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108 reviewsSUMMARYPatients 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 thesafety and feasibility of intravenous and local administration of anti-mesothelin CAR T cells in patients withadvanced PDAC. While therapy is well tolerated, it demonstrates limited clinical efficacy. Analyses of patientsamples provide insights into mechanisms of treatment resistance. Single-cell genomic approaches revealthat post-infusion CAR T cells express exhaustion signatures, including previously identified transcriptionfactors ID3 and SOX4, and display enrichment for a GZMK+ phenotype. Single knockout of ID3 or SOX4 enhances efficacy in xenograft models, though with donor-dependent variability. However, single-knockoutcells eventually fail. Conversely, ID3 and SOX4 double-knockout CAR T cells exhibit prolonged relapsefree survival, demonstrating a sustained therapeutic effect and a potential avenue for engineering morepotent CAR T cells in PDAC. This study was registered at ClinicalTrials.gov (NCT03323944).
