TNFα enhanced cancer gene therapy

Tumor necrosis factor alpha (TNFα) plays a key role in the control of tumor growth. Systemic application of recombinant TNFα is hampered by its high systemic toxicity dictating the need to target TNFα activity selectively to the tumor. In this project, localized antitumor activity of TNFα is achieved after systemic injection of tumor targeted polyplexes. Novel plasmid vectors with CpG free backbone and optimized promoter-enhancer combination allow high transgene expression. To harness the vessel permeabilizing properties of TNFα, gene delivery is combined with other macromolecular drugs, like liposomal doxorubicine (Caelyx®). This concept of a combined chemo-gene therapy was applied successfully not only in subcutaneously implanted syngeneic tumors, but also in mice bearing disseminated, gene marked metastases. Also human xenografts of colon carcinoma in a disseminated liver metastases model were successfully treated combining TNFα gene therapy with liposomal doxorubicine.