Pransky, Seth M.

ABSTRACT Objective To evaluate the long‐term safety and clinical effect of INO‐3107 immunotherapy in adults with recurrent respiratory papillomatosis (RRP). Methods RRP‐002 was a retrospective, observational extension study that followed patients enrolled in the 52‐week RRP‐001 study. Patients with moderate to severe juvenile or adult‐onset RRP who had undergone ≥ 2 surgical interventions in the year preceding dosing were eligible for enrollment in RRP‐001. Participants underwent surgical debulking within 14 days prior to initial dosing and then received INO‐3107 on Day 0, Weeks 3, 6, and 9. Efficacy assessments during RRP‐002 follow‐up were the frequency of surgical interventions and alternative medication use. The safety evaluation included reported serious adverse events (SAEs). Results Twenty‐eight (28) of 32 participants from the 52‐week RRP‐001 study were enrolled in RRP‐002. The median follow‐up time for RRP‐002 was 1.8 years (range: 1.2–2.4 years) for a total median assessment time of 2.8 years (range: 1.0–3.5 years). There were no SAEs or long‐term safety concerns identified. The mean number of surgeries was reduced from 4.1 in the pre‐treatment period to 1.7 in the first year post‐INO‐3107 treatment (Year 1) to 0.9 in the second year (Year 2). The complete response rate (0 surgeries per year) increased from 28% (9/32) in Year 1 to 50% (14/28) in Year 2. Conclusion INO‐3107 is well tolerated and provides a continued clinical effect against HPV‐6 and 11 RRP that results in further reduction of the surgical burden observed in Year 1. These data support the role of INO‐3107 immunotherapy for adult patients with RRP. Level of Evidence: III.

Abstract 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.

Objective To evaluate the safety, immunogenicity, and efficacy of INO‐3107, a DNA immunotherapy designed to elicit targeted T‐cell responses against human papillomavirus (HPV) types 6 and 11, in adult patients with recurrent respiratory papillomatosis (RRP; NCT04398433). Methods Eligible patients required ≥2 surgical interventions for RRP in the year preceding dosing. INO‐3107 was administered by intramuscular (IM) injection followed by electroporation (EP) on weeks 0, 3, 6, and 9. Patients underwent surgical debulking within 14 days prior to first dose, with office laryngoscopy and staging at screening and weeks 6, 11, 26, and 52. Primary endpoint was safety and tolerability, as assessed by treatment‐emergent adverse events (TEAEs). Secondary endpoints included frequency of surgical interventions post‐INO‐3107 and cellular immune responses. Results An initial cohort of 21 patients was enrolled between October 2020 and August 2021. Fifteen (71.4%) patients had ≥1 TEAE; 11 (52.4%) were Grade 1, and 3 (14.3%) were Grade 3 (none treatment related). The most frequently reported TEAE was injection site or procedural pain ( n = 8; 38.1%). Sixteen (76.2%) patients had fewer surgical interventions in the year following INO‐3107 administration, with a median decrease of 3 interventions versus the preceding year. The RRP severity score, modified by Pransky, showed improvement from baseline to week 52. INO‐3107 induced durable cellular responses against HPV‐6 and HPV‐11, with an increase in activated CD4 and CD8 T cells and CD8 cells with lytic potential. Conclusion The data suggest that INO‐3107 administered by IM/EP is tolerable and immunogenic and provides clinical benefit to adults with RRP. Level of Evidence 3 Laryngoscope , 133:3087–3093, 2023

Objectives/HypothesisThe purpose of this study is to develop consensus on key points that would support the use of systemic bevacizumab for the treatment of recurrent respiratory papillomatosis (RRP), and to provide preliminary guidance surrounding the use of this treatment modality.Study DesignDelphi method‐based survey series.MethodsA multidisciplinary, multi‐institutional panel of physicians with experience using systemic bevacizumab for the treatment of RRP was established. The Delphi method was used to identify and obtain consensus on characteristics associated with systemic bevacizumab use across five domains: 1) patient characteristics; 2) disease characteristics; 3) treating center characteristics; 4) prior treatment characteristics; and 5) prior work‐up.ResultsThe international panel was composed of 70 experts from 12 countries, representing pediatric and adult otolaryngology, hematology/oncology, infectious diseases, pediatric surgery, family medicine, and epidemiology. A total of 189 items were identified, of which consensus was achieved on Patient Characteristics (9), Disease Characteristics (10), Treatment Center Characteristics (22), and Prior Workup Characteristics (18).ConclusionThis consensus statement provides a useful starting point for clinicians and centers hoping to offer systemic bevacizumab for RRP and may serve as a framework to assess the components of practices and centers currently using this therapy. We hope to provide a strategy to offer the treatment and also to provide a springboard for bevacizumab's use in combination with other RRP treatment protocols. Standardized delivery systems may facilitate research efforts and provide dosing regimens to help shape best‐practice applications of systemic bevacizumab for patients with early‐onset or less‐severe disease phenotypes.Level of Evidence5 Laryngoscope, 131:E1941–E1949, 2021

Objectives/HypothesisCreate a competency‐based assessment tool for pediatric tracheotomy.Study DesignBlinded, modified, Delphi consensus process.MethodsUsing the REDCap database, a list of 31 potential items was circulated to 65 expert surgeons who perform pediatric tracheotomy. In the first round, items were rated as “keep” or “remove,” and comments were incorporated. In the second round, experts were asked to rate the importance of each item on a seven‐point Likert scale. Consensus criteria were determined a priori with a goal of 7 to 25 final items.ResultsThe first round achieved a response rate of 39/65 (60.0%), and returned questionnaires were 99.5% complete. All items were rated as “keep,” and 137 comments were incorporated. In the second round, 30 task‐specific and seven previously validated global rating items were distributed, and the response rate was 44/65 (67.7%), with returned questionnaires being 99.3% complete. Of the Task‐Specific Items, 13 reached consensus, 10 were near consensus, and 7 did not achieve consensus. For the 7 previously validated global rating items, 5 reached consensus and two were near consensus.ConclusionsIt is feasible to reach consensus on the important steps involved in pediatric tracheotomy using a modified Delphi consensus process. These items can now be considered to create a competency‐based assessment tool for pediatric tracheotomy. Such a tool will hopefully allow trainees to focus on the important aspects of this procedure and help teaching programs standardize how they evaluate trainees during this procedure.Level of Evidence5 Laryngoscope, 130:2700–2707, 2020