Superior Expansion and Cytotoxicity of Human Primary NK and CAR-NK Cells from Various Sources via Enriched Metabolic Pathways

Yang, Yan; Badeti, Saiaditya; Hsiang-Chi, Tseng; Tuyet, Minh; Liu, Ting; Jiang, Jie; Liu, Chen; Liu, Dongfang

doi:10.1016/j.omtm.2020.06.014

Cited by 57 publications

(57 citation statements)

References 90 publications

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“…Where necessary, patient consent was obtained before obtaining clinical samples. NK and CAR-NK cells were expanded with 100-Gy irradiated 721.221-mIL21 cells and supplemented with 200 U/mL IL-2 and 5 ng/mL IL-15 (Peprotech, Rocky Hill, CT, USA) 83 .…”

Section: Discussionmentioning

confidence: 99%

Efficacy of anti-CD147 chimeric antigen receptors targeting hepatocellular carcinoma

et al. 2020

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Chimeric antigen receptor (CAR) therapy is a promising immunotherapeutic strategy for treating multiple refractory blood cancers, but further advances are required for solid tumor CAR therapy. One challenge is identifying a safe and effective tumor antigen. Here, we devise a strategy for targeting hepatocellular carcinoma (HCC, one of the deadliest malignancies). We report that T and NK cells transduced with a CAR that recognizes the surface marker, CD147, also known as Basigin, can effectively kill various malignant HCC cell lines in vitro, and HCC tumors in xenograft and patient-derived xenograft mouse models. To minimize any on-target/off-tumor toxicity, we use logic-gated (log) GPC3–synNotch-inducible CD147-CAR to target HCC. LogCD147-CAR selectively kills dual antigen (GPC3+CD147+), but not single antigen (GPC3-CD147+) positive HCC cells and does not cause severe on-target/off-tumor toxicity in a human CD147 transgenic mouse model. In conclusion, these findings support the therapeutic potential of CD147-CAR-modified immune cells for HCC patients.

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Section: Discussionmentioning

confidence: 99%

Efficacy of anti-CD147 chimeric antigen receptors targeting hepatocellular carcinoma

et al. 2020

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“…Less differentiated NK cells which display a memory-like phenotype can also be generated by ex vivo expansion using 721,221 feeder cells with membrane-bound IL-21 [166]. Critically, these cells upregulated genes related to glucose and amino acid metabolism, including amino acid transporter SLC7A5 and the transcription factor c-Myc, which are critical for NK cell function [167].…”

Section: Memory-like Nk Cellsmentioning

confidence: 99%

Natural Killer Cells in Immunotherapy: Are We Nearly There?

Bachiller

Battram

Perez-Amill

et al. 2020

Cancers

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Natural killer (NK) cells are potent anti-tumor and anti-microbial cells of our innate immune system. They are equipped with a vast array of receptors that recognize tumor cells and other pathogens. The innate immune activity of NK cells develops faster than the adaptive one performed by T cells, and studies suggest an important immunoregulatory role for each population against the other. The association, observed in acute myeloid leukemia patients receiving haploidentical killer-immunoglobulin-like-receptor-mismatched NK cells, with induction of complete remission was the determinant to begin an increasing number of clinical studies administering NK cells for the treatment of cancer patients. Unfortunately, even though transfused NK cells demonstrated safety, their observed efficacy was poor. In recent years, novel studies have emerged, combining NK cells with other immunotherapeutic agents, such as monoclonal antibodies, which might improve clinical efficacy. Moreover, genetically-modified NK cells aimed at arming NK cells with better efficacy and persistence have appeared as another option. Here, we review novel pre-clinical and clinical studies published in the last five years administering NK cells as a monotherapy and combined with other agents, and we also review chimeric antigen receptor-modified NK cells for the treatment of cancer patients. We then describe studies regarding the role of NK cells as anti-microbial effectors, as lessons that we could learn and apply in immunotherapy applications of NK cells; these studies highlight an important immunoregulatory role performed between T cells and NK cells that should be considered when designing immunotherapeutic strategies. Lastly, we highlight novel strategies that could be combined with NK cell immunotherapy to improve their targeting, activity, and persistence.

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“…Recent clinical trials testing cancer immunotherapies have shown promising results for treating infectious diseases 14 . One of crucial barriers to using primary NK cells for immunotherapy is the difficulty in obtaining an adequate number of NK cells from peripheral blood or cold blood before expansion 18 . We have optimized the NK cell expansion technology to buffer this potential limitation.…”

Section: Discussionmentioning

confidence: 99%

“…1b). 293T cells were transfected with a combination of plasmids containing CR3022-CAR in the SFG backbone, RDF, and PegPam3, as previously described 17,18 . The SFG retrovirus particles were used to transduce NK-92MI cells.…”

Section: Generation Of Cr3022-car-nk-92mi Cellsmentioning

confidence: 99%

Efficacy of Targeting SARS-CoV-2 by CAR-NK Cells

Ma¹,

Badeti²,

Geng³

et al. 2020

Preprint

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SARS-CoV-2, which causes COVID-19 disease, is one of greatest global pandemics in history. No effective treatment is currently available for severe COVID-19 disease. One strategy for implementing cell-based immunity involves the use of chimeric antigen receptor (CAR) technology. Unlike CAR T cells, which need to be developed using primary T cells derived from COVID-19 patients with lymphopenia, clinical success of CAR NK cell immunotherapy is possible through the development of allogeneic, universal, and ‘off-the-shelf’ CAR-NK cells from a third party, which will significantly broaden the application and reduce costs. Here, we develop a novel approach for the generation of CAR-NK cells for targeting SARS-CoV-2. CAR-NK cells were generated using the scFv domain of CR3022 (henceforth, CR3022-CAR-NK), a broadly neutralizing antibody for SARS-CoV-1 and SARS-CoV-2. CR3022-CAR-NK cells can specifically bind to RBD of SARS-CoV-2 and pseudotyped SARS-CoV-2 S protein, and can be activated by pseudotyped SARS-CoV-2-S viral particles in vitro. Further, CR3022-CAR-NK cells can specifically kill pseudo-SARS-CoV-2 infected target cells. Thus, ‘off-the-shelf’ CR3022-CAR-NK cells may have the potential to treat patients with severe COVID-19 disease.

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Superior Expansion and Cytotoxicity of Human Primary NK and CAR-NK Cells from Various Sources via Enriched Metabolic Pathways

Cited by 57 publications

References 90 publications

Efficacy of anti-CD147 chimeric antigen receptors targeting hepatocellular carcinoma

Efficacy of anti-CD147 chimeric antigen receptors targeting hepatocellular carcinoma

Natural Killer Cells in Immunotherapy: Are We Nearly There?

Efficacy of Targeting SARS-CoV-2 by CAR-NK Cells

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