Long term follow up of the clinical and immunological responses following HPV 16 E6/E7 synthetic long peptides vaccination in women with HPV 16 positive vulvar intraepithelial neoplasia grade 3

Vulvar intraepithelial neoplasia (VIN) is a chronic disorder usually caused by
high-risk human papilloma virus (hrHPV), most commonly HPV type 16.Spontaneous
regression occurs in less than 1.5% of patients and the estimated risk of
progression to malignant disease is 4% after treatment and 9% without
treatment, while the recurrence rates are high with conventional treatments. A
T-cell response plays a pivotal role in the clearance of an HPV infection. The
early oncogene-encoded proteins E6 and E7 expressed in (pre)malignant HPV
lesions are the major targets for the immune system and consequently constitute
the antigens for immunotherapeutic approaches to treat anogenital HPV lesions.
A synthetic long overlapping peptide vaccine (SLP) against the HPV-16
oncogene-encoded E6 and E7 proteins (HPV16-SLP) was developed and several phase
I/II studies have been performed to evaluate the safety and efficacy of this
vaccine against HPV-16 associated anogenital disease.In a phase II clinical
trial, in which 20 patients with HPV16 positive high-grade precancerous lesions
(high grade vulvar intraepithelial neoplasia: VIN 3) were treated with
HPV16-SLP, an objective clinical response rate of 79% and a complete and
durable (>24 months) regression of the lesion in 47% of the patients was
obtained. Notably, the clinical outcome was strongly correlated with the
strength of the HPV16-specific T-cell associated IFN*-response as well as a
relatively smaller size of the lesion at study entry. The group of patients
with smaller lesions displayed stronger and broader vaccine-prompted
HPV16-specific proliferative responses with higher IFNy (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) No
severe side effects of the vaccination were reported though local side effects
of the vaccination site such as swelling and discoloration of the skin were
observed in the majority of vaccinated patients even in follow up. Histological
examination of the vaccination sites, in some patients with local symptoms
showed signs of granulomatous inflammation. In the current study we therefore
aim to evaluate both the long term clinical and immunological response of this
therapeutic vaccination as well as the adverse drug reactions.

To determine the long term clinical and immunological responses in patients
with high grade VIN who have been vaccinated with an HPV 16 E6/E7 SLP vaccine
approximately 3 years ago.

A prospective cohort study

The burden and risks associated with participation in this follow up study are
low since the interventions consist of considerably safe, venous
bloodcollection and biopsies. A questionnaire will be sent and the patients
will be asked to visit the outdoor patient clinic of the LUMC once. This visit
will take approximately one hour where a gynaecological research as well as
inspection of the inoculation sites will take place. Biopsies will be taken of
the vulva (even in case of complete respons) and if present of the most
prominent vaccination site.
This follow up visit is of importance for a better understanding of the long
term clinical and immunological respons after vaccination for further research
and development of the therapeutic HPV 16 E6/E7 SLP vaccin for (pre)malignant
anogenital diseases.