Developments in therapeutic human papillomavirus vaccination.

Much progress has been made in the prevention and therapy of premalignant and malignant dysplasia caused by human papillomavirus by encouraging screening programs and recently by introducing preventive vaccines. To further reduce the worldwide burden of HPV-associated cancer supplementation of the established therapies with immunotherapeutic methods would have the potential for significant impact. Dysplastic epithelial lesions and cancer of the anogenital and the oropharyngeal region show strong association with HPV. Therefore cervical carcinoma and HPV-associated squamous cell carcinoma of the head and neck differ from most other malignancies in that they harbour HPV-derived antigens. Expression of the viral oncogenes is mandatory to maintain the cancerous phenotype. These antigens are unique to the tumour and attractive targets for "proof of concept" studies in the development of therapeutic vaccines showing the general applicability of tumour vaccination and prove the correlation of immune response and clinical response. To date numerous clinical trials have been performed with candidate vaccines predominantly testing the efficacy for cervical cancer and its precursors. Although a naturally induced anti-HPV T cell response in patients was shown, clinical success of therapeutic vaccines was sparse. This may be attributed to immunosuppression, immunoselection, and immunoediting by the tumour cells. Factors of the individual that led to the failure of autonomous clearance of the initial infection may also contribute. Overriding this failure, reversing immunosuppression and application of vaccines in early stages of the disease is the key task for the future. The aim of this article is to summarize recent developments of therapeutic vaccines and discuss obstacles that hinder their success.