{"doi":"10.1016/j.ymthe.2025.05.033","title":"Targeting CD117 on hematopoietic stem and progenitor cells impairs CAR T cell activity","abstract":"CD117 is a cell-surface receptor expressed on hematopoietic stem and progenitor cells and acute myeloid leukemia (AML), and thus CD117-targeting chimeric antigen receptor T cells (CART117) can function as both conditioning for hematopoietic stem cell transplantation and a therapy for AML. We developed human and mouse CART117 to evaluate the safety and feasibility of targeting CD117 in preclinical mouse models. Human CART117 had potent anti-tumor activity while also mediating significant hematopoietic toxicity in a humanized mouse model. Murine CART117 (mCART117) led to systemic and hematopoietic toxicity without anti-leukemic benefit in immunocompetent C57BL/6 mice. Intriguingly, mCART117 was able to eliminate CD117 + cells in the spleen but not in the bone marrow (BM). Of note, proliferation of BM CD117 + cells in response to lymphodepleting chemotherapy amplified mCART117-mediated systemic toxicity. Alternative lymphodepletion with radiation ameliorated the systemic toxicity of mCART117 but did not improve anti-leukemic efficacy. Immunodeficient mice given mCART117 in the absence of lymphodepletion died from severe pancytopenia, and this effect was recapitulated by regulatory T cell depletion in immunocompetent mice. Increasing CD117 expression on AML improved the anti-leukemic efficacy and toxicity profile of mCART117. In conclusion, mCART117 anti-leukemic activity is impaired in immunocompetent mice when CD117 is expressed at physiological levels on AML.","journal":"Molecular Therapy","year":2025,"id":514753,"datarank":0.44238335235821624,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"self_citation_contribution":0.31191623125197543,"citation_network_contribution":0.13046712110624079,"self_endowment_contribution":0.31191623125197543,"citer_contribution":0.13046712110624079,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":7,"citers_with_citation_signal":4,"citers_with_endowment":4,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":375354,"name":"Julie Ritchey","orcid":null,"position":1,"is_corresponding":false},{"id":18437,"name":"John F. Dipersio","orcid":"0000-0002-0429-3133","position":2,"is_corresponding":false},{"id":575488,"name":"Miriam Kim","orcid":"0000-0001-9609-0685","position":3,"is_corresponding":false},{"id":1378808,"name":"Riedl Thomas","orcid":null,"position":0,"is_corresponding":true}],"reference_count":22,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:48:34.431522Z","pmid":"40450523","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":[]}