Animal Model for Adenovirus Oncolytic Vectors

DESCRIPTION (provided by applicant): Adenovirus vectors have also been evaluated for their efficacy in treating cancer. As cancer is the second leading cause of death in the U.S. and current therapeutics are not always sufficient, new cancer therapies are desired. Replication-competent oncolytic adenovirus vectors have been designed to kill cancer cells as part of their life cycle. Our laboratory has developed a series of unique oncolytic adenovirus vectors based on the overexpression of a protein named ADP. ADP promotes virus release from the cell late in infection and aids in the spread of adenovirus. Our vectors are efficacious in destroying human cancer cells in cell culture and suppressing the growth of tumors in immunodeficient (nude) mice. The human xenograft-nude mouse model is commonly used to evaluate oncolytic adenovirus vectors because the dogma holds that human adenoviruses do not replicate in animals. A more realistic animal model that is permissive or at least semi-permissive for hum,an adenovirus replication and that has an intact immune system would be of great value to the field of oncolytic adenovirus cancer gene therapy. We have identified an animal model for adenovirus with promising results. We found that adenovirus is able to infect, replicate, and spread from cell to cell in cancer cell lines of this animal, features that are critical in the treatment of cancer with adenovirus vectors. We propose to explore this animal model for oncolytic adenovirus cancer gene therapy. The goal of Specific Aim 1 is to further investigate the in vitro characteristics of adenovirus infection of cancer cell lines from this animal such as the timecourse of expression of adenovirus proteins. In addition, we will conduct cell viability assays for cells infected with ADP mutants to evaluate whether ADP functions in these animal cells. Specific Aim 2 will address the development of the animal model for adenovirus cancer gene therapy. We will inject subcutaneous tumors with vectors and evaluate the efficacy and safety of these vectors by gross pathology, immunohistochemistry, and histopathology.