DNA Immunotherapy for Recurrent Respiratory Papillomatosis (RRP): Phase 1/2 study assessing efficacy, safety, and immunogenicity of INO-3107

DNA Immunotherapy for Recurrent Respiratory Papillomatosis (RRP): Phase 1/2 study assessing efficacy, safety, and immunogenicity of INO-3107 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article DNA Immunotherapy for Recurrent Respiratory Papillomatosis (RRP): Phase 1/2 study assessing efficacy, safety, and immunogenicity of INO-3107 Matthew Morrow, Ted Mau, Elisabeth Gillespie, Albert Sylvester, and 17 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4770252/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Feb, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version 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. Biological sciences/Drug discovery/Biologics/Nucleic-acid therapeutics Biological sciences/Immunology/Immunotherapy Full Text Additional Declarations Yes there is potential Competing Interest. T.M., P.C.B., S.R.B., and D.G.L. received honoraria for consultancy for Inovio Pharmaceuticals. M.R.A. and R.C.P. have no funding, financial relationships, or conflicts of interest to disclose. A.D.F. received honoraria for consultancy for Inovio Pharmaceuticals and Precigen, Inc. A.M.K. receives support from the RRP Foundation for attending an RRPF Research meeting. S.M.P. receives honoraria for consultancy and advice for Inovio Pharmaceuticals; and is a member of the Recurrent Respiratory Task Force of the American Society of Pediatric Otolaryngology. N.F.S. provides advice for Inovio Pharmaceuticals; and provided compensated or non-compensated advisory role for Astra Zeneca, Merck, CUE Biopharma, and PDS. D.B.W. received renumeration as a member of the Board of Directors and consultant for Inovio Pharmaceuticals, and received honoraria for consultancy for Geneos, Flagship, and Advaccine, and as an advisor for Geneos, Astra Zeneca, BBI/Sumitomo, and Pfizer, and as a speaker for Astra Zeneca. M.P.M., E.G., A.S., G.S.T., S.W., S.A.M., E.L.R., K.S.R., M.D., and J.M.S. are employees of and may hold stock and/or stock options in Inovio Pharmaceuticals. Supplementary Files NatureMedicineINO3107ClinicalImmunologySupplementaryInformation.pdf Supplementary Information Cite Share Download PDF Status: Published Journal Publication published 12 Feb, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4770252","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":332385667,"identity":"b908727e-1042-405e-b59d-af45c8321f7b","order_by":0,"name":"Matthew 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M.R.A. and R.C.P. have no funding, financial relationships, or conflicts of interest to disclose. A.D.F. received honoraria for consultancy for Inovio Pharmaceuticals and Precigen, Inc. A.M.K. receives support from the RRP Foundation for attending an RRPF Research meeting. S.M.P. receives honoraria for consultancy and advice for Inovio Pharmaceuticals; and is a member of the Recurrent Respiratory Task Force of the American Society of Pediatric Otolaryngology. N.F.S. provides advice for Inovio Pharmaceuticals; and provided compensated or non-compensated advisory role for Astra Zeneca, Merck, CUE Biopharma, and PDS. D.B.W. received renumeration as a member of the Board of Directors and consultant for Inovio Pharmaceuticals, and received honoraria for consultancy for Geneos, Flagship, and Advaccine, and as an advisor for Geneos, Astra Zeneca, BBI/Sumitomo, and Pfizer, and as a speaker for Astra Zeneca. M.P.M., E.G., A.S., G.S.T., S.W., S.A.M., E.L.R., K.S.R., M.D., and J.M.S. are employees of and may hold stock and/or stock options in Inovio Pharmaceuticals.","formattedTitle":"DNA Immunotherapy for Recurrent Respiratory Papillomatosis (RRP): Phase 1/2 study assessing efficacy, safety, and immunogenicity of INO-3107","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4770252/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4770252/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"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.","manuscriptTitle":"DNA Immunotherapy for Recurrent Respiratory Papillomatosis (RRP): Phase 1/2 study assessing efficacy, safety, and immunogenicity of INO-3107","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-18 03:16:40","doi":"10.21203/rs.3.rs-4770252/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"bb750e08-f188-4a3d-b0da-dd871b0bb4a1","owner":[],"postedDate":"September 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":35198091,"name":"Biological sciences/Drug discovery/Biologics/Nucleic-acid therapeutics"},{"id":35198092,"name":"Biological sciences/Immunology/Immunotherapy"}],"tags":[],"updatedAt":"2025-02-13T08:05:58+00:00","versionOfRecord":{"articleIdentity":"rs-4770252","link":"https://doi.org/10.1038/s41467-025-56729-6","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2025-02-12 05:00:00","publishedOnDateReadable":"February 12th, 2025"},"versionCreatedAt":"2024-09-18 03:16:40","video":"","vorDoi":"10.1038/s41467-025-56729-6","vorDoiUrl":"https://doi.org/10.1038/s41467-025-56729-6","workflowStages":[]},"version":"v1","identity":"rs-4770252","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4770252","identity":"rs-4770252","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}