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PDAC is the third leading cause of cancer death in the United States4 and the seventh worldwide5. With an increasing incidence6, and a survival rate of 12%1 that has remained largely stagnant for nearly 60 years1, PDAC is projected to cause even greater global cancer deaths by 2025 (refs. 6,7). Surgery is the only curative treatment for PDAC. Yet, despite surgery, nearly 90% of patients have disease recurrence at a median of 7–9 months8,9, and the 5-year overall survival (OS) is only 8–10%8,9. Although adjuvant multiagent chemotherapies delay recurrence and are standard of care in surgically resected PDAC, nearly 80% of patients have disease recurrence at around 14 months4, and their 5-year OS is <30%10. Radiation, biologics and targeted therapies are also ineffective4.

PDACs are almost completely insensitive (<5% response rate11,12) to immune checkpoint inhibitors. This insensitivity is partially attributed to the fact that PDACs have a low mutation rate that generates few neoantigens12, mutation-generated proteins absent from healthy tissues that mark cancers as foreign to T cells, thus potenially rendering PDACs weakly antigenic with few infiltrating T cells. However, recent observations have shown that most PDACs in fact harbour more neoantigens2,3,13 than previously predicted14. Furthermore, studies of long-term survivors of PDAC2,3 have revealed that neoantigens may stimulate T cells in PDAC. Primary tumours enriched in immunogenic neoantigens also harbour around 12-fold higher densities of activated CD8+ T cells, which correlates with delayed disease recurrence and longer patient survival. Thus, as most PDACs harbour neoantigens with the potential to stimulate T cells, strategies to deliver neoantigens may induce neoantigen-specific T cells and affect patient outcomes.

Based on the observation that long-term survivors of PDAC mount spontaneous T cell responses against tumour-specific neoantigens not shared among patients2,3, we tested whether adjuvant individualized vaccines can stimulate neoantigen-specific T cells and provide clinical benefit in patients with surgically resected PDAC. Therapeutic mRNA vaccine technology has facilitated the rapid delivery of individualized neoantigen vaccines fully integrated into a routine oncologic workflow15. Moreover, mRNA can be rapidly manufactured as individualized vaccines with multiple neoantigens16, can activate antigen-presenting cells17,18,19,20 and can be efficiently delivered using newly developed clinical-stage formulations21. Therefore, we hypothesized that an effective individualized mRNA vaccine would induce neoantigen-specific T cells in PDAC, eliminate micrometastases and delay recurrence.

To test this hypothesis, we conducted an investigator-initiated, phase I clinical trial of sequential adjuvant atezolizumab (Genentech), autogene cevumeran22,23 (an individualized mRNA neoantigen vaccine containing up to 20 major histocompatibility complex class I (MHCI) and MHC class II (MHCII) restricted neoantigens in lipoplex nanoparticles intravenously delivered; Individualized NeoAntigen-Specific Therapy (iNeST), BioNTech and Genentech) and mFOLFIRINOX in patients with surgically resectable PDAC (Fig. 1a) to : (1) amplify neoantigen-specific T cells inhibited by PD-1 signalling; and (2) prime naive T cells to vaccine neoantigens.

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