We have shown that Fas ligand (FasL) gene therapy induces protective immune responses in rodent models. Yet, despite these unquestioned benefits to study mechanistic questions, various factors preclude precise extrapolation of safety data from rodent gene therapy studies to human trials. Hence, we have used spontaneous cancers of dogs as intermediaries for translational studies. The size and physiology of dogs, as well as the natural history of homologous tumors in these species, resemble those of humans more closely than rodent tumor models created in the laboratory. For this project, we will use a model of canine appendicular osteosarcoma (OS) to establish the safety of an adenovirus delivery vector for FasL gene therapy. Canine OS is an incurable disease that resembles the molecular features and the clinical presentation of OS in children, and which is amenable to intratumoral gene therapy. However, the disease is more prevalent in dogs, offering an efficient and clinically relevant opportunity to test new therapies and mechanistic hypotheses. A major aspect of public health significance is that this project will provide proof of principle for the development of this therapy in humans in the Phase II of this SBIR. Here, we will use a contemporary Bayesian method for dose finding that is designed to determine the differences between the probabilities of treatment efficacy and toxicity. This method can accommodate trinary or bivariate binary outcomes, as well as efficacy probabilities that may be nonmonotone in dose. Simulations can be produced to track dose-outcome scenarios that can assist in making decisions regarding dose treatment while achieving desirable efficacy-toxicity trade-offs. The study will consist of 30 dogs recruited over 18 months; subjects will be treated with intratumoral adenovirus FasL, followed by standard of care (limb amputation and adjuvant chemotherapy) after a 10 day delay. Major outcome measures will be local and systemic toxicity, with efficacy (disease free interval compared against a contemporary control population of 240 dogs treated with the same standard of care) considered as a secondary measure. Project Narrative: The immune system is designed to protect an individual from cancer or infectious agents. When it fails, disease can occur. This project will test an approach, generally termed immunotherapy, whereby a patient's immune system is strengthened such that it can now successfully respond and protect against disease. The relevance of this project to public health is that it offers an approach to treat cancer that utilizes enhancement of the patient's own defense mechanisms to fend off disease rather than subjecting them to toxic drugs. ? ? ?
| Modiano, Jaime F; Bellgrau, Donald; Cutter, Gary R et al. (2012) Inflammation, apoptosis, and necrosis induced by neoadjuvant fas ligand gene therapy improves survival of dogs with spontaneous bone cancer. Mol Ther 20:2234-43 |
