Clinical and immunological effects of imiquimod and HPV-vaccination compared to imiquimod alone in female patients with Usual type VIN: proof of principle.

Usual type Vulvar Intraepithelial Neoplasia (VIN) is a premalignant disorder
caused by a persistent HPV-infection that needs to be treated proactively.
Recently our group reported in the New England Journal of Medicine on a
randomized clinical trial (RCT) in which we successfully used a non-invasive
new treatment for usual type VIN. It was observed that imiquimod treatment
resulted in a complete response in 35% of patients and represented a
significant reduction in lesion size for an additional 46% of patients.
Furthermore, after treatment with imiquimod, HPV virus could no longer be
detected at the site of the lesion in 58% of patients. On the basis of these
findings we recommend to use imiquimod as a first-line treatment for VIN. In
the current proposal we are seeking to further improve imiquimod treatment by
combining it with a vaccination against HPV. The rationale behind this approach
is that this way we will be boosting different aspects of cellular immunity:
imiquimod binds TLR7 and 8, activates dendritic cells to produce cytokines thus
evoking an influx of immunocompetent cells in the treated area, while
vaccination induces a systemic cellular response by activating dendritic cells
to present antigen to naïve T-lymphocytes, thus activating them. This way we
will enhance cellular immunity and will consequently further enhance disease
clearance in patients suffering from VIN.

Primary objectives: (1) Evaluation of the efficacy of vaccination against HPV
16, 18, 6 and 11 followed by local applications of imiquimod 5% cream compared
to treatment with imiquimod alone for usual type VIN, (2) evaluation of the
systemic and local immune response to both treatments, and (3) evaluation of
the effect of treatments on HPV DNA presence in VIN lesions.
Secondary objectives: Evaluation of the effect of vaccination against HPV types
16,18, 6 and 11.

This study is designed as a randomized, placebo-controlled, double-blinded
proof of principle study.

Included patients will be double-blinded and randomized to receive 5% imiquimod
cream + HPV-vaccination or 5% imiquimod cream with placebo vaccination
(saline). Vaccination will take place in three dosages at weeks 0, 8 and 24.
Imiquimod will be applied to the site of the lesion twice weekly for a period
of 16 weeks (weeks 8-24). Clinical assessment will take place every 4 weeks
during treatment and 7 months after start of imiquimod treatment.

Risk and burden are linked to protocol procedures, such as injection of the
vaccine, blood withdrawal and biopsy sampling. Although these are routine
procedures, carried out by medical qualified personnel, they may cause side
effects or discomfort to the subject. However, it is expected that these
procedures will generally be well tolerated.
Gardasil® or placebo injection will be given three times; known side effects
from Gardasil® are local reactions at the injection site (e.g. pain, redness,
bruising, itch) and general reactions as fatigue, nausea and fever. Most side
effects are transient and considered mild. Rare complications are the
development of urticaria and bronchospasm (<0.01%).
Imiquimod will be applied twice weekly for 16 weeks; known local side effects
are erythema, ulceration, vesiculation, excoriation, and discharge, and are
readily reversible with discontinuation of dosing.