Vascular disrupting agent DMXAA enhances the antitumor effects generated by therapeutic HPV DNA vaccines

J Biomed Sci. 2011 Mar 8;18(1):21. doi: 10.1186/1423-0127-18-21.

Abstract

Antigen-specific immunotherapy using DNA vaccines has emerged as an attractive approach for the control of tumors. Another novel cancer therapy involves the employment of the vascular disrupting agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA). In the current study, we aimed to test the combination of DMXAA treatment with human papillomavirus type 16 (HPV-16) E7 DNA vaccination to enhance the antitumor effects and E7-specific CD8+ T cell immune responses in treated mice. We determined that treatment with DMXAA generates significant therapeutic effects against TC-1 tumors but does not enhance the antigen-specific immune responses in tumor bearing mice. We then found that combination of DMXAA treatment with E7 DNA vaccination generates potent antitumor effects and E7-specific CD8+ T cell immune responses in the splenocytes of tumor bearing mice. Furthermore, the DMXAA-mediated enhancement or suppression of E7-specific CD8+ T cell immune responses generated by CRT/E7 DNA vaccination was found to be dependent on the time of administration of DMXAA and was also applicable to other antigen-specific vaccines. In addition, we determined that inducible nitric oxide synthase (iNOS) plays a role in the immune suppression caused by DMXAA administration before DNA vaccination. Our study has significant implications for future clinical translation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • CD8-Positive T-Lymphocytes / immunology
  • Cancer Vaccines / administration & dosage*
  • Cancer Vaccines / genetics
  • Cancer Vaccines / therapeutic use
  • Human papillomavirus 16 / genetics
  • Human papillomavirus 16 / immunology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / therapy*
  • Papillomavirus Vaccines / administration & dosage*
  • Papillomavirus Vaccines / genetics
  • Papillomavirus Vaccines / therapeutic use
  • Vaccines, DNA / administration & dosage
  • Vaccines, DNA / genetics
  • Vaccines, DNA / therapeutic use
  • Xanthones / administration & dosage*

Substances

  • Antineoplastic Agents
  • Cancer Vaccines
  • Papillomavirus Vaccines
  • Vaccines, DNA
  • Xanthones
  • vadimezan