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

van Poelgeest, M. I. E., Welters, M. J. P., Vermeij, R., Stynenbosch, L. F. M., Loof, N. M., Berends-van der Meer, D. M. A., Lowik, M. J. G., Hamming, I. L. E., van Esch, E. M. G., Hellebrekers, B. W. J., van Beurden, M., Schreuder, H. W., Kagie, M. J., Trimbos, J. B. M. Z., Fathers, L. M., Daemen, T., Hollema, H., Valentijn, A. R. P. M., Oostendorp, J., Oude Elberink, J. H. N. G., Fleuren, G. J., Bosse, T., Kenter, G. G., Stijnen, T., Nijman, H. W., Melief, C. J. M. & van der Burg, S. H., 15-May-2016, In : Clinical Cancer Research. 22, 10, p. 2342-2350 9 p.

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  • Vaccination against Oncoproteins of HPV16 for Noninvasive Vulvar-Vaginal Lesions

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  • Mariette 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. Lowik
  • 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
  • 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 non-responders 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. (C) 2016 AACR.

Original languageEnglish
Pages (from-to)2342-2350
Number of pages9
JournalClinical Cancer Research
Issue number10
Publication statusPublished - 15-May-2016



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