Immunotherapy against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses

Sci Transl Med. 2012 Oct 10;4(155):155ra138. doi: 10.1126/scitranslmed.3004414.

Abstract

Despite the development of highly effective prophylactic vaccines against human papillomavirus (HPV) serotypes 16 and 18, prevention of cervical dysplasia and cancer in women infected with high-risk HPV serotypes remains an unmet medical need. We report encouraging phase 1 safety, tolerability, and immunogenicity results for a therapeutic HPV16/18 candidate vaccine, VGX-3100, delivered by in vivo electroporation (EP). Eighteen women previously treated for cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) received a three-dose (intramuscular) regimen of highly engineered plasmid DNA encoding HPV16 and HPV18 E6/E7 antigens followed by EP in a dose escalation study (0.3, 1, and 3 mg per plasmid). Immunization was well tolerated with reports of mild injection site reactions and no study-related serious or grade 3 and 4 adverse events. No dose-limiting toxicity was noted, and pain was assessed by visual analog scale, with average scores decreasing from 6.2/10 to 1.4 within 10 min. Average peak interferon-γ enzyme-linked immunospot magnitudes were highest in the 3 mg cohort in comparison to the 0.3 and 1 mg cohorts, suggesting a trend toward a dose effect. Flow cytometric analysis revealed the induction of HPV-specific CD8(+) T cells that efficiently loaded granzyme B and perforin and exhibited full cytolytic functionality in all cohorts. These data indicate that VGX-3100 is capable of driving robust immune responses to antigens from high-risk HPV serotypes and could contribute to elimination of HPV-infected cells and subsequent regression of the dysplastic process.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antigens, Viral / genetics
  • Antigens, Viral / immunology
  • Antigens, Viral / metabolism
  • Cervical Intraepithelial Neoplasia / immunology*
  • Cervical Intraepithelial Neoplasia / therapy*
  • Electroporation
  • Female
  • Human papillomavirus 16 / immunology*
  • Human papillomavirus 18 / immunology*
  • Humans
  • Immunotherapy / adverse effects
  • Immunotherapy / methods*
  • Papillomavirus Vaccines / immunology
  • Papillomavirus Vaccines / therapeutic use*
  • Vaccines, DNA / immunology
  • Vaccines, DNA / therapeutic use*

Substances

  • Antigens, Viral
  • Papillomavirus Vaccines
  • VGX-3100
  • Vaccines, DNA