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Researchers at Memorial Sloan Kettering Cancer Center have made a breakthrough in pancreatic cancer treatment, demonstrating that RNA neoantigen vaccines can generate long-lived, functional CD8+ T cells. Their findings suggest that this approach may help delay disease recurrence in patients with pancreatic ductal adenocarcinoma (PDAC), one of the most lethal forms of cancer.
The Challenge of Treating PDAC
PDAC is an aggressive cancer with limited treatment options. It also has a low mutational burden, meaning that it produces fewer neoantigens—proteins that alert T cells to the presence of abnormal cells. This makes it difficult for the immune system to recognize and attack PDAC tumors effectively. Traditional cancer vaccines have struggled to generate durable, tumor-specific T cell responses in such cases.
The Study and Its Findings
In a Phase I clinical trial, researchers evaluated the effects of an individualized mRNA–lipoplex vaccine called autogene cevumeran. The study, published in Nature, tested the vaccine in combination with surgery, the immune checkpoint inhibitor atezolizumab, and chemotherapy (mFOLFIRINOX) in 16 patients with resectable PDAC.
Following vaccination, eight patients developed strong neoantigen-specific CD8+ T cell responses and experienced significantly lower recurrence rates compared to non-responders. In contrast, the median time to recurrence in non-responders was 13.4 months. Due to the long-lasting immune response, researchers could not determine a median time to recurrence in responders, as most had not relapsed by the study’s end.
Using CloneTrack, a sequencing tool, the researchers identified 79 vaccine-induced CD8+ T cell clones in responders. These clones expanded significantly and demonstrated an average projected lifespan of 7.7 years, with some potentially persisting for decades. The vaccine-induced T cells transitioned into tissue-resident memory-like (TRM-like) cells, retaining their cancer-fighting ability for years.
Implications for Future Cancer Treatment
The study provides strong evidence that personalized RNA neoantigen vaccines can generate durable immune responses against PDAC. However, some tumors recurred despite vaccination, likely due to the selective loss of vaccine-targeted cancer clones. Researchers emphasize the need for further studies to address tumor heterogeneity and reduce clonal escape.
While this is an early-phase trial, the results are promising and could lead to broader applications of RNA vaccines in treating other difficult-to-target cancers. Larger clinical trials are required to confirm efficacy and optimize responder rates.
Reference
Sethna, Z. et al. RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer. Nature (2025). DOI: 10.1038/s41586-024-08508-4
Disclaimer
This article is for informational purposes only and does not constitute medical advice. Consult a healthcare professional for personalized treatment recommendations.
