An investigator-initiated phase I study evaluating the safety, tolerability, and preliminary efficacy of a personalized neoantigen mRNA vaccine (XP-004) combined with PD-1 inhibitor as adjuvant therapy in resected pancreatic cancer patients intoleran

2509 Background: Pancreatic cancer has a high postoperative recurrence rate. Although adjuvant chemotherapy is standard of care, many patients are unable to tolerate it, highlighting an unmet need for alternative adjuvant strategies. Personalized neoantigen mRNA vaccines can induce tumor-specific T-cell responses and may synergize with PD-1 blockade. This study evaluated the safety, tolerability, and preliminary clinical activity of XP-004 combined with a PD-1 inhibitor as adjuvant therapy in resected pancreatic cancer patients intolerant to chemotherapy. Methods: This open-label, single-arm, investigator-initiated phase I trial (2024PCV004; NCT06496373) initiated in May 2024 plans to enroll 16-20 patients with resected pancreatic cancer intolerant to chemotherapy. Patients received XP-004 intramuscularly (1.0 mg Q3W for 13 cycles), including a KRAS-targeted single-neoantigen vaccine for 4 cycles followed by a personalized multi-neoantigen vaccine for 9 cycles, combined with toripalimab (PD-1 inhibitor). Each personalized vaccine encoded 10–20 personalized neoantigens selected using next-generation sequencing and bioinformatic prediction. The primary endpoint was safety and tolerability; secondary endpoints included neoantigen-specific CD4⁺ and CD8⁺ T-cell responses, recurrence-free survival (RFS), and overall survival (OS). Results: As of December 15, 2025, 16 patients were enrolled. XP-004 mRNA vaccine was well tolerated. Treatment-related AEs included fever (100%), injection-site pain (87.5%), nausea (43.8%), vomiting (37.5%), pruritus (50.0%), rash (25.0%), and fatigue (37.5%). Grade ≥3 AEs were observed in 12.5% patients, including fever (12.5%) and pruritus (6.3%), the latter attributed to toripalimab. No other immune-related AEs were observed. Transient cytokine increases (IFN-γ, IL-5, IL-6, IL-8, IL-10) were observed without organ dysfunction. At a median postoperative follow-up of 43.9 weeks (range of 6.1–72.0 weeks), and a median follow-up of 37.6 weeks (range of 0.9–63.7 weeks) after first vaccination, all patients remained recurrence-free, with no clinical or molecular evidence of recurrence, including no tumor-informed MRD relapse. Among the 13 patients evaluable for immunogenicity, 13 (100.0%) developed neoantigen-specific T-cell responses; 53 of 165 neoantigens (32.1%) were immunogenic. Conclusions: XP-004 combined with PD-1 inhibitor demonstrated favorable safety and tolerability and induced robust neoantigen-specific T-cell responses in resected pancreatic cancer patients intolerant to chemotherapy. Early follow-up suggests potential RFS benefit, supporting further investigation of this adjuvant immunotherapy strategy. Clinical trial information: NCT06496373 .