Combination of human tumor necrosis factor alpha (hTNFα) gene delivery with gemcitabine is effective in models of pancreatic cancer

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Human tumor necrosis factor alpha (hTNFα) possesses potent anti-tumor activity, but its use is limited by the toxicity of systemic administration. We are developing a gene delivery approach of intratumoral injections of an adenoviral vector expressing hTNFα, in order to generate more hTNFα within the tumor, maximize local anti-tumor activity and avoid the systemic toxicities. TNFerade ™ is a replication deficient adenoviral vector carrying a transgene encoding hTNFα regulated by the radiation inducible promoter Egr-1 and has proved safe and effective in preclinical models. An ongoing phase III clinical trial is testing the efficacy of TNFerade™ injected intratumorally into locally advanced pancreatic cancer, followed by irradiation and chemotherapy with 5FU. An interim analysis of this trial shows a promising trend toward survival benefit. Since gemcitabine is a commonly used chemotherapeutic drug for pancreatic cancer we have explored in animal models the administration of locally administered TNFerade™ and systemic gemcitabine to determine whether gemcitabine can also induce the Egr-1 promoter and regulate local TNF release. We tested the expression of TNF from TNFerade™ in the context of gemcitabine in established pancreatic cancer cell lines (Panc-1, MiaPaca2 and AsPC1). Our results indicate a 2-20 fold induction of TNF expression, results similar to the induction previously seen by standard radiation treatment. In the pancreatic xenograft model (MiaPaca2) combined treatment was well tolerated with no deaths or substantial body weight loss. While anti-tumor activity of gemcitabine alone produced a tumor growth inhibition (TGI) of ~20% compared to control, the combination treatment with TNFerade™ and gemcitabine was highly active in tumor with a TGI of ~80%. Our results strongly suggest that combination of TNFerade™ and gemcitabine may offer an approach for the improved treatment of pancreatic cancer. Additional pre-clinical studies exploring TNFerade™ in combination with both gemcitabine and erlotinib are ongoing. Also, a phase I/II clinical trial exploring TNFerade™ as a component of first line therapy in the metastatic pancreatic cancer setting is planned.