{"doi":"10.1158/2159-8290.cd-23-1393","title":"Rational Protein Engineering to Enhance MHC-Independent T-cell Receptors","abstract":"Chimeric antigen receptor (CAR)-based therapies have pioneered synthetic cellular immunity but remain limited in their long-term efficacy. Emerging data suggest that dysregulated CAR-driven T-cell activation causes T-cell dysfunction and therapeutic failure. To re-engage the precision of the endogenous T-cell response, we designed MHC-independent T-cell receptors (miTCR) by linking antibody variable domains to T-cell receptor constant chains. Using predictive modeling, we observed that this standard \"cut and paste\" approach to synthetic protein design resulted in myriad biochemical conflicts at the hybrid variable-constant domain interface. Through iterative modeling and sequence modifications, we developed structure-enhanced miTCRs which significantly improved receptor-driven T-cell function across multiple tumor models. We found that 41BB costimulation specifically prolonged miTCR T-cell persistence and enabled improved leukemic control in vivo compared with classic CAR T cells. Collectively, we have identified core features of hybrid receptor structure responsible for regulating function. Significance: Improving the durability of engineered T-cell immunotherapies is critical to enhancing efficacy. We used a structure-informed design to evolve improved miTCR function across several models. This work underscores the central role of synthetic receptor structure in T-cell function and provides a framework for improved receptor engineering.","journal":"Cancer Discovery","year":2024,"id":438671,"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":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9545,"is_data_producer":false,"deposit_databanks":null,"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":856467,"name":"Jack H. Landmann","orcid":"0000-0002-1128-8914","position":1,"is_corresponding":false},{"id":1030765,"name":"Tien-Ching Chang","orcid":"0000-0003-0560-4930","position":2,"is_corresponding":false},{"id":281765,"name":"Mehmet Emrah Selli","orcid":"0000-0002-3478-8970","position":3,"is_corresponding":false},{"id":522011,"name":"Yangdon Tenzin","orcid":"0000-0002-2335-2354","position":4,"is_corresponding":false},{"id":289101,"name":"John M. Warrington","orcid":"0000-0001-6066-5491","position":5,"is_corresponding":false},{"id":375354,"name":"Julie Ritchey","orcid":null,"position":6,"is_corresponding":false},{"id":856468,"name":"Yu-Sung Hsu","orcid":"0000-0003-3040-6805","position":7,"is_corresponding":false},{"id":851728,"name":"Michael Slade","orcid":"0000-0001-8092-6644","position":8,"is_corresponding":false},{"id":938444,"name":"Deepesh Kumar Gupta","orcid":"0000-0001-9543-612X","position":9,"is_corresponding":false},{"id":18437,"name":"John F. Dipersio","orcid":"0000-0002-0429-3133","position":10,"is_corresponding":false},{"id":107330,"name":"Alex S. Holehouse","orcid":"0000-0002-4155-5729","position":11,"is_corresponding":false},{"id":617593,"name":"Nathan Singh","orcid":"0000-0002-0350-7574","position":12,"is_corresponding":false},{"id":1248806,"name":"Ju-Fang Chang","orcid":"0009-0007-4050-937X","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:00:43.618468Z","pmid":"38980802","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":[]}