Cervical carcinoma and several other malignancies arise as a result of persistent infection with high-risk types of human papillomavirus (HPV). Natural history studies indicate that nearly every sexually active individual will acquire at least one high-risk HPV infection during their lifetime. Fortunately, most infections are cleared by the immune system within 1-2 years of acquisition. Persistent infection only develops in about 2% of high-risk HPV infected people. The overall aim of this group is the development of a therapeutic HPV vaccine, to induce immune-mediated HPV clearance also in these patients.

Epitope Identification

Therapeutic vaccination aims to stimulate the immune system into recognizing and destroying malignant cells. Cytotoxic T cells (CTL) kill infected cells after recognizing bits of viral proteins, so-called epitopes, which are presented on human leukocyte antigen (HLA) molecules on the cell surface. There are thousands of different HLA types, all presenting different epitopes. As every human being has a different set of HLA molecules, epitopes for all major HLA groups need to be defined to generate a therapeutic cancer vaccine that is applicable to everyone regardless of the person’s HLA type.

We are currently working on the precise identification which HPV epitopes are presented on HPV-transformed tumor cells by a highly sensitive mass spectrometry (MS) approach. Only epitopes that are naturally processed and presented on these cells, and are found reproducibly on several tumor samples, are considered candidates for inclusion into a vaccine.

Our high-sensitivity MS methodology can also be used for epitope detection in other infectious diseases and malignancies. It is also capable of detecting tumor-specific mutation-derived tumor neo-epitopes, which forms a new area of interest in the lab.

Figure 1

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For the induction of robust CTL responses, and for memory formation, it is important to include T helper (Th) epitopes into vaccine formulations. Th cells have also been shown to be capable of exerting direct anti-tumor effects. Th epitopes derived from the same antigen as CTL epitopes have been observed to be superior to unspecific Th epitopes. Therefore, we are defining HPV-derived Th epitopes which are applicable in a large proportion of the population.

HPV and Antigen Processing

High-risk HPV infection changes the cellular antigen processing machinery (APM), and thus the repertoire of presented epitopes. We performed a systematic screen of all APM components in HPV-positive cells, and are currently analyzing the effects of HPV-mediated changes of single APM components on the HPV epitope repertoire presented on the cell surface.

Vaccine Formulation

Adjuvants and mode of delivery are important aspects of vaccine design. Epitopes can be administered as peptides, but also e.g. encoded in DNA minigenes or RNA constructs, or included into nanoparticle formulations. Various strategies are explored to determine the best way of delivery for inducing strong anti-HPV immune reponses.

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