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Background <p>Despite significant advancements in cancer immunotherapy, survival outcomes remain poor in patients with pancreatic ductal adenocarcinoma.</p> Methods <p>In this early phase II clinical trial, we evaluated the combined effects of immunotherapy with dual immune checkpoint inhibitors durvalumab and tremelimumab, local tumor ablation with microwave energy, and gemcitabine on progression-free survival in twelve patients with non-metastatic unresectable locally advanced pancreatic adenocarcinoma. Single-cell transcriptomics and T cell receptor profiling were used to characterize the tumor microenvironment and peripheral blood immune cell repertoire.</p> Results <p>Here we show that from these twelve patients (median progression-free survival = 8.9 months, 95% confidence interval 3.2–18.4), eight patients received the combination therapy (median progression-free survival of 11.2 months, 95% confidence interval 4.0–18.4). One of these eight patients experiences grade 5 toxicity. Using single-cell transcriptomics and T cell receptor profiling, we characterize the tumor microenvironment and peripheral blood immune cell repertoire of six patients, of which three patients contain paired samples before and after the start of immunotherapy. We find substantial overlap in T cell receptors and CD8-Temra cells in the tumor microenvironment and in peripheral blood. Integration of the single-cell dataset with an independent bulk transcriptome cohort reveals that a high CD8-Temra gene signature is associated with improved overall survival. While there are interesting trends, T cell receptor-related metrics do not show statistically significant correlations with progression-free survival in this dataset.</p> Conclusions <p>These findings suggest that CD8-Temra cells may serve as potential biomarkers and therapeutic targets for immunotherapy efficacy in pancreatic ductal adenocarcinoma, pending validation in larger cohorts. We hypothesize that local tumor ablation may enhance tumor immunogenicity and systemic anti-tumor responses, supporting their integration into future treatment strategies. Future studies with larger cohorts are needed to validate these findings and optimize treatment protocols for wider clinical applicability.</p>

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Progression-free survival for unresectable non-metastatic locally advanced pancreatic cancer after surgical microwave ablation plus durvalumab and tremelimumab: phase-2 non-randomized prospective clinical trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月18日

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  • Halit Topal,
  • Tom Venken,
  • Ayse Bassez,
  • Gabriela Chiritescu,
  • Eric Van Cutsem,
  • Schalk van der Merwe,
  • Diether Lambrechts,
  • Baki Topal

摘要

Background

Despite significant advancements in cancer immunotherapy, survival outcomes remain poor in patients with pancreatic ductal adenocarcinoma.

Methods

In this early phase II clinical trial, we evaluated the combined effects of immunotherapy with dual immune checkpoint inhibitors durvalumab and tremelimumab, local tumor ablation with microwave energy, and gemcitabine on progression-free survival in twelve patients with non-metastatic unresectable locally advanced pancreatic adenocarcinoma. Single-cell transcriptomics and T cell receptor profiling were used to characterize the tumor microenvironment and peripheral blood immune cell repertoire.

Results

Here we show that from these twelve patients (median progression-free survival = 8.9 months, 95% confidence interval 3.2–18.4), eight patients received the combination therapy (median progression-free survival of 11.2 months, 95% confidence interval 4.0–18.4). One of these eight patients experiences grade 5 toxicity. Using single-cell transcriptomics and T cell receptor profiling, we characterize the tumor microenvironment and peripheral blood immune cell repertoire of six patients, of which three patients contain paired samples before and after the start of immunotherapy. We find substantial overlap in T cell receptors and CD8-Temra cells in the tumor microenvironment and in peripheral blood. Integration of the single-cell dataset with an independent bulk transcriptome cohort reveals that a high CD8-Temra gene signature is associated with improved overall survival. While there are interesting trends, T cell receptor-related metrics do not show statistically significant correlations with progression-free survival in this dataset.

Conclusions

These findings suggest that CD8-Temra cells may serve as potential biomarkers and therapeutic targets for immunotherapy efficacy in pancreatic ductal adenocarcinoma, pending validation in larger cohorts. We hypothesize that local tumor ablation may enhance tumor immunogenicity and systemic anti-tumor responses, supporting their integration into future treatment strategies. Future studies with larger cohorts are needed to validate these findings and optimize treatment protocols for wider clinical applicability.