{"doi":"10.1016/j.ccell.2023.09.010","title":"Cooperative CAR targeting to selectively eliminate AML and minimize escape","abstract":"Acute myeloid leukemia (AML) poses a singular challenge for chimeric antigen receptor (CAR) therapy owing to its phenotypic heterogeneity and similarity to normal hematopoietic stem/progenitor cells (HSPCs). Here we expound a CAR strategy intended to efficiently target AML while minimizing HSPC toxicity. Quantification of target expression in relapsed/refractory patient samples and normal HSPCs reveals a therapeutic window for gated co-targeting of ADGRE2 and CLEC12A: We combine an attenuated ADGRE2-CAR with a CLEC12A-chimeric costimulatory receptor (ADCLEC.syn1) to preferentially engage ADGRE2posCLEC12Apos leukemic stem cells over ADGRE2lowCLEC12Aneg normal HSPCs. ADCLEC.syn1 prevents antigen escape in AML xenograft models, outperforms the ADGRE2-CAR alone and eradicates AML despite proximate myelopoiesis in humanized mice. Off-target HSPC toxicity is similar to that of a CD19-CAR and can be mitigated by reducing CAR T cell-derived interferon-γ. Overall, we demonstrate the ability of target density-adapted cooperative CAR targeting to selectively eliminate AML and potentially obviate the need for hematopoietic rescue.","journal":"Cancer Cell","year":2023,"id":316180,"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":113,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"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":218297,"name":"Jorge Mansilla‐Soto","orcid":"0000-0003-2889-1397","position":1,"is_corresponding":false},{"id":1019538,"name":"Sarah Nataraj","orcid":"0000-0002-1683-2763","position":2,"is_corresponding":false},{"id":1019539,"name":"Friederike Kogel","orcid":"0000-0002-8888-2268","position":3,"is_corresponding":false},{"id":451224,"name":"Qing Chang","orcid":"0000-0001-7406-8479","position":4,"is_corresponding":false},{"id":225995,"name":"Elisa de Stanchina","orcid":"0000-0002-3873-315X","position":5,"is_corresponding":false},{"id":496198,"name":"Michael Lopez","orcid":"0009-0001-5691-5272","position":6,"is_corresponding":false},{"id":640703,"name":"Mei Rosa Ng","orcid":"0000-0002-9743-8855","position":7,"is_corresponding":false},{"id":374454,"name":"Kathryn Fraser","orcid":"0000-0003-0941-726X","position":8,"is_corresponding":false},{"id":636479,"name":"Marion Subklewe","orcid":"0000-0001-9154-9469","position":9,"is_corresponding":false},{"id":292601,"name":"Jae H. Park","orcid":"0000-0002-2903-5130","position":10,"is_corresponding":false},{"id":615639,"name":"Xiuyan Wang","orcid":"0000-0002-1551-3330","position":11,"is_corresponding":false},{"id":617018,"name":"Isabelle Rivière","orcid":null,"position":12,"is_corresponding":false},{"id":218306,"name":"Michel Sadelain","orcid":"0000-0002-9031-8025","position":13,"is_corresponding":false},{"id":843519,"name":"Sascha Haubner","orcid":"0000-0002-5348-1456","position":0,"is_corresponding":true}],"reference_count":109,"raw_metadata":null,"created_at":"2026-07-19T01:06:38.213358Z","pmid":"37802054","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}