This proposal will investigate the mechanism of action of TNFerade, a promising cancer treatment now in clinical testing. In TNFerade, the TNF coding sequence is controlled by a radiation responsive promoter, egr-1, is contained within an adenovirus vector. Direct injection of TNFerade into a tumor restricts the expression of TNFerade to the region of radiation therapy. Early but encouraging data suggests that TNFerade causes complete tumor responses in multiple tumor types and in very large lesions. These results indicate that TNFerade acts by mechanisms in addition to the direct TNF induced cytolysis of cancer cells. In the phase I portion of the SBIR grant, the hypothesis that the host immune system contributes to the anti-tumor activity of TNFerade will be tested in animal models. To date, all published reports of TNFerade in animal models involve compromised immune systems and limited TNF signal transduction. In the first specific aim, a vector will be constructed that is equivalent to TNFerade but containing a murine TNF coding sequence to allow for the full induction of host TNF receptors. The anti-tumor activity of this vector in immuno-competent (syngeneic) animals will be compared with immuno-compromised animals. In a second specific aim, induced immune responses will be measured at distant, noninjected, tumors. This feasibility study will allow more detailed analysis of the TNFerade mechanism in the phase II portion of the grant leading to improvements in the clinical testing of TNFerade and the design of follow up products with improved efficacy for treatment of cancers.
| MacGill, Randall S; Davis, Thomas A; Macko, Jennifer et al. (2007) Local gene delivery of tumor necrosis factor alpha can impact primary tumor growth and metastases through a host-mediated response. Clin Exp Metastasis 24:521-31 |
