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

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.

SUBMITTER: Yilmaz A

PROVIDER: S-EPMC7720606 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Yilmaz Ahmet A Cui Hanwei H Caligiuri Michael A MA Yu Jianhua J

Journal of hematology & oncology 20201207 1

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 immun ...[more]

PMID: 33287875

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Project description:BackgroundThe anti-tumor immunity of natural killer (NK) cells can be paralyzed by the CD73-induced generation of immunosuppressive adenosine from precursor ATP within the hypoxic microenvironment of solid tumors. In an effort to redirect purinergic immunosuppression of NK cell anti-tumor function, we showed, for the first time, that immunometabolic combination treatment with NKG2D-engineered CAR-NK cells alongside blockade of CD73 ectonucleotidase activity can result in significant anti-tumor responses in vivo.MethodsNK cells were engineered non-virally with NKG2D.CAR-presenting vectors based on the piggyBac transposon system with DAP10 and CD3ζ co-signaling domains. The anti-tumor immunity of NKG2D.CAR.NK cells in combination with CD73 targeting was evaluated against multiple solid tumor targets in vitro and humanized mouse xenografts in immunodeficient tumor-bearing mice in vivo. Intratumoral migration was evaluated via immunohistochemical staining, while degranulation capacity and IFN-γ production of NK cells were measured in response to solid tumor targets.ResultsOur results showed that CD73 blockade can mediate effective purinergic reprogramming and enhance anti-tumor cytotoxicity both in vitro and in vivo by enhancing the killing ability of CAR-engineered NK cells against CD73+ solid tumor targets via mechanisms that might imply alleviation from adenosinergic immunometabolic suppression. CD73 blockade improved the intratumoral homing of CD56+ CAR-NK cells in vivo. These engineered NK cells showed synergistic therapeutic efficacy in combination with CD73 targeting against CD73+ human lung cancer xenograft models. Interestingly, CD73 blockade could inhibit tumor growth in vivo independently of adaptive immune cells, innate immunity or NK cell-mediated ADCC.ConclusionsImmunotherapies targeting the adenosinergic signaling cascade, which act by neutralizing CD73 ectoenzymatic activity, had thus far not been evaluated in humanized tumor models, nor had the implication of innate immunity been investigated. Taken together, our pre-clinical efficacy data demonstrate, for the first time, the potential of targeting CD73 to modulate purinergic signaling and enhance adoptive NK cell immunotherapy via mechanisms that could implicate autocrine tumor control as well as by mediating adenosinergic signaling.

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

Publications

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

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