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Updated: Sep 10, 2025
A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
Clinical and molecular dissection of CAR T cell resistance in pancreatic cancer
M Angela Aznar1, Charly R Good2, Julie S Barber-Rotenberg3
1Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
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).
Insights
Advanced pancreatic cancer (PDAC) treatment needs improvement. Engineering CAR T-cells by knocking out ID3 and SOX4 shows promise for sustained efficacy against PDAC by overcoming treatment resistance.
Area of Science:
- Immunotherapy
- Oncology
- Genomics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, necessitating novel therapeutic strategies.
- Current treatment options for advanced PDAC offer limited survival benefits.
Purpose of the Study:
- To assess the safety and feasibility of anti-mesothelin CAR T-cell therapy in advanced PDAC.
- To investigate mechanisms of treatment resistance and identify strategies for enhancing CAR T-cell efficacy.
Main Methods:
- Phase 1 clinical trial of intravenous and local anti-mesothelin CAR T-cell administration.
- Single-cell genomic analysis of patient samples to identify CAR T-cell exhaustion markers.
- Xenograft models to evaluate the efficacy of gene-edited CAR T-cells.
Main Results:
- CAR T-cell therapy was well-tolerated but showed limited clinical efficacy.
- CAR T-cells exhibited exhaustion signatures, including ID3 and SOX4 expression and a GZMK+ phenotype.
- Double knockout of ID3 and SOX4 in CAR T-cells prolonged relapse-free survival in preclinical models.
Conclusions:
- Targeting ID3 and SOX4 represents a promising strategy for enhancing CAR T-cell therapy in PDAC.
- Further development of gene-edited CAR T-cells could improve outcomes for patients with advanced PDAC.
