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Enantiospecific adjuvant activity of cationic lipid DOTAP in cancer vaccine

Abstract

Commercially available DOTAP is a racemic mixture of two enantiomers. The adjuvanticity of each isomer was examined using a peptide/lipid complex as a therapeutic vaccine in an established murine cervical cancer model. This simple vaccine consists of a cationic lipid (DOTAP) and a major histocompatibility complex (MHC) class I–restricted epitope of the Human Papillomavirus (HPV) 16 protein E7. Dose-dependent tumor regression experiments have been completed for racemic DOTAP/E7, (R)-DOTAP/E7 and (S)-DOTAP/E7. Tumor-bearing mice treated with (R)-DOTAP/E7 complexes have shown tumor regression in a dose-dependent manner comparable to those mice treated with a racemic DOTAP with E7 peptide. These data are supported by IFN-γ production by CD8+ splenocytes, in vivo cytotoxic T-lymphocytes (CTL) response, CD8+ tumor-infiltrating lymphocytes (TIL), and IFN-γ production by CD8+ TIL in (R)-DOTAP/E7-vaccinated mice. When (S)-DOTAP/E7 is delivered, tumor progression is delayed. While IFN-γ production is absent from CD8+ splenocytes in mice vaccinated with (S)-DOTAP/E7, IFN-γ production by CD8+ TIL is present, supporting our hypothesis that (S)-DOTAP has limited activity. Activation of bone marrow-derived dendritic cells by the enantiomeric formulations has also been evaluated, as well as cytokine production and toxicity with no considerable differences between the groups. The results show the DOTAP enantiomers act differently as adjuvants in vivo, with (R)-DOTAP being more effective at stimulating a CD8+ anti-tumor response.

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Abbreviations

BMDC:

Bone marrow-derived dendritic cells

CCL2:

Chemokine C–C motif ligand 2

CFSE:

Carboxyfluorescein succinimidyl ester

(R)-DOTAP:

(R)-1,2-dioleoyl-3-trimethylammonium-propane

(S)-DOTAP:

(S)-1,2-dioleoyl-3-trimethylammonium-propane

HPV:

Human Papillomavirus

IFN-γ:

Interferon gamma

MHC:

Major histocompatibility complex

ROS:

Reactive oxygen species

TIL:

Tumor-infiltrating lymphocytes

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Acknowledgments

Angela Yang’s assistance with tissue processing and formatting of figures is greatly appreciated. This research was supported by PDS Biotechnology Corporation and by NIH grant CA129421. EAV is supported by a Pre-Doctoral Fellowship in Pharmaceutics from the PhRMA Foundation.

Conflict of interest

Grants from PDS Biotechnology Corporation and the NIH have funded this research. LH is a co-founder and on the scientific board of advisors of PDS Biotechnology Corporation, in addition to financial interests in the company. EAV, WC, and LH are named in a US pending patent on the technology described in this paper.

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Correspondence to Leaf Huang.

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Vasievich, E.A., Chen, W. & Huang, L. Enantiospecific adjuvant activity of cationic lipid DOTAP in cancer vaccine. Cancer Immunol Immunother 60, 629–638 (2011). https://doi.org/10.1007/s00262-011-0970-1

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Keywords

  • Therapeutic vaccine
  • Cervical cancer
  • Enantiomers
  • Cationic lipid