Clinical and molecular dissection of CAR T cell resistance in pancreatic cancer
- PMID: 40829595
- DOI: 10.1016/j.xcrm.2025.102301
Clinical and molecular dissection of CAR T cell resistance in pancreatic cancer
Abstract
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, though with donor-dependent variability. However, single-knockout cells eventually fail. Conversely, ID3 and SOX4 double-knockout CAR T cells exhibit prolonged relapse-free survival, demonstrating a sustained therapeutic effect and a potential avenue for engineering more potent CAR T cells in PDAC. This study was registered at ClinicalTrials.gov (NCT03323944).
Keywords: CAR T cells; ID3; SOX4; T cell dysfunction; T cell exhaustion; cancer; clinical trial; immunotherapy; pancreatic cancer; single-cell RNA-seq.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of interests J.K.J. consults for BlueWhale Bio. A.J.R. consults for Affini-T Therapeutics. C.H.J. is an inventor on patents related to CAR therapy products and may receive a portion of royalties from Kite to the University of Pennsylvania. J.A.F. receives funding from Tmunity Therapeutics and Danaher Corporation, consults for Retro Biosciences, and serves on the Scientific Advisory Boards for Cartography Bio and Shennon Biotechnologies, Inc. C.H.J. is a scientific co-founder and holds equity in Capstan Therapeutics, Dispatch Biotherapeutics, and BlueWhale Bio; serves on the board of AC Immune; and is a scientific advisor to BlueSphere Bio, Cabaletta, Carisma, Cartography, Cellares, CellCarta, Celldex, Danaher, Decheng, ImmuneSensor, Kite Pharma, Poseida, Verismo, Viracta, ViTToria, and WIRB-Copernicus Group. C.H.J. and R.M.Y. are inventors on patents and/or patent applications licensed to Novartis and Kite Pharma and may receive revenue from them. M.H.O. is a consultant for Alligator and Merus and received funding from BMS, Akamis, Genmab, Geistlich, Arcus, Celldex, Elicio, and Revolution Medicine.
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