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: Ilham Bettahi, Gargi Dasgupta, Olivier Renaudet, Aziz Alami Chentoufi, Xiuli Zhang, Dale Carpenter, Susan Yoon, Pascal Dumy, Lbachir BenMohamed
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 58 Issue 2 Pg. 187-200 (Feb 2009) ISSN: 1432-0851 [Electronic] Germany
• PMID: 18584174 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• Cancer Vaccines
• Epitopes, T-Lymphocyte
• Glycolipids
• Lipopeptides
• Interferon-gamma
• Ovalbumin
• Protein Kinases
• MTOR protein, human
• mTOR protein, mouse
• TOR Serine-Threonine Kinases

Topics

• Adjuvants, Immunologic
• Animals
• B-Lymphocytes (immunology)
• CD4-Positive T-Lymphocytes (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cancer Vaccines (chemistry, immunology, therapeutic use)
• Cell Line
• Cell Line, Tumor
• Epitopes, T-Lymphocyte (immunology)
• Female
• Glycolipids (immunology)
• Humans
• Interferon-gamma (metabolism)
• Lipopeptides (therapeutic use)
• Mice
• Mice, Inbred C57BL
• Molecular Structure
• Ovalbumin (metabolism)
• Protein Kinases (immunology)
• TOR Serine-Threonine Kinases