Testing the safety and immune response of HPV-DNA vaccination in patients with a HPV-positive preinvasive lesion of the vulva.

Human papilloma virus (HPV) infection (genotypes 16 and 18) is strongly associated with the development of squamous cell cancer, such as cancers of the anogenital region and head and neck cancer. HPV16 infection may also cause a chronic skin disorder of the vulva known as vulvar intraepithelial neoplasia (VIN). Patients often have a weak or no spontaneous HPV-specific T-cell response which is thought to be important in the clearance of infection and disease. Because the persistence of oncogenic HPV proteins E6 and E7 is required for carcinogenesis, these viral antigens are exquisite targets for immunotherapeutic interventions.

In this phase I study patients with vulvar intraepithelial neoplasia grade III (VINIII) will be vaccinated with a novel and potent intradermal HPV-DNA vaccination strategy. In preclinical studies this strategy was shown to be much more potent in the induction of (E6 and) E7-specific CD8+ cytotoxic T-cell immunity than existing DNA vaccination strategies, providing a strong rationale for its clinical evaluation.

This study will allow us to define the optimal dosage and value of this novel DNA vaccination strategy for the treatment of HPV16+ (pre)malignancies.

HPV16 E7 DNA vaccination may give a HPV-specific T-cell response which is thought to be important in the clearance of infection and disease.

Vaccination will be on days 0, 3 and 6, and boost vaccination on days 28, 31 and 34.

Anti-HPV T-cell immunity will be evaluated before start of DNA vaccination and at time points 14, 28, 42 and 56 days using peripheral blood mononuclear cells (PBMC).

Lesions will be examined by vulvoscopy, described in detail and measured bi-dimensionally by the same qualified treating physician and a qualified investigator, taking the largest diameters in two dimensions. Drawings will be made on a predesigned vulvoscopy form. In case of multifocality the total lesion size will be determined. Furthermore, monitoring of the lesions by digital photography will take place at time points 0 and 12 weeks after the last vaccination.

Skin biopsies from the vaccination site will be taken at time point t=0 (prior to vaccination), at t=14 and at 42 days.

Biopsies from the VINIII lesion will be taken at time point t=0 and around t=118 days. The effect of vaccination on the VIN lesion microenvironment will be determined.

The HPV16 E7 DNA vaccine (TTFC-E7SH) will be injected intradermally on days 0, 3 and 6 using a permanent make-up device, and boost vaccinations after 4 weeks (days 28, 31, and 34) (Derm.MT GmbH, Berlin, Germany). The TTFC-E7SH will be injected at the skin surface area of one of the upper legs, close to the inguinal lymph node area.