Cancer gene therapy is a novel approach for treatment of malignancies resistant to more traditional modalities. Although convincing preclinical results exist, it has recently been recognized that the major limitation in clinical applications is inefficient transduction of target tissue. A promising way to overcome this problem is by modifying viruses to allow controlled replication in tumor tissue with conditionally replicating adenoviruses (CRADs). A major problem in the field of CRAD research is our inability to study host-vector interactions. Human adenoviruses do not productively replicate in mouse or other commonly used animal tissues. Further, xenograft studies are less than ideal as a syngeneic system is necessary for retaining immune competence. Importantly, studies with replicating herpes viruses have demonstrated the feasibility of immune suppression to achieve more efficient anti-tumor effect, thus, establishing the concept that immunomodulation can be synergistic with a replicating viral system. There is also abundant data that transient immune suppression increases the level and persistence of transgene expression after infection with human adenovirus. We propose a strategy for modification of a canine adenovirus to create a syngeneic CRAD for dog osteosarcoma, a tumor that frequently spontaneously develops in large dogs. Specifically, we will clone the osteocalcin promoter to control replication of canine adenovirus type 2. The novel virus will then be tested in canine osteosarcoma cell lines, xenografts and primary tumor explants. Finally, in vivo replication, biodistribution and toxicology of the vector in dogs will be performed. This is in anticipation of a clinical trial being undertaken to compare efficacy of the CRAD replication and therapeutic effect with or without immunomodulation. This approach may lead to a novel treatment for canine osteosarcoma with possible benefits for human disease. In summary, we hypothesize that a conditionally replicating canine adenovirus model can be developed for studying host-vector interactions for more effective local and distant antitumor oncolytic effects.
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