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Enhancing CAR T Cell Therapy in Patients with Pancreatic Cancer

GSE276061 Homo sapiens Expression profiling by high throughput sequencing 5 samples Submitted 2025/07/07 Platform GPL18573
Summary
Patients with advanced pancreatic ductal adenocarcinoma (PDAC) have a median survival time of less than a year, highlighting the urgent need for treatment advancements. We conducted a phase 1 clinical trial assessing the safety and feasibility of intravenous and local administration of anti-mesothelin CAR T cells in patients with unresectable or metastatic PDAC. Though therapy was well tolerated, limited clinical efficacy was observed. Analyses of patient samples provide insights into mechanisms of treatment resistance. Using single-cell genomic approaches, we found that CAR T cells post-infusion express exhaustion signatures, including previously identified transcription factors ID3 and SOX4, and display enrichment for Treg and GZMK+ phenotypes. Single knockout of ID3 or SOX4 appeared to enhance efficacy in xenograft models, but eventually failed, whereas double-knockout ID3 and SOX4 CAR T cells exhibit prolonged relapse-free survival, demonstrating sustained therapeutic effect and a potential avenue for engineering a more potent CAR T cell in pancreatic cancer.
Published in
Clinical and molecular dissection of CAR T cell resistance in pancreatic cancer
Aznar MA, Good CR, Barber-Rotenberg JS et al. · Cell reports. Medicine 2025 · PMID 40829595 · doi:10.1016/j.xcrm.2025.102301
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Also filed as BioProject PRJNA1154619 and SRA study SRP529712. Searching any of these in the dataset finder brings you back here.

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