{"doi":"10.1136/jitc-2024-009743","title":"IL-18R supported CAR T cells targeting oncofetal tenascin C for the immunotherapy of pediatric sarcoma and brain tumors","abstract":"BACKGROUND: Oncofetal splice variants of extracellular matrix (ECM) proteins present a unique group of target antigens for the immunotherapy of pediatric cancers. However, limited data is available if these splice variants can be targeted with T cells expressing chimeric antigen receptors (CARs). METHODS: To determine the expression of the oncofetal version of tenascin C (TNC) encoding the C domain (C.TNC) in pediatric brain and solid tumors, we used quantitative reverse transcription PCR and immunohistochemistry. Genetically modified T cells were generated from human peripheral blood mononuclear cells and evaluated in vitro and in vivo. RESULTS: We demonstrate that C.TNC is expressed on a protein level in pediatric tumors, including diffuse intrinsic pontine glioma, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma. We generate C.TNC-CAR T cells and establish that these recognize and kill C.TNC-positive tumor cells. However, their antitumor activity in vivo is limited. To improve the effector function of C.TNC-CAR T cells, we design a leucine zipper-based chimeric cytokine receptor that activates interleukin-18 signaling pathways (Zip18R). Expression of Zip18R in C.TNC-CAR T cells improves their ability to secrete cytokines and expand in repeat stimulation assays. C.TNC-CAR.Zip18R T cells also have significantly greater antitumor activity in vivo compared with unmodified C.TNC-CAR T cells. CONCLUSIONS: Our study identifies the C domain of the ECM protein TNC as a promising CAR T-cell therapy for pediatric solid tumors and brain tumors. While we focus here on pediatric cancer, our work has relevance to a broad range of adult cancers that express C.TNC.","journal":"Journal for ImmunoTherapy of Cancer","year":2024,"id":425297,"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":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9656,"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":663759,"name":"Shannon Lange","orcid":"0000-0002-8067-8932","position":1,"is_corresponding":false},{"id":230917,"name":"Jessica Wagner","orcid":"0000-0003-2587-3310","position":2,"is_corresponding":false},{"id":736108,"name":"Jorge Ibañez-Vega","orcid":"0000-0003-4317-8573","position":3,"is_corresponding":false},{"id":271064,"name":"Liqing Tian","orcid":"0000-0001-9921-0603","position":4,"is_corresponding":false},{"id":377548,"name":"Meifen Lu","orcid":null,"position":5,"is_corresponding":false},{"id":55235,"name":"Heather Sheppard","orcid":"0000-0002-9623-2812","position":6,"is_corresponding":false},{"id":260231,"name":"Jason Chiang","orcid":"0000-0003-3623-8996","position":7,"is_corresponding":false},{"id":733682,"name":"Selene C. 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