{"doi":"10.1093/neuonc/noac024","title":"Off-the-shelf, steroid-resistant, IL13Rα2-specific CAR T cells for treatment of glioblastoma","abstract":"BACKGROUND: Wide-spread application of chimeric antigen receptor (CAR) T cell therapy for cancer is limited by the current use of autologous CAR T cells necessitating the manufacture of individualized therapeutic products for each patient. To address this challenge, we have generated an off-the-shelf, allogeneic CAR T cell product for the treatment of glioblastoma (GBM), and present here the feasibility, safety, and therapeutic potential of this approach. METHODS: We generated for clinical use a healthy-donor derived IL13Rα2-targeted CAR+ (IL13-zetakine+) cytolytic T-lymphocyte (CTL) product genetically engineered using zinc finger nucleases (ZFNs) to permanently disrupt the glucocorticoid receptor (GR) (GRm13Z40-2) and endow resistance to glucocorticoid treatment. In a phase I safety and feasibility trial we evaluated these allogeneic GRm13Z40-2 T cells in combination with intracranial administration of recombinant human IL-2 (rhIL-2; aldesleukin) in six patients with unresectable recurrent GBM that were maintained on systemic dexamethasone (4-12 mg/day). RESULTS: The GRm13Z40-2 product displayed dexamethasone-resistant effector activity without evidence for in vitro alloreactivity. Intracranial administration of GRm13Z40-2 in four doses of 108 cells over a two-week period with aldesleukin (9 infusions ranging from 2500-5000 IU) was well tolerated, with indications of transient tumor reduction and/or tumor necrosis at the site of T cell infusion in four of the six treated research subjects. Antibody reactivity against GRm13Z40-2 cells was detected in the serum of only one of the four tested subjects. CONCLUSIONS: This first-in-human experience establishes a foundation for future adoptive therapy studies using off-the-shelf, zinc-finger modified, and/or glucocorticoid resistant CAR T cells.","journal":"Neuro-Oncology","year":2022,"id":233105,"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":144,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9458,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":347177,"name":"Analiz Rodriguez","orcid":"0000-0003-3426-0508","position":1,"is_corresponding":false},{"id":436064,"name":"Joycelynne Palmer","orcid":"0000-0001-6480-7557","position":2,"is_corresponding":false},{"id":569666,"name":"Julie R. Ostberg","orcid":"0000-0001-5439-3725","position":3,"is_corresponding":false},{"id":846916,"name":"Araceli Naranjo","orcid":null,"position":4,"is_corresponding":false},{"id":808098,"name":"Jamie R. Wagner","orcid":"0000-0001-7961-3253","position":5,"is_corresponding":false},{"id":249972,"name":"Brenda Aguilar","orcid":"0000-0002-6408-8422","position":6,"is_corresponding":false},{"id":249976,"name":"Renate Starr","orcid":"0000-0002-2200-6900","position":7,"is_corresponding":false},{"id":457030,"name":"Lihong Weng","orcid":"0009-0002-6280-2212","position":8,"is_corresponding":false},{"id":392954,"name":"Timothy W. Synold","orcid":"0000-0002-4075-2544","position":9,"is_corresponding":false},{"id":460081,"name":"Vivi Tran","orcid":null,"position":10,"is_corresponding":false},{"id":212510,"name":"Shelley Wang","orcid":null,"position":11,"is_corresponding":false},{"id":846917,"name":"Andreas Reik","orcid":null,"position":12,"is_corresponding":false},{"id":775854,"name":"Massimo D’Apuzzo","orcid":"0000-0001-8146-0997","position":13,"is_corresponding":false},{"id":95491,"name":"Julie A. Ressler","orcid":"0000-0003-3086-3045","position":14,"is_corresponding":false},{"id":846918,"name":"Yuanyue Zhou","orcid":null,"position":15,"is_corresponding":false},{"id":299728,"name":"Matthew Mendel","orcid":"0000-0002-5070-0561","position":16,"is_corresponding":false},{"id":845693,"name":"Philip D. Gregory","orcid":"0000-0001-9249-2468","position":17,"is_corresponding":false},{"id":845694,"name":"Michael C. Holmes","orcid":"0000-0002-6697-4225","position":18,"is_corresponding":false},{"id":846919,"name":"Winson W. Tang","orcid":null,"position":19,"is_corresponding":false},{"id":249979,"name":"Stephen J. Forman","orcid":"0000-0002-2803-4152","position":20,"is_corresponding":false},{"id":296016,"name":"Michael C. Jensen","orcid":"0000-0001-7477-3063","position":21,"is_corresponding":false},{"id":249978,"name":"Behnam Badie","orcid":"0000-0001-9811-9306","position":22,"is_corresponding":false},{"id":249980,"name":"Christine E. 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