domain [31– 33] They were not effective in initiating T cell activation or tumor elimination as they lacked co-stimulatory signaling required for full T cell activation. Nanobodies composed only of heavy chains are being utilized for CAR NK cell production [39] These single-chain antibodies possess specificity comparable to scFvs and are much smaller in size, facilitating transduction. Their use in CAR NK cell production is currently at the experimental stage. The intent-to-treatment (ITT) rate, as defined by the number of patients with ORR divided by the number of 1 leukapheresis
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