Aznar, M Angela, Good, Charly R, Barber-Rotenberg, Julie S, Agarwal, Sangya, Wilson, Wesley, Watts, Alex, Zhang, Zhen, Gonzales, Donna, Donahue, Greg, Hwang, Wei-Ting, Rennels, Austin K, Rech, Andrew J, Kuramitsu, Shunichiro, Huang, Hua, Glastad, Karl M, Alexander, Katherine A, Plesa, Gabriela, Dowd, Emily, Brennan, Andrea, Siegel, Donald L, Tanyi, Janos, Haas, Andrew, Torigian, Drew A, Nadolski, Gregory, Gonzalez, Vanessa E, Hexner, Elizabeth O, Fraietta, Joseph A, Jadlowsky, Julie K, Young, Regina M, Berger, Shelley L, June, Carl H, O'Hara, Mark H (August 2025) Clinical and molecular dissection of CAR T cell resistance in pancreatic cancer. Cell Reports Medicine. p. 102301. ISSN 2666-3791
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).
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Alexander lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 13 August 2025 |
| Date Deposited: | 20 Aug 2025 15:34 |
| Last Modified: | 20 Aug 2025 15:34 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41942 |
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