{"doi":"10.1016/j.medj.2023.04.004","title":"A chimeric antigen receptor uniquely recognizing MICA/B stress proteins provides an effective approach to target solid tumors","abstract":"BACKGROUND: The advent of chimeric antigen receptor (CAR) T cell therapies has transformed the treatment of hematological malignancies; however, broader therapeutic success of CAR T cells has been limited in solid tumors because of their frequently heterogeneous composition. Stress proteins in the MICA and MICB (MICA/B) family are broadly expressed by tumor cells following DNA damage but are rapidly shed to evade immune detection. METHODS: We have developed a novel CAR targeting the conserved α3 domain of MICA/B (3MICA/B CAR) and incorporated it into a multiplexed-engineered induced pluripotent stem cell (iPSC)-derived natural killer (NK) cell (3MICA/B CAR iNK) that expressed a shedding-resistant form of the CD16 Fc receptor to enable tumor recognition through two major targeting receptors. FINDINGS: We demonstrated that 3MICA/B CAR mitigates MICA/B shedding and inhibition via soluble MICA/B while simultaneously exhibiting antigen-specific anti-tumor reactivity across an expansive library of human cancer cell lines. Pre-clinical assessment of 3MICA/B CAR iNK cells demonstrated potent antigen-specific in vivo cytolytic activity against both solid and hematological xenograft models, which was further enhanced in combination with tumor-targeted therapeutic antibodies that activate the CD16 Fc receptor. CONCLUSIONS: Our work demonstrated 3MICA/B CAR iNK cells to be a promising multi-antigen-targeting cancer immunotherapy approach intended for solid tumors. FUNDING: Funded by Fate Therapeutics and NIH (R01CA238039).","journal":"Med","year":2023,"id":332337,"datarank":0.4943755299006494,"base_score":3.295836866004329,"endowment":3.295836866004329,"self_citation_contribution":0.4943755299006494,"citation_network_contribution":0.0,"self_endowment_contribution":0.4943755299006494,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":479038,"name":"Wen-I Yeh","orcid":"0000-0002-5705-4232","position":1,"is_corresponding":false},{"id":431213,"name":"Bryan Hancock","orcid":null,"position":2,"is_corresponding":false},{"id":33687,"name":"Robert Blum","orcid":"0000-0002-5270-3854","position":3,"is_corresponding":false},{"id":672075,"name":"Tianhao Xu","orcid":"0000-0003-2935-6353","position":4,"is_corresponding":false},{"id":1058489,"name":"Bi-Huei Yang","orcid":"0000-0003-3363-4408","position":5,"is_corresponding":false},{"id":1059053,"name":"Chia‐Wei Chang","orcid":null,"position":6,"is_corresponding":false},{"id":853833,"name":"Brian Groff","orcid":null,"position":7,"is_corresponding":false},{"id":1058490,"name":"Earl Avramis","orcid":"0000-0002-4595-9536","position":8,"is_corresponding":false},{"id":529192,"name":"Mochtar Pribadi","orcid":null,"position":9,"is_corresponding":false},{"id":256876,"name":"Yijia Pan","orcid":null,"position":10,"is_corresponding":false},{"id":1059054,"name":"Hui-Yi Chu","orcid":null,"position":11,"is_corresponding":false},{"id":1059055,"name":"Shohreh Sikaroodi","orcid":null,"position":12,"is_corresponding":false},{"id":1059056,"name":"Lauren Fong","orcid":null,"position":13,"is_corresponding":false},{"id":306284,"name":"Nicholas Brookhouser","orcid":null,"position":14,"is_corresponding":false},{"id":629138,"name":"Thomas Dailey","orcid":null,"position":15,"is_corresponding":false},{"id":629136,"name":"Miguel Meza","orcid":null,"position":16,"is_corresponding":false},{"id":408381,"name":"Matthew Denholtz","orcid":null,"position":17,"is_corresponding":false},{"id":1059057,"name":"Evelyn Diaz","orcid":null,"position":18,"is_corresponding":false},{"id":1059058,"name":"Judy Martin","orcid":null,"position":19,"is_corresponding":false},{"id":1058491,"name":"Péter Szabó","orcid":"0000-0003-0892-6791","position":20,"is_corresponding":false},{"id":956111,"name":"Sarah Cooley","orcid":"0000-0001-5905-241X","position":21,"is_corresponding":false},{"id":91047,"name":"Lucas Ferrari de Andrade","orcid":"0000-0002-2137-2271","position":22,"is_corresponding":false},{"id":627641,"name":"Tom T. 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