Date of Award

12-2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Jeffrey C. Phillips

Committee Members

James T. Blackford, Stephen Kania, Robert Wang

Abstract

Melanomas are among the most common skin tumors in horses (second only to sarcoids), with prevalence rates reaching as high as 80% in adult gray horses. Despite the wide availability of measures of local control, there are currently no systemic therapies that can effectively prevent spread, or treat metastatic or locally advanced/non-resectable melanoma in horses. A form of gene immunotherapy based on a plasmid DNA construct containing a xenogeneic form of the antigen tyrosinase have been developed and optimized for targeting cancer in both humans and dogs; and have demonstrated significant immunoreactivity and clinical benefit in the treatment of melanocytic tumors in these species. This study describes how our group has performed all the necessary steps to extend this therapy to a new species: The horse. This project has taken this idea all the way from conceptualization to: (1) proof of target, by demonstrating tyrosinase overexpression in equine melanomas and thus supporting its role as a valid tumor antigen in this species; (2) to the identification of the best administration strategies for this vaccine; (3) to the evaluation of the vaccine’s ability to induce a tyrosinase-specific immune response in vaccinated horses, both healthy and melanoma-bearing. This last step included the first (modified) phase I dose escalation study with this immunotherapy in this species. To this objective antigen-specific humoral and cellular immunoassays optimized to tyrosinase immunoreactivity. Tyrosinase xenogeneic vaccination was able to induce a significant antigen-specific immune response, both humoral and cellular, in most of the vaccinated patients. Dose appeared, however, not to have a significant effect in this response. Toxicity data was also documented, and this DNA vaccine appears to be safe and well tolerated in horses.

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