Advances in Vaccine-Based Therapies for Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, with a 5-year survival rate that has improved only marginally over the past 30 years, despite numerous clinical trials. PDAC poses several unique challenges, including early metastatic spread and a predilection for liver metastasis. It is also highly resistant to anti-tumor immunity and immunotherapy due to its dense and immunosuppressive tumor microenvironment, low immunogenicity, and systemic immune suppression. PDAC has a low mutational burden, defective antigen presentation, and immune checkpoint molecule upregulation, which reduce immune recognition. Together, these factors leave PDAC as an "immune cold" tumor with minimal cytotoxic T-cell activity. Novel therapeutic approaches are urgently needed to reinvigorate anti-tumor immunity. Recent advances, such as adjuvant personalized mRNA neoantigen vaccines and mutant-KRAS targeted vaccines, have demonstrated sustained vaccine-induced T cell responses that are associated with improved recurrence-free survival in surgically resected PDAC. Combining different vaccine approaches with optimal sequencing of chemotherapy, surgery, radiotherapy, and other immunotherapies may further enhance outcomes. PDAC vaccines represent a promising strategy for overcoming PDAC's resistance to conventional therapies, with ongoing trials exploring their potential to improve long-term survival.

Keywords: MRNA vaccination; PDAC; Pancreatic cancer; Pancreatic ductal adenocarcinoma; Vaccine-based therapies.

Fig. 1

Mechanisms of immunosuppression and immune evasion in pancreatic cancer. Abbreviations: CAF, cancer-associated fibroblasts; CTLA-4, cytotoxic T-lymphocyte associated protein 4; MDSC, myeloid-derived suppressor cells; MHC-I, major histocompatibility complex class I; MMPs, matrix metalloproteinases; NETs, neutrophil extracellular traps; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PDAC, pancreatic ductal adenocarcinoma; PGE2, prostaglandin E2; TAM, tumor-associated macrophage; TAN, tumor-associated neutrophil; TCR, T-cell receptor; TIGIT, T-cell immunoreceptor with Ig and ITIM domains; TME, tumor microenvironment; Treg, regulatory T cells; VEGF, vascular endothelial growth factor. Created in BioRender. McMillan, M. (2025) https://BioRender.com/j11h254

Fig. 2

In patients with surgically resected pancreatic cancer treated with either A personalized mRNA neoantigen vaccines or B peptide-based neoantigen vaccines, greater tumor-specific T cell responses are associated with improved relapse-free survival. Figure adapted under Creative Commons Attribution 4.0 International License (CC BY 4.0) from Fig. 3 in Rojas et al. [21] and Fig. 4 in Pant et al. [33] (http://creativecommons.org/licenses/by/4.0/)