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A simple but effective cancer vaccine consisting of an antigen and a cationic lipid

Abstract

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.

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Abbreviations

LPD:

Liposome-polycations-DNA

DLN:

Draining lymph node

Treg:

Regulatory T cell

DOTAP:

1,2-Dioleoyl-3-trimethylammonium propane

NBD-DOTAP:

1-Oleoyl-2-[6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl]-3-trimethylammonium propane

DOEPC:

1,2-Dioleoyl-sn-glycero-3-ethylphosphocholine

DOTMA:

N-[1-(2,3-Dioleyloxy)propyl] -N,N,N-trimethylammonium chloride

DOPG:

1,2-Dioleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)]

DOPC:

1,2-Dioleoyl-sn-glycero-3-phosphocholine

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Acknowledgments

This work was supported by Mary Kay Ash Charitable Foundation for women cancers. We thank Shyh-Dar Li, Histopathology Facility and Michael Hooker Microscopy Facility in the University of North Carolina at Chapel Hill for the frozen section and microscopy assistance.

Disclosures

LH has financial interest in PDS Biotechnology, Inc., which has licensed the basic intellectual properties described here.

Author information

Correspondence to Leaf Huang.

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Chen, W., Yan, W. & Huang, L. A simple but effective cancer vaccine consisting of an antigen and a cationic lipid. Cancer Immunol Immunother 57, 517–530 (2008). https://doi.org/10.1007/s00262-007-0390-4

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Keywords

  • Cancer immunotherapy
  • Cationic liposomes
  • Cervical cancer
  • CTL
  • ROS
  • Vaccine adjuvant