{"doi":"10.1073/pnas.2122379119","title":"Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia","abstract":"Acute myeloid leukemia (AML) remains a therapeutic challenge, and a paucity of tumor-specific targets has significantly hampered the development of effective immune-based therapies. Recent paradigm-changing studies have shown that natural killer (NK) cells exhibit innate memory upon brief activation with IL-12 and IL-18, leading to cytokine-induced memory-like (CIML) NK cell differentiation. CIML NK cells have enhanced antitumor activity and have shown promising results in early phase clinical trials in patients with relapsed/refractory AML. Here, we show that arming CIML NK cells with a neoepitope-specific chimeric antigen receptor (CAR) significantly enhances their antitumor responses to nucleophosphmin-1 (NPM1)-mutated AML while avoiding off-target toxicity. CIML NK cells differentiated from peripheral blood NK cells were efficiently transduced to express a TCR-like CAR that specifically recognizes a neoepitope derived from the cytosolic oncogenic NPM1-mutated protein presented by HLA-A2. These CAR CIML NK cells displayed enhanced activity against NPM1-mutated AML cell lines and patient-derived leukemic blast cells. CAR CIML NK cells persisted in vivo and significantly improved AML outcomes in xenograft models. Single-cell RNA sequencing and mass cytometry analyses identified up-regulation of cell proliferation, protein folding, immune responses, and major metabolic pathways in CAR-transduced CIML NK cells, resulting in tumor-specific, CAR-dependent activation and function in response to AML target cells. Thus, efficient arming of CIML NK cells with an NPM1-mutation-specific TCR-like CAR substantially improves their innate antitumor responses against an otherwise intracellular mutant protein. These preclinical findings justify evaluating this approach in clinical trials in HLA-A2 + AML patients with NPM1c mutations.","journal":"Proceedings of the National Academy of Sciences","year":2022,"id":233307,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":134,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9581,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":35400,"name":"James Dongjoo Ham","orcid":"0000-0003-0971-7940","position":1,"is_corresponding":false},{"id":626205,"name":"Guangan Hu","orcid":"0000-0003-1828-0509","position":2,"is_corresponding":false},{"id":108324,"name":"Guozhu Xie","orcid":"0000-0002-3377-3099","position":3,"is_corresponding":false},{"id":847204,"name":"Juliana Vergara","orcid":null,"position":4,"is_corresponding":false},{"id":108326,"name":"Yong Liang","orcid":"0000-0001-5643-8966","position":5,"is_corresponding":false},{"id":550367,"name":"Alaa Kassim Ali","orcid":"0000-0002-7490-0592","position":6,"is_corresponding":false},{"id":689198,"name":"Mubin Tarannum","orcid":"0000-0002-4440-1565","position":7,"is_corresponding":false},{"id":846183,"name":"Hannah Donner","orcid":"0009-0003-8463-0690","position":8,"is_corresponding":false},{"id":846184,"name":"Joanna Bagińska","orcid":"0000-0001-5182-7575","position":9,"is_corresponding":false},{"id":846185,"name":"Yasmin Abdulhamid","orcid":"0009-0000-9564-9424","position":10,"is_corresponding":false},{"id":846186,"name":"Khanhlinh Dinh","orcid":"0009-0005-1343-083X","position":11,"is_corresponding":false},{"id":282402,"name":"Robert J. 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