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Despite significant advancements in cancer immunotherapy, survival outcomes remain poor in patients with pancreatic ductal adenocarcinoma. 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. 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. 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. Pancreatic cancer is one of the deadliest forms of cancer, and current treatments have only limited success. This study aimed to explore whether combining immunotherapy with local tumor ablation and chemotherapy could improve outcomes for patients with advanced pancreatic cancer that cannot be surgically removed. Local tumor ablation is a treatment that destroy cancer cells inside the body by applying heat without surgery. We treated twelve patients and studied how their immune systems responded, using advanced techniques to analyze cancer and blood samples. We found that certain immune cells, called CD8-Temra cells, were linked to better survival, suggesting they could help guide future treatments. Our findings suggest that combining local tumor ablation with immunotherapy may improve the body’s ability to fight cancer, but larger studies are needed to confirm these results. Topal et al. evaluate a novel combination of local ablation, checkpoint inhibition, and chemotherapy in advanced pancreatic cancer, indicating a potential role for CD8-Temra cells in predicting immunotherapy benefit.
Topal et al. (Tue,) studied this question.