Due to recent progress in the identification of tumor associated antigens, a large number of new Major Histocompatibility Class I restricted peptides have been characterized in detail over the last few years. Cytotoxic T lymphocytes (CTL) were observed against these epitopes in patients. Based on these results, several peptide based immunotherapy clinical trials have ben started worldwide. However, it has been shown that the naturally presented tumor associated peptides are not necessarily the most potent to raise an effective immune response. There are two predominant reasons for that; first the affinity of the natural epitope for the MHC molecule is usually not very high, limiting its exposition to the immune system. Second, the half life of the peptide is extremely short once injected under the skin due to protease degradation. Recent studies have proved that using peptides modified to address these two issues can form much more efficient vaccines.
The goal of this project is to develop a rational strategy to improve the known peptides to make them more suitable vaccines. Due to our local experience in melanoma, this tumor will
be the first target. However, several other malignancies will be included in this approach like colo-rectal or breast cancer for which recent tumor associated peptides have been discovered.
The theoretical basis needed to develop a rational peptide modification approach have been in part developed during my MD-PhD thesis and I intend to apply them now to clinically significant peptides. These techniques belong to molecular biophysics and bioinformatics and include homology modeling, molecular dynamics, free energy simulations and drug design methods. The development of these methodological aspects is done in collaboration with several groups at the EPFL and with international collaborations, in particular that of Martin Karplus at Harvard University. We envision to make use of simple amino-acid substitution as well as more elaborated non natural side chains design to reach our goal.
The role of these in silico predictions is to guide peptide modifications in a more effective way by selecting the best candidates among a virtual infinite number of possibilities when using non natural aminoacid modifications. The most promising peptides will be tested in vitro using CTL obtained from patients. The translational research program currently in place between the Ludwig Institute of Cancer Research and the Multidisciplinary Oncology Center of the Lausanne University Hospital (CePO) provides a direct access to patient material and, in particular, to CTL.
Once modified peptides have been validated in vitro, in vivo testing through the ongoing clinical trials of the CePO will be possible. Several modified peptides were recently included in these clinical trials. Additional peptides could be incorporated in the existing trials, without the need to redesign a complete study. This unique setup provides a very fast and efficient transfer of information from the molecular design to the patient and back.
