Integrative analysis of VB10.16 and atezolizumab in advanced HPV16-positive cervical cancer: Linking biomarker insights to clinical outcomes.

5538 Background: Therapeutic cancer vaccines combined with immune checkpoint inhibitors offer a promising strategy to enhance anti-tumor responses. We recently demonstrated the safety and clinical efficacy of VB10.16, a DNA-based therapeutic cancer vaccine encoding HPV16 E6/E7 oncoproteins fused to CCL3L1 for antigen-presenting cell targeting, in HPV16-positive persistent, recurrent or metastatic cervical cancer 1 . This analysis explores the association between HPV16-specific T cell responses, tumor microenvironment (TME) characteristics, and clinical outcomes in the phase 2a trial. Methods: In this multicenter, open-label trial, 52 patients with advanced HPV16-positive cervical cancer received VB10.16 (3 mg intramuscularly) combined with atezolizumab (1200 mg intravenously) for up to 48 weeks. Primary endpoints were safety and objective response rate per RECIST v1.1. Secondary endpoints included overall survival (OS) and HPV16-specific T cell responses via IFN-γ ELISpot (n=36). Predefined exploratory endpoints included systemic immunosuppression and TME inflammatory status in baseline tumors, assessed via myeloid cell counts (baseline to ~week 9, n=47), flow cytometry (T cell/myeloid-derived suppressor cells [MDSC] ratio, n=21), and gene expression analyses (n=29). Results: Patients with reduced on-treatment systemic immunosuppression demonstrated stronger HPV16-specific T cell responses than patients without (myeloid cell counts decreased in 17/47 patients; T cell/MDSC ratio increased in 12/21 patients). On-treatment reduction in systemic immunosuppression was associated with a higher clinical benefit rate (complete response [CR]/partial response [PR]/stable disease [SD] in 17/28 vs 4/19 patients by myeloid counts and 10/12 vs 2/9 by T cell/MDSC ratio), suggesting associations between T cell response, systemic immunosuppression and effect of immunotherapies. Among the 9 responders in the efficacy population (n=47; 3 CR; 6.4% and 6 PR; 12.8%), 5 patients had available gene expression data from baseline tumors. Patients with pro-inflammatory/proliferative TME signatures demonstrated higher CR/PR rates (4/14 vs. 1/15) and longer OS compared to patients with stromal/immunosuppressive signaling (mOS not reached vs 8.3 months). Clinical benefit was also observed in stromal/immunosuppressive TMEs (1/15 CR, 6/15 SD), highlighting VB10.16’s potential to overcome local immunosuppression. Conclusions: VB10.16 combined with atezolizumab induces durable responses, mitigates local and systemic immunosuppression, and demonstrates synergy between biomarkers and clinical outcomes. High CR/PR rates with favorable immune and TME characteristics highlight the promise of this combination therapy, warranting further exploration. 1 Hillemanns P et al , 2025 doi:10.1136/jitc-2024-010827. Clinical trial information: NCT04405349 .