Clinical 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<sup>+</sup> 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).
Authors
- Carl H. June (ORCID: https://orcid.org/0000-0003-0241-3557)
- Andrea Brennan (ORCID: https://orcid.org/0000-0002-4925-6109)
- Shunichiro Kuramitsu
- Gabriela Plesa (ORCID: https://orcid.org/0000-0002-4279-5943)
- Greg Donahue (ORCID: https://orcid.org/0000-0002-2378-1618)
- Alan G. Watts
- Julie S. Barber-Rotenberg (ORCID: https://orcid.org/0009-0003-9556-3219)
- Shelley L. Berger (ORCID: https://orcid.org/0000-0001-5398-4400)
- Sangya Agarwal (ORCID: https://orcid.org/0000-0003-4272-515X)
- Vanessa Gonzalez (ORCID: https://orcid.org/0000-0003-3603-7457)
- Zhen Zhang (ORCID: https://orcid.org/0000-0001-8057-7624)
- Joseph A. Fraietta (ORCID: https://orcid.org/0000-0001-7900-8993)
- János L. Tanyi (ORCID: https://orcid.org/0000-0002-5657-3698)
- Mark H. O’Hara (ORCID: https://orcid.org/0000-0003-2751-6122)
- Andrew J. Rech (ORCID: https://orcid.org/0000-0002-6585-8839)
- Charly R. Good (ORCID: https://orcid.org/0000-0002-9934-9696)
- Karl M. Glastad (ORCID: https://orcid.org/0000-0002-8142-1821)
- Wei-Ting Hwang
- Emily Dowd
- Katherine A. Alexander (ORCID: https://orcid.org/0000-0001-6418-6615)
- M. Ángela Aznar (ORCID: https://orcid.org/0000-0002-7970-1672)
- G. Nadolski (ORCID: https://orcid.org/0000-0003-4721-8288)
- Wesley V. Wilson (ORCID: https://orcid.org/0000-0003-2506-5698)
- Donna Gonzales (ORCID: https://orcid.org/0000-0002-5345-946X)
- Drew A. Torigian (ORCID: https://orcid.org/0000-0001-8999-9735)
- Julie K. Jadlowsky (ORCID: https://orcid.org/0009-0005-5115-1321)
- Austin K. Rennels (ORCID: https://orcid.org/0009-0009-0059-5677)
- Hua Huang (ORCID: https://orcid.org/0000-0002-8936-3371)
- Elizabeth Olson Hexner (ORCID: https://orcid.org/0000-0002-1125-4060)
- Regina M. Young
- Andrew R. Haas
- Donald L. Siegel
Institutions
- Parker Institute for Cancer Immunotherapy (US)
- Translational Therapeutics (United States) (US)
- Penn Center for AIDS Research (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-08-18
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102301
- Citations
- 3
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- University of Pennsylvania
- Parker Institute for Cancer Immunotherapy
- National Institutes of Health
- Stand Up To Cancer
- National Cancer Institute