TY - JOUR
T1 - HPV-16 E6/E7 DNA tattoo vaccination using genetically optimized vaccines elicit clinical and immunological responses in patients with usual vulvar intraepithelial neoplasia (uVIN): A phase I/II clinical trial
T2 - A phase I/II clinical trial
AU - Bakker, Noor Alida Maria
AU - Rotman, Jossie
AU - van Beurden, Marc
AU - Zijlmans, Henry J. Maa
AU - van Ruiten, Maartje
AU - Samuels, Sanne
AU - Nuijen, Bastiaan
AU - Beijnen, Jos
AU - de Visser, Karin
AU - Haanen, John
AU - Schumacher, Ton
AU - de Gruijl, Tanja D.
AU - Jordanova, Ekaterina S.
AU - Kenter, Gemma G.
AU - van den Berg, Joost H.
AU - van Trommel, Nienke E.
N1 - Funding Information: Competing interests JB is (part time) employee of Modra Pharmaceuticals and stockholder in Modra Pharmaceuticals. (not related to the manuscript). TS is advisor for Adaptive Biotechnologies, Allogene Therapeutics, Merus, Neogene Therapeutics, and Scenic Biotech; is a recipient of research support from Merck KgaA; is a stockholder in Allogene Therapeutics, Merus, Neogene Therapeutics and Scenic Biotech; and is venture partner at Third Rock Ventures, all not related to the current work. JH is advisor to Achilles Therapeutics, Bristol-Myers Squibb, BioNTech USA, Ipsen, Gadeta, Immunocore, MSD, Merck Serono, Molecular Partners, Neogene Therapeutics, Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, Third Rock Ventures, is stock holder in Neogene Therapeutics, and is a recipient of grant or research support from Bristol-Myers Squibb, MSD, Novartis and BioNTech USA. KDV reports research funding from Roche and is consultant for Third Rock Ventures, all outside the scope of this work. TDdG has served as advisor to TILT Biotherapeutics, LAVA Therapeutics, Macrophage Pharma and DCPrime, is a recipient of a grant from Idera Pharmaceuticals, and is co-founder and shareholder of LAVA Therapeutics. JHvdB is a recipient of grant or research support from BioNTech USA and Astra Zeneca, and is currently employed at CellPoint B.V. Funding Information: Funding We thank the Rational molecular Assessment Innovative Drug selection (RAIDs) consortium (http://www.raids-fp7.eu). This trial is part of the RAIDs project and received funding from the European Union’s Seventh Program for Research, Technological Development, and Demonstration (Grant No. 304810). Additional funding was obtained through the Louise Vehmeijer Foundation, The Netherlands. Part of the salary costs were provided by Oncode Institute, The Netherlands. Publisher Copyright: © Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/8/2
Y1 - 2021/8/2
N2 - Background Usual vulvar intraepithelial neoplasia (uVIN) is a premalignancy caused by persistent infection with high-risk types of human papillomavirus (HPV), mainly type 16. Even though different treatment modalities are available (eg, surgical excision, laser evaporation or topical application of imiquimod), these treatments can be mutilating, patients often have recurrences and 2%-8% of patients develop vulvar carcinoma. Therefore, immunotherapeutic strategies targeting the pivotal oncogenic HPV proteins E6 and E7 are being explored to repress carcinogenesis. Method In this phase I/II clinical trial, 14 patients with HPV16+ uVIN were treated with a genetically enhanced DNA vaccine targeting E6 and E7. Safety, clinical responses and immunogenicity were assessed. Patients received four intradermal HPV-16 E6/E7 DNA tattoo vaccinations, with a 2-week interval, alternating between both upper legs. Biopsies of the uVIN lesions were taken at screening and +3 months after last vaccination. Digital photography of the vulva was performed at every check-up until 12 months of follow-up for measurement of the lesions. HPV16-specific T-cell responses were measured in blood over time in ex vivo reactivity assays. Results Vaccinations were well tolerated, although one grade 3 suspected unexpected serious adverse reaction was observed. Clinical responses were observed in 6/14 (43%) patients, with 2 complete responses and 4 partial responses (PR). 5/14 patients showed HPV-specific T-cell responses in blood, measured in ex vivo reactivity assays. Notably, all five patients with HPV-specific T-cell responses had a clinical response. Conclusions Our results indicate that HPV-16 E6/E7 DNA tattoo vaccination is a biologically active and safe treatment strategy in patients with uVIN, and suggest that T-cell reactivity against the HPV oncogenes is associated with clinical benefit. Trial registration number NTR4607.
AB - Background Usual vulvar intraepithelial neoplasia (uVIN) is a premalignancy caused by persistent infection with high-risk types of human papillomavirus (HPV), mainly type 16. Even though different treatment modalities are available (eg, surgical excision, laser evaporation or topical application of imiquimod), these treatments can be mutilating, patients often have recurrences and 2%-8% of patients develop vulvar carcinoma. Therefore, immunotherapeutic strategies targeting the pivotal oncogenic HPV proteins E6 and E7 are being explored to repress carcinogenesis. Method In this phase I/II clinical trial, 14 patients with HPV16+ uVIN were treated with a genetically enhanced DNA vaccine targeting E6 and E7. Safety, clinical responses and immunogenicity were assessed. Patients received four intradermal HPV-16 E6/E7 DNA tattoo vaccinations, with a 2-week interval, alternating between both upper legs. Biopsies of the uVIN lesions were taken at screening and +3 months after last vaccination. Digital photography of the vulva was performed at every check-up until 12 months of follow-up for measurement of the lesions. HPV16-specific T-cell responses were measured in blood over time in ex vivo reactivity assays. Results Vaccinations were well tolerated, although one grade 3 suspected unexpected serious adverse reaction was observed. Clinical responses were observed in 6/14 (43%) patients, with 2 complete responses and 4 partial responses (PR). 5/14 patients showed HPV-specific T-cell responses in blood, measured in ex vivo reactivity assays. Notably, all five patients with HPV-specific T-cell responses had a clinical response. Conclusions Our results indicate that HPV-16 E6/E7 DNA tattoo vaccination is a biologically active and safe treatment strategy in patients with uVIN, and suggest that T-cell reactivity against the HPV oncogenes is associated with clinical benefit. Trial registration number NTR4607.
KW - adaptive immunity
KW - cytokines
KW - immunogenicity
KW - vaccine
UR - http://www.scopus.com/inward/record.url?scp=85112653166&partnerID=8YFLogxK
U2 - https://doi.org/10.1136/jitc-2021-002547
DO - https://doi.org/10.1136/jitc-2021-002547
M3 - Article
C2 - 34341131
SN - 2051-1426
VL - 9
JO - Journal for Immunotherapy of Cancer
JF - Journal for Immunotherapy of Cancer
IS - 8
M1 - 002547
ER -