Development of a broadly protective vaccine against HPV-induced oropharyngeal carcinoma

High-risk human papillomavirus (HPV) has been identified as the causative agent of cervical carcinoma. In recent years, a distinct subset of head and neck squamous cell carcinoma (HNSCC) has been described that is also associated with HPV. These tumors arise mostly in the oropharynx (on the lingual and palatine tonsils), and are in the vast majority HPV-16 positive. Patients with HPV-induced oropharyngeal carcinoma tend to be younger than other HNSCC patients, nonsmokers, and nondrinkers. The transforming potential of high-risk HPVs, like HPV-16, is largely a result of the function of two viral oncoproteins, E6 and E7, which functionally inactivate two human tumor-suppressor proteins, p53 and pRb, respectively. As the induction and maintenance of the malignant phenotype depends on these two oncogenic proteins, they are attractive targets for vaccination approaches. In this case, cancer cells cannot evade immune attack through antigen loss. Furthermore, unlike many other tumor-specific antigens, E6 and E7 are completely foreign viral proteins, therefore self-tolerance is not an issue. It is known from studies on spontaneously regressing HPV-induced lesions, and from HPV prevalence in immunosuppressed and HIV-infected patients, that cell-mediated immune responses are crucial in clearing established HPV infection. Various forms of vaccines targeting T cells to E6 and E7 have already been explored, including cell-based regimens, polynucleotide vaccines, viral and bacterial vectors, and protein- or peptide-based immunogens. As E6 and E7 are oncogenic, care must be taken when administering the whole proteins. Peptide vaccination circumvents this issue, but is limited by the fact that T cell epitopes are HLA restricted, and so far have only been defined for the most prevalent HLA haplotype. This project aims at developing a peptide-based vaccine that offers protection for the entire population. To this end, a bioinformatic approach will be used to predict T cell epitopes binding to HLA supertypes covering over 95% of people. These candidates will be tested for their stimulatory potential of T cells from uninfected, HPV- exposed but healthy, and HPV-infected individuals. For vaccine formulation, the resulting peptides will be encapsulated in nanoparticles optimized for uptake by antigen presenting cells. Taken together, HPV-induced oropharyngeal cancer represents an optimal test case for active cancer immunotherapy, due to well-understood cancer pathogenesis, causative viral antigens that can be targeted by an immune response, and favorable patient characteristics. If this new approach of population-covering peptide vaccination succeeds, it could be a novel platform technology for therapeutic cancer vaccines.