Phase 1 study of VLPONC-01, a novel IL-12–encoding saRNA viral replicon particle, alone and in combination with pembrolizumab in head and neck cancer patients: Protocol summary.

TPS6134 Background: Head and neck squamous cell carcinoma (HNSCC) has high recurrence rates despite standard perioperative treatments such as surgery with adjuvant radiotherapy and/or chemotherapy, with about 35% of patients relapsing. Neoadjuvant immune checkpoint therapy has shown promise: in the Phase III KEYNOTE-689 trial, adding perioperative pembrolizumab to standard care significantly improved median event-free survival (51.8 vs 30.4 months), leading to FDA approval in June 2025. However, only 9.4% of patients achieved a major pathologic response, a key predictor of reduced relapse and a surrogate for long-term benefit in other cancers. This low response rate underscores the need for more effective strategies to expand and deepen durable immune-mediated tumor responses in HNSCC. Our strategy is to develop a combination immunotherapy/gene therapy targeting the immunosuppressive myeloid populations such as tumor-associated macrophages (TAMs) and neutrophils (TANs), which are increasingly recognized as key mediators of immune evasion and poor outcomes. VLPONC-01 is a novel, non-replicating, viral particle-based therapy to target TAMs and TANs. VLPONC-01 efficiently delivers self-amplifying RNA (saRNA) encoding an engineered human Interleukin 12 (IL-12) gene into cells in the tumor microenvironment (TME), leveraging the natural tropism of Venezuelan equine encephalitis virus (VEEV). Within transfected cells, the RNA amplifies itself and directs the cell to produce and secrete IL-12 protein. The released IL-12 is expected to concentrate in the TME, where it activates immune cells and enhances their ability to attack cancer cells. Methods: This is a first-in-human, phase 1, open-label trial evaluating the safety and early efficacy of intratumoral administration of VLPONC-01 in patients with HNSCC, focusing on its ability to reduce tumor burden and lessen surgical morbidity. Furthermore, it will characterize IL-12-driven alterations in the tumor microenvironment and determine the synergistic potential of combining this approach with anti-PD-1 immunotherapy. The study includes two cohorts: Cohort A tests weekly intratumoral injection in recurrent and/or metastatic tumor patients to assess safety and determine dose levels, while Cohort C randomizes patients with resectable tumors into three groups to receive low-dose VLPONC-01 plus pembrolizumab, high-dose VLPONC-01 plus pembrolizumab, or pembrolizumab alone, prior to surgery. Outcomes include dose-limiting toxicities, surgical delays, systemic cytokine responses, and tumor response assessed by imaging and pathology. Clinical trial information: NCT06736379 .