{"doi":"10.1136/jitc-2024-009147","title":"Regression of renal cell carcinoma by T cell receptor-engineered T cells targeting a human endogenous retrovirus","abstract":"BACKGROUND: We discovered a novel human endogenous retrovirus (CT-RCC HERV-E) that was selectively expressed in most clear cell renal cell carcinomas (ccRCC) and served as a source of antigens for T cell-mediated killing. Here, we described the cloning of a novel T cell receptor (TCR) targeting a CT-RCC HERV-E-derived antigen specific to ccRCC and characterized antitumor activity of HERV-E TCR-transduced T cells (HERV-E T cells). METHODS: T cell clone from a patient with immune-mediated regression of ccRCC post-allogeneic stem cell transplant that recognized the CT-RCC-1 HERV-E-derived peptide in an HLA-A11-restricted manner. We used 5'Rapid Amplification of cDNA Ends (RACE) to clone the full length HERV-E TCR and generated retrovirus encoding this TCR for transduction of T cells. We characterized HERV-E T cells for phenotype and function in vitro and in a murine xenograft model. Lastly, we implemented a good manufacturing practice-compliant method for scalable production of HERV-E T cells. RESULTS: ccRCC cells expressing CT-RCC HERV-E compared with unmodified T cells. Killing by HERV-E T cells was lost when cocultured against HERV-E knockout ccRCC cells. HERV-E T cells induced regression of established ccRCC tumors in a murine model and improved survival of tumor-bearing mice. Large-scale production of HERV-E T cells under good manufacturing practice conditions generated from healthy donors retained specific antigen recognition and cytotoxicity against ccRCC. CONCLUSIONS: This is the first report showing that human ccRCC cells can be selectively recognized and killed by TCR-engineered T cells targeting a HERV-derived antigen. These preclinical findings provided the foundation for evaluating HERV-E TCR-transduced T cell infusions in patients with metastatic ccRCC in a clinical trial (NCT03354390).","journal":"Journal for ImmunoTherapy of Cancer","year":2024,"id":428681,"datarank":0.7627658806922175,"base_score":2.639057329615259,"endowment":2.639057329615259,"self_citation_contribution":0.3958585994422889,"citation_network_contribution":0.36690728124992866,"self_endowment_contribution":0.3958585994422889,"citer_contribution":0.36690728124992866,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":13,"citers_with_citation_signal":6,"citers_with_endowment":6,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9517,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT03354390"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1172365,"name":"Elizabeth M. Brahmbhatt","orcid":null,"position":1,"is_corresponding":false},{"id":1165957,"name":"Elena Cherkasova","orcid":"0000-0002-7269-6516","position":2,"is_corresponding":false},{"id":1172008,"name":"Timothy T. 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Stroncek","orcid":"0000-0001-5867-3265","position":12,"is_corresponding":false},{"id":467694,"name":"Steven L. Highfill","orcid":"0000-0003-0135-0961","position":13,"is_corresponding":false},{"id":375093,"name":"Annika V. Dalheim","orcid":null,"position":14,"is_corresponding":false},{"id":343640,"name":"Robert Reger","orcid":null,"position":15,"is_corresponding":false},{"id":373463,"name":"Michael I. Nishimura","orcid":"0009-0008-2288-6021","position":16,"is_corresponding":false},{"id":276347,"name":"Richard Childs","orcid":null,"position":17,"is_corresponding":false},{"id":905119,"name":"Stefan Barisic","orcid":"0000-0003-4273-2907","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T01:59:02.165535Z","pmid":"39266213","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":[]}