Table of Contents

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 our 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.

HPV and Inflammation

An inflammatory milieu changes the cellular antigen processing machinery, and thus the repertoire of presented epitopes. It is still not fully elucidated if inflammation is a co-factor in HPV-mediated malignant transformation, or if inflammation at the infection site is necessary for initiating an efficient anti-HPV T cell response. However, it has been shown that local inflammatory cytokines are beneficial for the generation of anti-HPV effector T cells.

We are therefore working on characterizing the differences in epitope presentation between HPV-infected cells that have been exposed to inflammatory stimuli, and cells that have not. We plan to investigate early HPV-induced lesions from people who mount effective immune responses. The results of these studies will contribute to the optimal (adjuvant) formulation of a therapeutic HPV vaccine.

Vaccine Formulation

Future aims are to examine various vaccine delivery and adjuvant formulations. Epitopes can be administered as peptides, but also e.g. encoded in DNA minigenes or RNA constructs. Various strategies will be explored to determine the best way of delivery.