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

Clin Cancer Res. 2016 May 15;22(10):2342-50. doi: 10.1158/1078-0432.CCR-15-2594. Epub 2016 Jan 26.


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. Clin Cancer Res; 22(10); 2342-50. ©2016 AACRSee related commentary by Karaki et al., p. 2317.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Aminoquinolines / therapeutic use
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / virology
  • Cancer Vaccines / immunology
  • Carcinoma in Situ / drug therapy
  • Carcinoma in Situ / immunology
  • Female
  • Human papillomavirus 16 / drug effects
  • Human papillomavirus 16 / immunology*
  • Humans
  • Imiquimod
  • Interferon-gamma / immunology
  • Middle Aged
  • Oncogene Proteins, Viral / immunology*
  • Papillomavirus E7 Proteins / immunology
  • Papillomavirus Infections / immunology*
  • Papillomavirus Infections / virology
  • Papillomavirus Vaccines / immunology*
  • Uterine Cervical Neoplasms / drug therapy
  • Uterine Cervical Neoplasms / immunology
  • Vaccination / methods
  • Vaginal Neoplasms / immunology*
  • Vaginal Neoplasms / virology
  • Vulvar Neoplasms / immunology*
  • Vulvar Neoplasms / virology
  • Young Adult


  • Aminoquinolines
  • Cancer Vaccines
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Papillomavirus Vaccines
  • Interferon-gamma
  • Imiquimod