Development of DNA Vaccination Approach for Tumor Immunotargeting

Authors

Nathaniel Sangster, Lincoln UniversityFollow

Document Type

Presentation

Publication Date

8-2012

Abstract

The emergence of immunotherapy as a prominent modality to treat cancer is a crucial advancement in the fight against this devastating disease. Although DNA vaccines against cancer have not been effective in treating pre-existing tumors, this approach holds much promise particularly for the activation of immune responses to specific mutant antigens responsible for tumorigenesis. Recent studies demonstrated that Q209L point mutation in the GNAQ (and GNA11) is responsible for the development of more than 70% of uveal melanomas and pre-malignant cutaneous blue nevus in humans. Based on the epitope prediction, we hypothesized that DNA vaccination with mutant GNAQ may result in presentation of the mutant GNAQ peptide by human and mouse MHC class I and activation of the mutation specific immune response. A DNA vaccine was developed containing a plasmid encoding VP22-mutant GNAQ-PADRE fusion protein (pEF1-VP22-mtGNAQ-PADRE). To enhance vaccine efficacy, pBOOST2-mIRF7/3 plasmid encoding interferon regulatory factors 7/3 and chemokines (CCL20 and CCL21) were used along with vaccination. Three separate experimental naïve mouse groups were vaccinated with variable vaccine compositions via intradermal in vivo electroporation. Assessment of the immune response induction by IFNg ELISpot assay showed activation of the mutation specific immune response in all vaccinated groups. This analysis also demonstrated detrimental and stimulating effects of CCL20 and CCL21, respectively on the activation of mtGNAQ-specific immune response. Moreover, in all vaccinated groups we observed GNAQ-specific activation of humoral immune responses. Collectively, our studies demonstrated that mutant GNAQ-specific immune response can be induced by the enhanced DNA vaccination. This suggests potential therapeutic utility of this approach for the treatment/prophylactics of GNAQ/GNA11 uveal melanoma.

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