Glycopetide-Based Immunotherapy for Prophylaxis and Treatment of Mammary Adenocarcinomas
Final rept. 1 Sep 2002-31 May 2006
CALIFORNIA UNIV SAN DIEGO DEPT OF MEDICINE
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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 199707, 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 199707. 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 83440, 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 83440, 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 83440, see appendix.
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