biostudies-literatureAznar MAParker Institute for Cancer ImmunotherapyStand up to CancerNational Cancer InstituteNational Institutes of HealthAmerican Cancer Society Inc102301https://www.ebi.ac.uk/biostudies/studies/S-EPMC12490220biostudies-literatureUnknown6(9)Patients with advanced pancreatic ductal adenocarcinoma (PDAC) have a median survival of less than a year, highlighting the urgent need for treatment advancements. We report on a phase 1 clinical trial assessing the safety and feasibility of intravenous and local administration of anti-mesothelin CAR T cells in patients with advanced PDAC. While therapy is well tolerated, it demonstrates limited clinical efficacy. Analyses of patient samples provide insights into mechanisms of treatment resistance. Single-cell genomic approaches reveal that post-infusion CAR T cells express exhaustion signatures, including previously identified transcription factors ID3 and SOX4, and display enrichment for a GZMK⁺ phenotype. Single knockout of ID3 or SOX4 enhances efficacy in xenograft models, tCell reports. MedicineClinical and molecular dissection of CAR T cell resistance in pancreatic cancer.PMC12490220SU2C-RT6162P30 CA016520PF-19-202-01-DMCS10 OD023465-01A1R50CA305050SU2C-AACR-DT21-17CA263922Dowd ENadolski GRennels AKAgarwal SWilson WHuang HHaas AHwang WTGonzalez VETorigian DAJune CHBarber-Rotenberg JSGood CRBerger SLO'Hara MHTanyi JYoung RMAznar MARech AJSiegel DLGlastad KMHexner EODonahue GBrennan AZhang ZJadlowsky JKWatts AGonzales DFraietta JAAlexander KAPlesa GKuramitsu SfalseClinical and molecular dissection of CAR T cell resistance in pancreatic cancer.Patients with advanced pancreatic ductal adenocarcinoma (PDAC) have a median survival of less than a year, highlighting the urgent need for treatment advancements. We report on a phase 1 clinical trial assessing the safety and feasibility of intravenous and local administration of anti-mesothelin CAR T cells in patients with advanced PDAC. While therapy is well tolerated, it demonstrates limited clinical efficacy. Analyses of patient samples provide insights into mechanisms of treatment resistance. Single-cell genomic approaches reveal that post-infusion CAR T cells express exhaustion signatures, including previously identified transcription factors ID3 and SOX4, and display enrichment for a GZMK⁺ phenotype. Single knockout of ID3 or SOX4 enhances efficacy in xenograft models, t2025-01-01T00:00:00Z2025 Sep2026-07-15T06:49:53.679Z2026-06-30T03:22:46.844ZS-EPMC124902204082959510.1016/j.xcrm.2025.102301