The median survival of patients with advanced pancreatic ductal adenocarcinoma (PDAC) is less than one year, highlighting the urgent need for treatment advances. Recently, a research paper titled "Clinical and molecular dissection of CAR T cell resistance in pancreatic cancer" was published in Cell Reports Medicine, a subsidiary of Cell. The paper reported a phase 1 clinical trial evaluating the safety and efficacy of anti-MSLN CAR-T cell therapy in patients with advanced pancreatic ductal adenocarcinoma (PDAC). Results showed that the CAR-T cell therapy was well tolerated but not highly effective. The research team further demonstrated in mouse studies that simultaneous knockout of both ID3 and SOX4 in these CAR-T cells improved long-term relapse-free survival.
Combination chemotherapy is the standard treatment for metastatic pancreatic ductal adenocarcinoma (PDAC), but its overall efficacy is limited, and PDAC remains one of the most lethal malignancies. Furthermore, despite the success of immune checkpoint blockade (ICB) and CAR-T cell therapy in various other cancers, their efficacy in PDAC remains limited.
Mesothelin (MSLN) is an attractive target for CAR-T cell therapy for solid tumors because it is overexpressed in various cancers, including PDAC. Furthermore, elevated MSLN levels are associated with poor prognosis in PDAC patients and are linked to tumor progression.
The team has previously conducted several Phase 1 clinical trials of mesothelin (MSLN)-targeted CAR-T cell therapies. Initially, the team treated patients with chemotherapy-resistant metastatic PDAC with T lymphocytes electroporated with murine anti-human MSLN ScFv SS-1 mRNA. This resulted in transient expression of the CAR and a best-effort response of stable disease in two of five treated patients. A subsequent study evaluated stable transduction of SS-1-based CARs in patients with malignant pleural mesothelioma, ovarian cancer, and pancreatic ductal adenocarcinoma. Although well-tolerated, the efficacy of this therapy was limited, with stable disease in only 11 of 15 patients, including two of the five patients with PDAC.
In the Phase 1 clinical trial described in this paper, the team evaluated the safety and efficacy of a fully human anti-MSLN CAR construct (huCART-meso) in patients with histologically confirmed metastatic PDAC. To better understand treatment response, the research team reported the results of analyses of blood, ascites, and paired pre- and post-treatment biopsies to assess metastases. The team also combined in vivo mouse models with high-throughput genomics experiments to gain insight into the mechanisms of resistance to CAR-T cell therapy in PDAC patients.
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The Phase 1 clinical trial consisted of three groups (three patients each): Group 1 received CAR-T cells via intravenous infusion, Group 2 received intraperitoneal infusion, and Group 3 received transhepatic artery infusion. Results showed that CAR-T cells were well tolerated and generally safe, with no treatment-related adverse events of grade 3 or higher. All patients died before entering long-term follow-up. In Group 1, one patient had stable disease at day 28, but progressed by three months, and all three patients withdrew from the study before entering hospice care. In Groups 2 and 3, all six patients experienced disease progression by day 28 and died during the study, five from disease progression and one from acute kidney injury. The median overall survival was 6.7 weeks, and the median progression-free survival was 3.9 weeks.
Figure 1. Double KO of SOX4 and ID3 in huCART-meso cells provides sustained protection against tumor recurrence. (Aznar M A, et al., 2025)
Single-cell genomics revealed that infused CAR-T cells expressed exhaustion markers, including the previously identified transcription factors ID3 and SOX4, and were enriched for a GZMK+ phenotype. In xenograft mouse models, knocking out either ID3 or SOX4 in CAR-T cells alone enhanced efficacy, although this was donor-dependent. While single-gene knockout cells eventually fail, CAR-T cells with both ID3 and SOX4 double knockout demonstrated prolonged relapse-free survival, suggesting a sustained therapeutic effect. This provides a potential avenue for designing more effective CAR-T cells for pancreatic ductal adenocarcinoma (PDAC).
Reference
Aznar M A, et al. Clinical and molecular dissection of CAR T cell resistance in pancreatic cancer. Cell Reports Medicine, 2025.