Development of antitumoral multiantigenic synthetic vaccines – VacSyn

To do this, it seems particularly important to consider how the saccharide antigens are exposed to the tumor surface which is heterogenic and in constant evolution during the disease. Also, we propose to combine several osidic markers on a cyclopeptide platform to get heterogeneous clusters varying in density and composition and thus induce an immune
response against the largest population of tumors and at different stages of the disease. The synthesis of compounds combining several multifunctional structural units (sugars and peptides) is still very complex.

In our project, we have developed a chemical approach based
on the use of orthogonal «multi-click« strategies to conjugate different tumor glycosides and peptide antigens or oligonucleotides (ODN) at well-defined positions of the cyclopeptide scaffold. This methodology represents a major advance in this field since no multiantigenic molecule of this type has been described in the literature so far.

It can be extended to the synthesis of other biologically active molecules, such as anti-adhesive or diagnostic agents. Preliminary studies have highlighted the influence of both the antigen valency and composition in the recognition with antibodies.

To date, the results obtained in the frame of this this project have been published in the form of 15 papers in international peer-reviewed journals (including 1 Angew. Chemie, 2 Chem. Commun. 1 Bioconjugate Chem.)

Cancer remains the major cause of mortality worldwide. Despite declining mortality rates due to early diagnosis and multiple treatment modalities, fatal recurrences are common. Among the main treatments, standard chemotherapy still induces unacceptably high toxicity, radiotherapy treatments often kill both normal tissue and tumors while stray cancer cells sometimes escape surgery. Immunotherapy offers an attractive alternative to overcome these problems. In particular, the development of therapeutic and/or prophylactic vaccines that could treat and, ideally, protect the human population from cancers represents a challenging task. Recent researches in this field have revealed that such an antitumoral vaccine should trigger both humoral and cellular responses as well as a memory effect. This challenge can be achieved by combining, within a single molecule, a cluster of carbohydrate antigen expressed on the surface of tumors (B-cell antigen), peptides capable to stimulate both CD4+ and CD8+ T-cells (T-cell antigens) and an adjuvant. However, presumably because of synthetic difficulties, no molecule including these four elements was reported in literature until a recent study in our group. We indeed demonstrated for the first time that the synthesis of four-component vaccine candidates is not only feasible, but also that they can induce a potent and long-lasting immune response against tumors in mice without administration of external adjuvant. In the VacSyn project, we propose to capitalize on this preliminary study to prepare a new generation of multiantigenic vaccine candidates to promote multi-faced immune response against breast cancers. We propose to synthesize original vaccines containing, on a carrier molecule, a human chimeric CD4+/CD8+ T-cell peptide antigen extended at their N-terminal with a lipid adjuvant. More importantly, one important fact that is rarely considered in a vaccine design is that different carbohydrate antigens are associated with a given cancer type, and that these antigens are likely expressed at varying levels during tumor development. Therefore, we think that it is of prime importance to consider that point in the VacSyn project. We thus propose to incorporate in our vaccine candidates different carbohydrate antigens as heteroglycoclusters with high density and various compositions. Beside the synthetic challenge that represents this project, we expect that these heteroglycoclusters could activate different population of B-cells to produce Abs with multiple selectivity and that the induced Abs could target a large population of breast tumors and at different stage of the disease progression. It should be mentioned that no fully synthetic vaccine displaying different associations of TACAs, CD4+ and CD8+ peptides and immunoadjuvant has been describe so far.