Thesis defense: Carlo Pifferi

on the December 15, 2017

At 9:00 a.m.
Carlo Pifferi from I2BM will defend his thesis : "Design and synthesis of multivalent glycoconjugates for anti-cancer immunotherapy ". His thesis is directed by Olivier RENAUDET (Director) and Nathalie BERTHET (Co-director)
Cancer is one on the leading causes of death in developed countries; although surgical resection, direct irradiation and cytotoxic chemotherapy represent nowadays the main treatment options for patients suffering with malignancies, their severe side effects paved the way for the rise in popularity of antitumoral immunotherapy. Apart from passive immunotherapy, which is comprised of antibodies or other immune system components that are made outside of the body and has been shown to be associated to potentially life threatening immune reactions, we focused our efforts towards active immunotherapy, which purpose is stimulate the patient immune system to selectively eradicate malignant cells. The identification of tumor-associated carbohydrate antigens (TACAs) on the surface of cancer cells has allowed the development of antigen-specific vaccines. It has been known for over four decades that the majority of human cancers are characterized by aberrant glycosylation. Tumor cells may over-express truncated versions of oligosaccharides, unusual terminal oligosaccharide sequences, or increase sialylation of cell-surface glycolipids and O- and N-linked glycoproteins. A truncated oligosaccharide of a glycoprotein may render a part of the peptide backbone, which is normally shielded by the glycan, more accessible to the immune system. Among the assortment of TACAs we focussed our attention on Tn and TF antigens, which can be found in membrane-bound glycoproteins like MUC-1, over-expressed in more than 90% of breast carcinomas. Although the design of such immuno-modulators still relies on empiric rules, it is noteworthy important to trigger both humoral and cellular responses, and a memory effect. This challenge can be achieved by combining, within a single molecule, carbohydrate antigen expressed on the surface of tumors (B-cell epitope), peptides capable to stimulate both CD4+ and CD8+ T-cells (T-cell epitopes) and an adjuvant, to gather immune system elements in the injection site and boost the antigen uptake. Previous studies of our research group reported for the first time the synthesis and immunological evaluation of a four-component anticancer vaccine prototype capable of inducing a long-lasting immune response in mice models. In my PhD work we aimed to synthesize TACA-based anticancer vaccine prototypes with improved immunological properties. The principles which guided our design strategies rely on (i) the importance of a high density of carbohydrate epitopes to promote a more effective antigen capture and processing by antigen-presenting cells, and (ii) the evidence of heterogenic expression patterns of TACAs during the course of the disease and among different individuals. Addressing these two aspects would provide a stronger and multifaceted immune response.

Key words: tumor-associated carbohydrate antigens (TACAs), cancer immunothereapy, click chemistry, multivalent glycoconjugates

Published on August 23, 2018

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