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. Level of Evidence 3.