A simple but effective cancer vaccine consisting of an antigen and a cationic lipid.
Developing a cancer vaccine with a potent adjuvant, which is safe for human use, remains to be an unmet need. In this study, we developed a simple, safe, yet efficient, peptide-based therapeutic cancer vaccine, DOTAP/E7 complex, which comprises only two molecules: a DOTAP cationic lipid and a peptide antigen derived from E7 oncoprotein of human papillomavirus (HPV) type 16. The anti-cancer activity of DOTAP/E7 against existing HPV positive TC-1 tumor was compared to that of our previous LPD/E7 formulation, which contains bacterial DNA CpG motifs. Tumor-bearing mice showed significant tumor inhibition following a single vaccination of either formulation at the optimal lipid dose, suggesting that DOTAP liposome alone can provide a potent adjuvant activity without plasmid DNA. E7 peptide formulated with DOTAP induced migration of activated dendritic cells (DC) to the draining lymph node (DLN) and efficiently generated functional antigen-specific CD8+ T lymphocyte responses. Accumulation of CD8+ tumor infiltrating T cells and apoptosis at tumor sites were observed after treatment with DOTAP/E7 complexes, which was also associated with a decreased amount of CD25(+)Foxp3(+) regulatory T cells in treated animals. Reactive oxygen species (ROS) induced by DOTAP cationic lipid in DLN revealed a plausible mechanism of the initial interaction between DC and DOTAP. An adequate amount of ROS generation was apparently required for the initiation of the vaccine mechanism; however, an overdose of DOTAP induced massive ROS production and apoptosis of DC in DLN, which led to diminished anti-cancer immunity. Overall, these results indicate that cationic lipid DOTAP alone serves as an efficient vaccine adjuvant for the induction of a therapeutic, antigen-specific anti-cancer activity.
Chen
Weihsu
W
Division of Molecular Pharmaceutics, School of Pharmacy, University of North Carolina at Chapel Hill, 2316 Kerr Hall, CB# 7360, Chapel Hill, NC 27599, USA.
Yan
Weili
W
Huang
Leaf
L
D000276:Adjuvants, Immunologic; D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D002412:Cations / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005229:Fatty Acids, Monounsaturated / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008055:Lipids / Q000276:immunology; D008081:Liposomes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000628:therapy*; D009856:Oncogene Proteins, Viral / Q000276:immunology* / Q000378:metabolism; D050725:Papillomavirus E7 Proteins; D000644:Quaternary Ammonium Compounds / Q000276:immunology* / Q000378:metabolism; D017382:Reactive Oxygen Species
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D002412:Cations; D005229:Fatty Acids, Monounsaturated; D008055:Lipids; D008081:Liposomes; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D000644:Quaternary Ammonium Compounds; D017382:Reactive Oxygen Species; C059731:oncogene protein E7, Human papillomavirus type 16; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane