{"doi":"10.1182/blood.2020007748","title":"Targeting a cytokine checkpoint enhances the fitness of armored cord blood CAR-NK cells","abstract":"Immune checkpoint therapy has resulted in remarkable improvements in the outcome for certain cancers. To broaden the clinical impact of checkpoint targeting, we devised a strategy that couples targeting of the cytokine-inducible Src homology 2-containing (CIS) protein, a key negative regulator of interleukin 15 (IL-15) signaling, with fourth-generation \"armored\" chimeric antigen receptor (CAR) engineering of cord blood-derived natural killer (NK) cells. This combined strategy boosted NK cell effector function through enhancing the Akt/mTORC1 axis and c-MYC signaling, resulting in increased aerobic glycolysis. When tested in a lymphoma mouse model, this combined approach improved NK cell antitumor activity more than either alteration alone, eradicating lymphoma xenografts without signs of any measurable toxicity. We conclude that targeting a cytokine checkpoint further enhances the antitumor activity of IL-15-secreting armored CAR-NK cells by promoting their metabolic fitness and antitumor activity. This combined approach represents a promising milestone in the development of the next generation of NK cells for cancer immunotherapy.","journal":"Blood","year":2021,"id":1597,"datarank":0.8478733770402977,"base_score":5.652489180268651,"endowment":5.652489180268651,"self_citation_contribution":0.8478733770402977,"citation_network_contribution":0.0,"self_endowment_contribution":0.8478733770402977,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":284,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0489,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-02-04","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":18327,"name":"Rafet Basar","orcid":null,"position":1,"is_corresponding":false},{"id":18328,"name":"Elif Gokdemir","orcid":null,"position":2,"is_corresponding":false},{"id":18329,"name":"Natalia Baran","orcid":"0000-0003-0618-4798","position":3,"is_corresponding":false},{"id":18330,"name":"Nadima Uprety","orcid":"0000-0003-4379-6208","position":4,"is_corresponding":false},{"id":18331,"name":"Ana Karen Nunez Cortes","orcid":"0000-0001-5380-9274","position":5,"is_corresponding":false},{"id":18332,"name":"Mayela Mendt","orcid":null,"position":6,"is_corresponding":false},{"id":18333,"name":"Lucila Nassif Kerbauy","orcid":"0000-0003-4864-9098","position":7,"is_corresponding":false},{"id":18334,"name":"Pinaki P. 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