DNA Immunotherapy ( INO ‐3107) Long‐Term Efficacy Supported by Enhanced Immunogenicity in HPV ‐6/11 RRP

OBJECTIVES: Recurrent respiratory papillomatosis (RRP), caused by chronic HPV-6/11 infection, leads to repeated papilloma growth requiring frequent surgical removal. DNA immunotherapy INO-3107 aims to induce HPV antigen-specific T-cell responses and reduce surgical burden. This analysis evaluated HPV-specific immune responses after INO-3107 and their association with long-term clinical outcomes. METHODS: Adults with HPV-6/11-associated RRP received INO-3107 in a Phase 1/2 trial and were followed for one year, with additional clinical follow-up in a long-term extension. Number of surgeries in Years 1 and 2 was compared with the pre-treatment year. Blood and laryngotracheal tissue collected at Day 0 and Year 1 were analyzed for treatment-related changes in T-cell activity. Safety was assessed throughout. RESULTS: Thirty-two patients were treated; 28 continued into Year 2. At Year 1, most evaluable patients showed increased T-cell activity: 73% (19/26) demonstrated persistent expanded T-cell populations in blood, 71% (12/17) showed higher T-cell clone counts in laryngotracheal tissue, indicating site-specific immune infiltration. Antiviral T-cell signatures were enriched in 88% for CD4+ Th1 and CD8+ cytotoxic, and 71% for CD8+ effector memory, suggesting durable proinflammatory and memory responses in airway tissue. Mean annual surgeries decreased over time in the overall population (Baseline: 4.1, Year 1: 1.7, Year 2: 0.9). Similar durable reductions were observed in Responder subgroups. INO-3107 was well-tolerated, with no treatment-related serious adverse events. CONCLUSION: INO-3107 generates increased HPV-directed T-cell responses and substantially reduced surgical procedures over two years, supporting its ability to provide long-term clinical benefit in RRP without requiring additional surgeries during the dosing window.