{"doi":"10.1126/sciadv.adg9845","title":"Multi-tiered approach to detect autoimmune cross-reactivity of therapeutic T cell receptors","abstract":"T cell receptor (TCR)-engineered T cell therapy using high-affinity TCRs is a promising treatment modality for cancer. Discovery of high-affinity TCRs especially against self-antigens can require approaches that circumvent central tolerance, which may increase the risk of cross-reactivity. Despite the potential for toxicity, no standardized approach to screen cross-reactivity has been established in the context of preclinical safety evaluation. Here, we describe a practical framework to prospectively detect clinically prohibitive cross-reactivity of therapeutic TCR candidates. Cross-reactivity screening consisted of multifaceted series of assays including assessment of p-MHC tetramer binding, cell line recognition, and reactivity against candidate peptide libraries. Peptide libraries were generated using conventional contact residue motif-guided search, amino acid substitution matrix-based search unguided by motif information, and combinatorial peptide library scan-guided search. We demonstrate the additive nature of a layered approach, which efficiently identifies unsafe cross-reactivity including one undetected by conventional motif-guided search. These findings have important implications for the safe development of TCR-based therapies.","journal":"Science Advances","year":2023,"id":340005,"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":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9535,"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":351451,"name":"John Davies","orcid":"0000-0002-9482-1066","position":1,"is_corresponding":false},{"id":725719,"name":"Andrew Sinkoe","orcid":"0000-0001-8311-1993","position":2,"is_corresponding":false},{"id":1073999,"name":"Kilyna A. Nguyen","orcid":"0000-0001-7767-3260","position":3,"is_corresponding":false},{"id":725720,"name":"Scott M. Norberg","orcid":"0000-0001-5232-2448","position":4,"is_corresponding":false},{"id":1074334,"name":"Crystal P. McIntosh","orcid":null,"position":5,"is_corresponding":false},{"id":1029438,"name":"Tejas Kadakia","orcid":"0000-0001-8269-228X","position":6,"is_corresponding":false},{"id":352374,"name":"Carylinda Serna","orcid":null,"position":7,"is_corresponding":false},{"id":300503,"name":"Zachary Rae","orcid":null,"position":8,"is_corresponding":false},{"id":226280,"name":"Michael C. Kelly","orcid":"0000-0003-0654-2778","position":9,"is_corresponding":false},{"id":256071,"name":"Christian S. Hinrichs","orcid":"0000-0001-5597-2841","position":10,"is_corresponding":false},{"id":309017,"name":"Kazusa Ishii","orcid":"0000-0002-1915-6334","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-19T01:10:49.535464Z","pmid":"37494434","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":[]}