Effect of TA-CIN (HPV 16 L2E6E7) booster immunisation in vulval intraepithelial neoplasia patients previously vaccinated with TA-HPV (vaccinia virus encoding HPV 16/18 E6E7)

Abstract

Heterologous prime-boost vaccination schedules employing TA-HPV, a vaccinia virus encoding HPV 16/18 E6 and E7, in combination with TA-CIN, an HPV 16 L2E6E7 fusion protein, may offer advantages over the use of either agent alone for the immunotherapy of human papillomavirus (HPV) type 16-associated vulval intraepithelial neoplasia (VIN). In the present study, 10 women with HPV 16-positive high grade VIN, previously primed with TA-HPV, received three booster immunisations with TA-CIN. All but one demonstrated HPV 16-specific proliferative T-cell and/or serological responses following vaccination. Three patients additionally showed lesion shrinkage or symptom relief, but no direct correlation between clinical and immunological responses was seen.

Introduction

Vulval intraepithelial neoplasia (VIN) is an uncommon precancerous condition affecting women from the third decade of life [1]. It causes unpleasant symptoms such as itch and pain, has an appreciable risk of progression to invasive disease and is often recalcitrant to conventional therapy [2]. In the past, many women have required repeated surgical or laser excision to affected areas of the vulva, with devastating functional and psychosexual consequences [3].

The discovery that VIN is commonly associated with human papillomavirus (HPV) type 16 infection [4], [5] has provided the opportunity for an immunotherapeutic approach to its treatment. The HPV 16 E6 and E7 oncoproteins offer attractive targets for immunotherapy because they are exclusively expressed in virally infected and neoplastic, but not in normal, cells [6]. Numerous animal models have shown that the induction of E6- and/or E7-specific T-cells by vaccination can effectively control established tumours (reviewed in [7]), and several vaccine candidates are now being tested in early phase clinical trials. Two such vaccines are TA-HPV and TA-CIN, developed by Xenova Research. TA-HPV is a live recombinant vaccinia virus encoding modified HPV 16 and 18 E6 and E7 oncoproteins [8]. Phase I/II studies of this vaccine in patients with advanced cervical cancer [9], early stage cervical cancer [10] and high grade CIN (reviewed in [11]) have demonstrated both safety and immunogenicity. TA-CIN is a recombinant HPV 16 L2E6E7 fusion protein which has been shown to induce HPV 16-specific T-cell responses in a pre-clinical mouse model [12] and in a phase I trial of healthy volunteers [13].

We have previously reported a phase II trial of TA-HPV in 18 women with HPV 16-positive high grade VIN [14]. Twelve women showed clinical improvement, as defined by lesion shrinkage and/or symptom relief, following immunisation. Vaccine immunogenicity was established with increased HPV 16-specific T-cell responses in 13 of the 18 vaccinated women, as determined by γ-interferon ELISPOT and/or proliferation assays. Similar clinical and T-cell responses were reported in a separate trial by Baldwin et al. [15]. In general, the boosted HPV-specific immunity was only detectable transiently in the peripheral blood at 4–8 weeks following immunisation. This may be due to primed HPV-specific lymphocytes homing to the lesion. If long-term cure depends on sustained systemic anti-HPV immunity, however, a single vaccination may not be sufficient. While a second vaccination with TA-HPV did not confer any additional immunological benefit in women with early cervical cancer [10], preclinical studies have indicated that a prime-boost strategy of TA-HPV administered in combination with TA-CIN results in enhanced immunogenicity compared with the use of either agent alone [12].

In the present study, 10 women with HPV 16-positive high grade VIN received three booster vaccinations with TA-CIN following their priming immunisation with TA-HPV 7–15 months earlier. This is the first report of a prime-boost vaccination strategy used to treat HPV-associated neoplastic disease. The aim was to determine whether the use of TA-CIN in women previously primed with TA-HPV was associated with enhanced HPV-specific immunity and further clinical improvement.