title: Antitumor activity of a self-adjuvanting glyco-lipopeptide vaccine bearing B cell, CD4+ and CD8+ T cell epitopes.
abstract: Molecularly defined synthetic vaccines capable of inducing both antibodies and cellular anti-tumor immune responses, in a manner compatible with human delivery, are limited. Few molecules achieve this target without utilizing external immuno-adjuvants. In this study, we explored a self-adjuvanting glyco-lipopeptide (GLP) as a platform for cancer vaccines using as a model MO5, an OVA-expressing mouse B16 melanoma. A prototype B and T cell epitope-based GLP molecule was constructed by synthesizing a chimeric peptide made of a CD8(+) T cell epitope, from ovalbumin (OVA(257-264)) and an universal CD4(+) T helper (Th) epitope (PADRE). The resulting CTL-Th peptide backbones was coupled to a carbohydrate B cell epitope based on a regioselectively addressable functionalized templates (RAFT), made of four alpha-GalNAc molecules at C-terminal. The N terminus of the resulting glycopeptides (GP) was then linked to a palmitic acid moiety (PAM), obviating the need for potentially toxic external immuno-adjuvants. The final prototype OVA-GLP molecule, delivered in adjuvant-free PBS, in mice induced: (1) robust RAFT-specific IgG/IgM that recognized tumor cell lines; (2) local and systemic OVA(257-264)-specific IFN-gamma producing CD8(+) T cells; (3) PADRE-specific CD4(+) T cells; (4) OVA-GLP vaccination elicited a reduction of tumor size in mice inoculated with syngeneic murine MO5 carcinoma cells and a protection from lethal carcinoma cell challenge; (5) finally, OVA-GLP immunization significantly inhibited the growth of pre-established MO5 tumors. Our results suggest self-adjuvanting glyco-lipopeptide molecules as a platform for B Cell, CD4(+), and CD8(+) T cell epitopes-based immunotherapeutic cancer vaccines.
authors.affiliation: Laboratory of Cellular and Molecular Immunology, The Gavin S. Herbert Eye Institute, University of California Irvine, College of Medicine, Irvine, Orange, CA 92868, USA.
authors.forename: Ilham
authors.initials: I
authors.lastname: Bettahi
authors.forename: Gargi
authors.initials: G
authors.lastname: Dasgupta
authors.forename: Olivier
authors.initials: O
authors.lastname: Renaudet
authors.forename: Aziz Alami
authors.initials: AA
authors.lastname: Chentoufi
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhang
authors.forename: Dale
authors.initials: D
authors.lastname: Carpenter
authors.forename: Susan
authors.initials: S
authors.lastname: Yoon
authors.forename: Pascal
authors.initials: P
authors.lastname: Dumy
authors.forename: Lbachir
authors.initials: L
authors.lastname: BenMohamed
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use; D002460:Cell Line; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D006017:Glycolipids / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D055666:Lipopeptides / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010047:Ovalbumin / Q000378:metabolism; D011494:Protein Kinases / Q000276:immunology; D058570:TOR Serine-Threonine Kinases
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D006017:Glycolipids; D055666:Lipopeptides; D007371:Interferon-gamma; D010047:Ovalbumin; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases