Success or failure of vaccination for HPV16-positive vulvar lesions correlates with kinetics and phenotype of induced T-cell responses

Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11895-9. doi: 10.1073/pnas.1006500107. Epub 2010 Jun 14.


One half of a group of 20 patients with human papillomavirus type 16 (HPV16)-induced vulvar intraepithelial neoplasia grade 3 displayed a complete regression (CR) after therapeutic vaccination with HPV16 E6/E7 synthetic long peptides. Patients with relatively larger lesions generally did not display a CR. To investigate immune correlates of treatment failure, patients were grouped according to median lesion size at study entry, and HPV16-specific immunity was analyzed at different time points by complementary immunological assays. The group of patients with smaller lesions displayed stronger and broader vaccine-prompted HPV16-specific proliferative responses with higher IFNgamma (P = 0.0003) and IL-5 (P < 0.0001) levels than patients with large lesions. Characteristically, this response was accompanied by a distinct peak in cytokine levels after the first vaccination. In contrast, the patient group with larger lesions mounted higher frequencies of HPV16-specific CD4(+)CD25(+)Foxp3(+) T cells (P = 0.005) and displayed a lower HPV16-specific IFNgamma/IL-10 ratio after vaccination (P < 0.01). No disparity in T memory immunity to control antigens was found, indicating that the differences in HPV-specific immunity did not reflect general immune failure. We observed a strong correlation between a defined set of vaccine-prompted specific immune responses and the clinical efficacy of therapeutic vaccination. Notably, a high ratio of HPV16-specific vaccine-prompted effector T cells to HPV16-specific CD4(+)CD25(+)Foxp3(+) T cells was predictive of clinical success. Foxp3(+) T cells have been associated previously with impaired immunity in malignancies. Here we demonstrate that the vaccine-prompted level of this population is associated with early treatment failure.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / immunology
  • Cancer Vaccines / administration & dosage
  • Cancer Vaccines / therapeutic use*
  • Carcinoma in Situ / immunology*
  • Carcinoma in Situ / pathology
  • Carcinoma in Situ / therapy*
  • Cytokines / biosynthesis
  • Female
  • Forkhead Transcription Factors / metabolism
  • Human papillomavirus 16 / immunology*
  • Humans
  • In Vitro Techniques
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Kinetics
  • Lymphocyte Activation
  • Papillomavirus Infections / immunology*
  • Papillomavirus Infections / pathology
  • Papillomavirus Infections / therapy*
  • Papillomavirus Vaccines / administration & dosage
  • Papillomavirus Vaccines / therapeutic use*
  • Remission Induction
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes, Regulatory / immunology
  • Treatment Failure
  • Vulvar Neoplasms / immunology*
  • Vulvar Neoplasms / pathology
  • Vulvar Neoplasms / therapy*


  • Cancer Vaccines
  • Cytokines
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • IL2RA protein, human
  • Interleukin-2 Receptor alpha Subunit
  • Papillomavirus Vaccines