{"doi":"10.1136/jitc-2022-006121","title":"TCR-engineered adoptive cell therapy effectively treats intracranial murine glioblastoma","abstract":"BACKGROUND: Adoptive cellular therapies with chimeric antigen receptor T cells have revolutionized the treatment of some malignancies but have shown limited efficacy in solid tumors such as glioblastoma and face a scarcity of safe therapeutic targets. As an alternative, T cell receptor (TCR)-engineered cellular therapy against tumor-specific neoantigens has generated significant excitement, but there exist no preclinical systems to rigorously model this approach in glioblastoma. METHODS: neoantigen (mImp3) previously identified within the murine glioblastoma model GL261. This TCR was used to generate the Mutant Imp3-Specific TCR TransgenIC (MISTIC) mouse in which all CD8 T cells are specific for mImp3. The therapeutic efficacy of neoantigen-specific T cells was assessed through a model of cellular therapy consisting of the transfer of activated MISTIC T cells and interleukin 2 into lymphodepleted tumor-bearing mice. We employed flow cytometry, single-cell RNA sequencing, and whole-exome and RNA sequencing to examine the factors underlying treatment response. RESULTS: We isolated and characterized the 3×1.1C TCR that displayed a high affinity for mImp3 but no wild-type cross-reactivity. To provide a source of mImp3-specific T cells, we generated the MISTIC mouse. In a model of adoptive cellular therapy, the infusion of activated MISTIC T cells resulted in rapid intratumoral infiltration and profound antitumor effects with long-term cures in a majority of GL261-bearing mice. The subset of mice that did not respond to the adoptive cell therapy showed evidence of retained neoantigen expression but intratumoral MISTIC T cell dysfunction. The efficacy of MISTIC T cell therapy was lost in mice bearing a tumor with heterogeneous mImp3 expression, showcasing the barriers to targeted therapy in polyclonal human tumors. CONCLUSIONS: We generated and characterized the first TCR transgenic against an endogenous neoantigen within a preclinical glioma model and demonstrated the therapeutic potential of adoptively transferred neoantigen-specific T cells. The MISTIC mouse provides a powerful novel platform for basic and translational studies of antitumor T-cell responses in glioblastoma.","journal":"Journal for ImmunoTherapy of Cancer","year":2023,"id":336937,"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":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"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":649416,"name":"Rupen Desai","orcid":"0000-0002-2052-7243","position":1,"is_corresponding":false},{"id":649700,"name":"Anthony Z. Wang","orcid":"0000-0003-4824-9908","position":2,"is_corresponding":false},{"id":297955,"name":"Alexandra J. Livingstone","orcid":"0000-0001-5471-4576","position":3,"is_corresponding":false},{"id":297954,"name":"Dale K. Kobayashi","orcid":"0000-0002-6370-2099","position":4,"is_corresponding":false},{"id":911385,"name":"Andrew T. Coxon","orcid":"0000-0002-9632-0871","position":5,"is_corresponding":false},{"id":297953,"name":"Jay A. Bowman-Kirigin","orcid":"0000-0002-7687-3727","position":6,"is_corresponding":false},{"id":235664,"name":"Connor J. Liu","orcid":"0000-0002-2285-1928","position":7,"is_corresponding":false},{"id":326074,"name":"Li Mao","orcid":"0000-0002-6058-5229","position":8,"is_corresponding":false},{"id":552302,"name":"Diane Bender","orcid":"0000-0003-1233-3323","position":9,"is_corresponding":false},{"id":1067887,"name":"Michael J. White","orcid":"0000-0001-5378-6359","position":10,"is_corresponding":false},{"id":297956,"name":"David M. Kranz","orcid":"0000-0002-4931-126X","position":11,"is_corresponding":false},{"id":297957,"name":"Tanner M. Johanns","orcid":"0000-0003-1094-1528","position":12,"is_corresponding":false},{"id":231268,"name":"Gavin P. Dunn","orcid":"0000-0001-9302-4834","position":13,"is_corresponding":false},{"id":297952,"name":"Maximilian O. Schaettler","orcid":"0000-0001-7545-6342","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T01:10:21.947540Z","pmid":"36808076","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":[]}