{"doi":"10.1136/jitc-2022-006509","title":"Single CAR-T cell treatment controls disseminated ovarian cancer in a syngeneic mouse model","abstract":"Background Treatment of some blood cancers with T cells that express a chimeric antigen receptor (CAR) against CD19 have shown remarkable results. In contrast, CAR-T cell efficacy against solid tumors has been difficult to achieve. Methods To examine the potential of CAR-T cell treatments against ovarian cancers, we used the mouse ovarian cancer cell line ID8 in an intraperitoneal model that exhibits disseminated solid tumors in female C57BL/6J mice. The CAR contained a single-chain Fv from antibody 237 which recognizes a Tn-glycopeptide-antigen expressed by ID8 due to aberrant O-linked glycosylation in the absence of the transferase-dependent chaperone Cosmc . The efficacy of four Tn-dependent CARs with varying affinity to Tn antigen, and each containing CD28/CD3ζ cytoplasmic domains, were compared in vitro and in vivo in this study. Results In line with many observations about the impact of aberrant O-linked glycosylation, the ID8 Cosmc knock-out (ID8 Cosmc -KO) exhibited more rapid tumor progression compared with wild-type ID8. Despite the enhanced tumor growth in vivo, 237 CAR and a mutant with 30-fold higher affinity, but not CARs with lower affinity, controlled advanced ID8 Cosmc -KO tumors. Tumor regression could be achieved with a single intravenous dose of the CARs, but intraperitoneal administration was even more effective. The CAR-T cells persisted over a period of months, allowing CAR-treated mice to delay tumor growth in a re-challenge setting. The most effective CARs exhibited the highest affinity for antigen. Antitumor effects observed in vivo were associated with increased numbers of T cells and macrophages, and higher levels of cleaved caspase-3, in the tumor microenvironment. Notably, the least therapeutically effective CAR mediated tonic signaling leading to antigen-independent cytokine expression and it had higher levels of the immunosuppressive cytokine interleukin10. Conclusion The findings support the development of affinity-optimized CAR-T cells as a potential treatment for established ovarian cancer, with the most effective CARs mediating a distinct pattern of inflammatory cytokine release in vitro. Importantly, the most potent Tn-dependent CAR-T cells showed no evidence of toxicity in tumor-bearing mice in a syngeneic, immunocompetent system.","journal":"Journal for ImmunoTherapy of Cancer","year":2023,"id":357858,"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":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"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":459418,"name":"Preeti Sharma","orcid":"0000-0002-8210-9004","position":1,"is_corresponding":false},{"id":1099264,"name":"Claire P. Schane","orcid":"0009-0004-1752-8829","position":2,"is_corresponding":false},{"id":1107640,"name":"Amber N Lewis","orcid":"0009-0008-3651-9062","position":3,"is_corresponding":false},{"id":1108007,"name":"Edward F. Valdez","orcid":null,"position":4,"is_corresponding":false},{"id":459419,"name":"Venkata V.V.R. Marada","orcid":"0000-0003-1142-7854","position":5,"is_corresponding":false},{"id":1107641,"name":"Marlies V. Hager","orcid":"0000-0001-8050-4943","position":6,"is_corresponding":false},{"id":843054,"name":"Will Montgomery","orcid":null,"position":7,"is_corresponding":false},{"id":441176,"name":"Steven P. Wolf","orcid":"0009-0008-2723-695X","position":8,"is_corresponding":false},{"id":441173,"name":"Karin Schreiber","orcid":"0009-0000-1414-9365","position":9,"is_corresponding":false},{"id":441180,"name":"Hans Schreiber","orcid":"0000-0002-1908-6233","position":10,"is_corresponding":false},{"id":405187,"name":"Keith Bailey","orcid":"0000-0001-8096-6291","position":11,"is_corresponding":false},{"id":612795,"name":"Timothy M. Fan","orcid":"0000-0003-2510-7050","position":12,"is_corresponding":false},{"id":313454,"name":"Paul J. Hergenrother","orcid":"0000-0001-9018-3581","position":13,"is_corresponding":false},{"id":689876,"name":"Edward J. Roy","orcid":"0000-0003-3480-3699","position":14,"is_corresponding":false},{"id":297956,"name":"David M. Kranz","orcid":"0000-0002-4931-126X","position":15,"is_corresponding":false},{"id":263521,"name":"Diana Rose E. Rañoa","orcid":"0000-0002-2363-6111","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T01:13:39.186262Z","pmid":"37258040","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":[]}