Therapeutic HPV vaccination is a promising strategy for HPV-induced precancerous lesions and cancer as shown for patients with high-grade VIN lesions by us and others [14
]. The aim of this study was to examine the systemic and local HPV16-specific T-cell responses after HPV16-SLP vaccination in patients with HPV16-induced HSIL. We were able to identify enough patients within 18 months, yet we experienced problems in accrual, due to patient anxiety at having to postpone standard surgical treatment. The study was extended in time; however, the accrual stayed extremely low and it was decided to stop the study prematurely. These problems have been described before in other attempts to test potential vaccines in patients with HSIL [27
]. Overall, the inclusion rate in this study was 19 %. This was quite unexpected as the inclusion rate in our previous trials in which this vaccine was tested in patients with cancer or VIN was well over 60 % [15
]. In contrast to patients with VIN3—for whom treatment is mutilating, disfiguring and of which the effects are mostly transient as recurrences are high [15
]—this is not the case for patients with HSIL as they have no symptoms of their lesion and can be treated relatively easily by surgery. The side effects including among others swellings of 8 cm of the injection site and flu-like symptoms were expected on the basis of our earlier trials [15
]. However, though they did not bear much impact on the study in patients with VIN3, it did cause a high drop out of patients in this trial. This clearly shows that strong disparities in the side effects and benefit between the standard of care and new therapies may outweigh the potential benefits of newly tested therapeutic modalities and affect clinical testing.
This was the first placebo-controlled trial with this HPV16-SLP vaccine. Although the numbers were small, it allowed us to show that the standard care, which includes a biopsy, can induce a broad and strong HPV16-specific response. However, this response was neither associated with the production of IFNγ nor with a positive skin test. In contrast to the placebo group, all vaccinated subjects displayed a strong vaccine-induced IFNγ-associated T-cell response as measured by ex vivo IFNγ-ELISPOT. This placebo-controlled trial thus sustains our notion to use the IFNγ-ELISPOT assay to determine vaccine-induced HPV16-specific T-cell reactions. The skin test assay may be an alternative as the pattern of skin reactions found in the 2 vaccinated and 4 placebo-treated patients tested matched well the results of the IFNγ-ELISPOT assay, confirming our previous observations that they have quite similar detection rates [26
]. Notably, IFNγ-ELISPOT reactivity correlated with clinical responsiveness in our previous study in patients with vulvar lesions [15
]. Only 1 vaccinated patient (3006) showed a robust Th-1 profile at week 7 after receiving only one vaccination.
An earlier randomized blinded placebo-controlled study with E6 and E7 protein in ISCOMATRIX in HSIL patients reported stronger HPV16-specific T-cell responses in immunized subjects than in placebo recipients. No clinical effects were observed [27
]. In addition, a recent report on the use of an encapsulated plasmid DNA vaccine revealed that about half of the patients mounted a transient HPV-specific CD8 T-cell response [30
]. Furthermore, HSIL patients vaccinated with a MVA viral vector expressing HPV16 E6 and E7 as well as IL-2 displayed some clinical efficacy at 6 months but the correlation with vaccine-induced T-cell reactivity was not assessed [28
Overall, our placebo-controlled study shows that the HPV16-SLP vaccine is capable of increasing the numbers of circulating IFNγ-producing HPV16-specific T cells in patients with HSIL. These responses can be reliably detected using a DTH skin test. Importantly, motivational problems and the local and systemic side effects of the HPV16-SLP vaccine in HSIL patients must be taken into account when considering further studies in patients with premalignant lesions for whom an effective treatment is available. Future efforts should be focused on the development of a well-tolerated formulation, capable of inducing strong immune responses in patients with premalignant HPV-induced disease.