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Vaccination against Oncoproteins of HPV16 for Noninvasive Vulvar/Vaginal Lesions : Lesion Clearance Is Related to the Strength of the T-Cell Response

By Mariëtte I E van Poelgeest, Marij J P Welters, Renee Vermeij, Linda F M Stynenbosch, Nikki M Loof, Dorien M A Berends-van der Meer, Margriet J G Löwik, Ineke L E Hamming, Edith M G van Esch, Bart W J Hellebrekers, Marc van Beurden, Henk W Schreuder, Marjolein J Kagie, J Baptist M Z Trimbos, Lorraine M Fathers, Toos Daemen, Harry Hollema, A Rob P M Valentijn, Jaap Oostendorp, J Hanneke N G Oude Elberink, Gertjan J Fleuren, Tjalling Bosse, Gemma G Kenter, Theo Stijnen, Hans W Nijman, Cornelis J M Melief and Sjoerd H van der Burg


PURPOSE: Therapeutic vaccination with human papillomavirus type 16 (HPV16) E6 and E7 synthetic long peptides (SLP) is effective against HPV16-induced high-grade vulvar and vaginal intraepithelial neoplasia (VIN/VaIN). However, clinical nonresponders displayed weak CD8(+) T-cell reactivity. Here, we studied if imiquimod applied at the vaccine site could improve CD8(+) T-cell reactivity, clinical efficacy, and safety of HPV16-SLP (ISA101). EXPERIMENTAL DESIGN: A multicenter open-label, randomized controlled trial was conducted in patients with HPV16(+) high-grade VIN/VaIN. Patients received ISA101 vaccination with or without application of 5% imiquimod at the vaccine site. The primary objective was the induction of a directly ex vivo detectable HPV16-specific CD8(+) T-cell response. The secondary objectives were clinical responses (lesion size, histology, and virology) and their relation with the strength of vaccination-induced immune responses. RESULTS: Forty-three patients were assigned to either ISA101 with imiquimod (n = 21) or ISA101 only (n = 22). Imiquimod did not improve the outcomes of vaccination. However, vaccine-induced clinical responses were observed in 18 of 34 (53%; 95% CI, 35.1-70.2) patients at 3 months and in 15 of 29 (52%; 95% CI, 32.5-70.6) patients, 8 of whom displayed a complete histologic response, at 12 months after the last vaccination. All patients displayed vaccine-induced T-cell responses, which were significantly stronger in patients with complete responses. Importantly, viral clearance occurred in all but one of the patients with complete histologic clearance. CONCLUSIONS: This new study confirms that clinical efficacy of ISA101 vaccination is related to the strength of vaccine-induced HPV16-specific T-cell immunity and is an effective therapy for HPV16-induced high-grade VIN/VaIN

Topics: Journal Article
Year: 2016
OAI identifier: oai:dspace.library.uu.nl:1874/336264
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