Abstract CT126: A synthetic DNA plasmid encoding HPV6 E6 and E7 proteins in patients with HPV6-associated aerodigestive lesions
Authors: Aggarwal Charu , Cohen Roger B. , Morrow Matthew P. , Kraynyak Kimberly A. , Cheung Jocelyn , Dickerson Kelsie , Schulten Veronique , Knoblock Dawson , Gillespie Elisabeth , Bauml Joshua M. , Diehl Malissa , Boyer Jean , Dallas Michael , Weiner David B. , Skolnik Jeffrey M. 
Published: September 2020

Abstract
Introduction: Human papilloma virus (HPV)-6 and 11-associated aerodigestive neoplasms can occur in the oropharynx, larynx, and upper respiratory tract. HPV is implicated in recurrent respiratory papillomatosis (RRP), the most common benign tumor of the laryngeal epithelium. RRP is rare, with an incidence rate of 1.8 per 100,000 adults in the United States, but the clinical course can be significant and patients with RRP have a higher risk of developing laryngeal cancer. DNA therapies focusing on treating HPV-related disease may be of benefit in RRP. Methods: A pilot clinical study was conducted in subjects with HPV-6-associated RRP or invasive carcinoma (NCT02241369). Subjects with HPV-6-associated aerodigestive disease received four doses (one dose every three weeks) of INO-3106, a synthetic DNA plasmid encoding HPV-6 E6 and E7 proteins, with and without INO-9012, a synthetic DNA plasmid encoding IL-12. INO-3106 and INO-9012 were administered intramuscularly (IM), followed by electroporation with the CELLECTRA® 2000 device. Subjects were assessed for safety and tolerability, antigen-specific T cell responses, and efficacy, as assessed by disease-free interval. Flow cytometry and immune gene transcript assessments focused on CD8+ T cells. Results: Three subjects were enrolled; one with invasive carcinoma and two with RRP. All subjects received all four doses of INO-3106; two doses with, and two without, INO-9012. The most common adverse event was injection site discomfort in all patients; no other related AEs were reported on this study. One patient with laryngeal cancer reported an SAE of stroke, unrelated to study therapy. An assessment of cellular immune responses from the two RRP subjects by flow cytometry after completion of study therapy demonstrated the induction of HPV-6-specific CD8+ T cells co-expressing various activation markers and lytic proteins consistent with a Cytolytic T Cell (CTL) phenotype. Among the T cell populations induced by study treatment, CTLs co-expressing CD137, CD38, Ki67, Granzyme A, Granzyme B and Perforin were increased following study treatment. Both RRP subjects had required frequent (every six month) surgery prior to enrolling on-study; following study therapy, one patient remained disease-free for over 500 days, and the other remains disease-free over 900 days. Conclusions: INO-3106, with INO-9012, given IM followed by EP with CELLECTRA® is tolerable, immunogenic, and may provide clinical benefit. A larger study is currently planned to explore the efficacy of this therapy in adults, adolescents and children with RRP.
Citation Format: Charu Aggarwal, Roger B. Cohen, Matthew P. Morrow, Kimberly A. Kraynyak, Jocelyn Cheung, Kelsie Dickerson, Veronique Schulten, Dawson Knoblock, Elisabeth Gillespie, Joshua M. Bauml, Malissa Diehl, Jean Boyer, Michael Dallas, David B. Weiner, Jeffrey M. Skolnik. A synthetic DNA plasmid encoding HPV6 E6 and E7 proteins in patients with HPV6-associated aerodigestive lesions [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT126.