Gene expression analysis following RRP therapy INO-3107

Recurrent respiratory papillomatosis (RRP) is a debilitating chronic disease of the airway caused by Human Papillomavirus (HPV). Here we describe the efficacy, safety, and immunogenicity from a Phase 1/2 trial of INO-3107, a DNA immunotherapy designed to elicit T-cell responses against HPV-6 and HPV-11, in adults with RRP (NCT04398433). Thirty-two eligible patients with HPV-6 and/or HPV-11 RRP, who required ≥2 surgical interventions in the year preceding dosing, were administered 4 doses of INO-3107 by intramuscular (IM) injection followed by electroporation (EP). The primary endpoint was safety and tolerability. Efficacy and immunology endpoints included the frequency of surgical interventions in the year following the first dose of INO-3107 and assessment of immune responses. The majority (26/32; 81%) of patients experienced a reduction in the number of surgeries in the year following initiation of treatment with INO-3107, when compared with the year prior. Peripheral blood assessments revealed HPV-6 and HPV-11 antigen-specific T-cell induction, inclusive of cytolytic CD8+ T-cells. RNA sequencing identified the presence of an inflammatory response in patient papillomas after treatment with INO-3107, inclusive of cytolytic CD8+ T-cell signatures. T-cell receptor sequencing revealed emergent T-cell clones in the blood and assessment of airway tissue confirmed trafficking of these clones to papillomas, which was associated with clinical benefit. Treatment was well tolerated, with 13/32 (41%) patients reporting a treatment-related adverse event (AE), all of which were low-grade. INO-3107 provides clinical benefit to adults with HPV-6 and/or HPV-11 associated RRP, is well tolerated, and generates an antigen-specific immune response against HPV. Importantly, treatment-induced peripheral T-cell responses traffick to airway tissue and are associated with clinical response, consistent with the proposed mechanism of action. RRP-001 (ClinicalTrials.gov identifier: NCT04398433) was a Phase 1/2, single-arm, open-label study conducted across 8 centers in the United States. This was a single dose-level trial using a 6-patient safety run-in with a one-week waiting period between each patient. Eligible patients were men and women 18 years or older with histologically documented HPV-6 or HPV-11 positive RRP, who required frequent RRP surgical interventions. Patients received one dose of INO-3107 on Day 0 and Weeks 3, 6, and 9 administered intramuscularly followed immediately by electroporation using the CELLECTRA proprietary device. Peripheral blood mononuclear cells were cryopreserved, and tissue collected during surgical intervention or biopsy was formalin fixed and embedded in paraffin for use in RNA seq.