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Background Advanced pancreatic cancer remains a highly lethal malignancy with limited treatment options. This investigator-initiated, open-label, single-arm study ( NCT06026800) evaluated the feasibility, safety, and efficacy of iNeo-Vac-R01— a novel personalized mRNA neoantigen vaccine—in combination with standard first-line chemotherapy in patients with advanced digestive system tumors, with a primary focus on pancreatic cancer. To our knowledge, this is the first study globally to report clinical outcomes of a personalized mRNA neoantigen vaccine in the first-line treatment of advanced pancreatic cancer.Methods Eligible patients had histologically confirmed advanced digestive system cancer, at least one measurable lesion (RECIST 1.1), and were either untreated or just beginning first-line therapy. Participants received iNeo-Vac-R01 (100 μg, subcutaneously, every 21 days for up to 9 doses) alongside standard chemotherapy. Key endpoints included safety, objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and vaccine-induced immune response via ELISpot.Results As of August 31, 2025, 13 patients with advanced pancreatic cancer were enrolled, and 10 received at least one dose of iNeo-Vac-R01. Baseline characteristics (n=10): median age <65 years (60%), pancreatic head tumor (60%), liver metastases (60%), ECOG 1 (100%). Six patients (60%) completed all 9 doses. Treatment-related adverse events were primarily grade 1-2, including injection site reactions (redness (62.5%), itching (12.5%), fever (50%), fatigue (25%), and dizziness (12.5%)). With a median follow-up of 15.5 months, one patient achieved CR (after radiofrequency ablation), three achieved PR, and the rest had SD. Among 9 evaluable patients, median PFS was 14.9 months (95% CI: 8.9-20.9), and median OS was 19.7 months (95% CI: 13.9-25.5). The 12-month PFS and OS rates were 51.6% and 88.9%, respectively. These survival outcomes compare favorably with historical controls (MPACT: mPFS 3.5 months, mOS 8.5 months; PRODIGE 4: mPFS 6.4 months, mOS 11.1 months). ELISpot analysis demonstrated neoantigen-specific T-cell responses in 100% (9/9) of evaluated patients. Among 153 tested neoantigens, 60.8% (93/153) elicited immune responses, with spot-forming cells (SFCs) exceeding 100 per 2×10 5 PBMCs in three patients (max: 742.5 SFCs).Conclusions iNeo-Vac-R01 combined with first-line chemotherapy demonstrates promising efficacy, encouraging survival benefit and robust vaccine-induced immunogenicity, supporting further development of personalized mRNA neoantigen vaccines in advanced pancreatic cancer.Trial Registration Clinical Trial Registration: NCT06026800Ethics Approval Ethics approval was obtained from the ethics committees of Sir Run Run Shaw Hospital, affiliated with Zhejiang University School of Medicine. The ID of the approval is 2023-0466. Written informed consent was obtained from the patients before taking part.Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.