Trial in progress: A phase I study of personalized neoantigen vaccination combined with PD-1 blockade and CD40 agonism in resected pancreatic ductal adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal even in localized stages, with frequent recurrence despite curative-intent resection and perioperative chemotherapy. Personalized neoantigen vaccination offers a promising strategy to elicit tumor-specific T cell responses against micrometastatic disease in the adjuvant setting. Our personalized peptide-based vaccine platform - termed NeoAg-VAX - targets up to 10 neoantigens per patient and has demonstrated favorable safety and immunogenicity across solid tumors, including lung and colorectal cancer (Li F et al, JITC 2021; Haldar SD et al, AACR 2025). However, PDAC has a profoundly “cold,” immunosuppressive microenvironment that can limit effective priming and durability of vaccine-induced antitumor immunity, supporting rational combinations with PD-1 blockade and CD40 agonism to enhance antigen presentation and reinvigorate effector function. Methods: This study is a single-center, non-randomized, open-label, investigator-initiated phase 1 trial of NeoAg-VAX in combination with anti-PD-1 pembrolizumab +/- CD40 agonist APX005M in patients with surgically resected PDAC. Whole exome/RNA sequencing of resected tumor tissue is performed with HLA binding prediction to identify patient-specific neoantigen peptides for vaccine formulation. Key eligibility criteria include complete R0/R1 resection, receipt of > 1 line of standard chemotherapy, adequate organ/marrow function, and ECOG 0-1. The co-primary endpoints are safety and feasibility. Secondary endpoints include immunogenicity, ctDNA clearance, RFS, and OS. Vaccines are given subcutaneously (SQ) with topical imiquimod adjuvant and APX005M (0.3 mg/kg IV + 250 μg SQ) on weeks 0, 1, 3, 4, 6, 9, 12, 15, 18, 21, and 24. Pembrolizumab 200 mg IV is given every 3 weeks during weeks 3-24. Although drug supply for APX005M was terminated in August 2023, accrual for vaccine plus anti-PD-1 therapy has continued thereafter. Translational studies evaluating vaccine-induced ctDNA dynamics and functional neoantigen-specific T cell responses are in progress. As of January 2026, 6 patients have been vaccinated in this cohort with follow-up and analyses ongoing (NCT02600949).