Naturally occurring translational models for development of cancer gene therapy

Most cancer deaths occur from metastatic spread of cancer cells. Immunotherapy and gene therapy are appealing modalities to treat cancer, not only because tumors that are resistant to conventional treatment such as radiation and chemotherapy can be treated using immunologic and genetic approaches, but also because these modalities can reach distant metastases and tumors that are inaccessible for conventional treatment. One gene therapy-based immunologic approach that has shown preclinical promise in laboratory animals is the use of Fas ligand (FasL) gene transfer. FasL promotes tumor cell killing directly and indirectly, and it induces reliable antitumor immune responses that protect animals against subsequent tumor challenge. Yet, despite the unquestioned benefits to study mechanistic questions, factors such as size, pharmacokinetic distribution, and route of administration preclude precise extrapolation of safety data from laboratory mice to humans. We have used spontaneous cancers of dogs as intermediaries for translational studies because the size and physiology of dogs, as well as the natural history of homologous tumors in this species resemble those of humans more closely than rodent models created in the laboratory. Here, we use appendicular osteosarcoma (OS) as an example to document clinical and biological similarities between the disease in dogs and humans. Specifically, we underscore the unique properties of this model to develop therapy approaches prior to translation into clinical trials of human cancer patients.