Glycopetide-Based Immunotherapy for Prophylaxis and Treatment of Mammary Adenocarcinomas

Abstract

Abstract : This proposal aimed at defining the use of glycopeptides containing tumor associated carbohydrate antigens (TACA), that bind multiple MHC class I alleles, as potential preventive vaccines for carcinomas on a large scale. Our recent results (JEM 2004; 199:707, see appendix) suggest that CD8+ T cells (CTL) are capable of recognizing TACA in a conventional class I MHC-restricted fashion. TF, a disaccharide, and Tn, its immediate precursor, are TACA largely expressed in carcinomas. TF and Tn can be successfully used as T helper (Th)-independent vaccines when conjugated to designer peptide with optimal binding affinity for class I MHC molecules. TF- and Tn-specific CTL generated with this strategy are capable of recognizing TACA-expressing tumors in vitro, suggesting that glycopeptides are as effectively presented by class I MHC molecules as non-glycosylated peptides (JEM 2004; 199:707). Because the exact sequences of endogenously synthesized glycopeptides are unknown, the TACA-specific T cell repertoire elicited by carbohydrate-based vaccines is assumed to be degenerate. Here we report that mice genetically manipulated to develop TACA-expressing mammary tumors are not tolerant to glycopeptide vaccination (Figures 1 and 2, Immunol and Cell Biol., 2005; 83:440, see appendix). Moreover, we tested the immunogenicity of designer glycopeptides, capable of binding multiple MHC class I alleles (Table 1, Immunol and Cell Biol., 2005; 83:440, see appendix), as a novel approach for the development of vaccines potentially useful for vaccination of a large fraction of the general population. Our results have suggested that CTL derived from normal donors respond with high efficiency to glycopeptides in vitro, opening a new avenue for the design of prospective vaccines for cancer prevention (Table 2, Immunol and Cell Biol., 2005; 83:440, see appendix).