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

Pancreatic adenocarcinoma is an aggressive and highly lethal malignancy. Currently, gemcitabine is commonly used in patients with pancreatic cancer. However, the life expectancy of pancreatic cancer patients remains poor. We explored the possibility of increased anti-tumor activity by combining human tumor necrosis factor-alpha (hTNF-α) with current front-line therapy. Human TNF-α displays potent anti-tumor activity, but its use is limited by the toxicity of systemic administration. We developed a gene delivery approach using intratumoral injections of an adenoviral vector expressing hTNF-α, AdEgr.TNF.11D (TNFerade), to increase local concentrations of hTNF-α within the tumor, thereby maximizing local anti-tumor activity and yet minimizing the systemic toxicities. An ongoing phase III clinical trial is testing the efficacy of AdEgr.TNF.11D-injected intratumorally and combining with chemotherapy in locally advanced pancreatic cancer. In this study, we show that treatment with AdEgr.TNF.11D and gemcitabine results in a high level of hTNF-α expression in human pancreatic cancer cell lines. The combined treatment was well tolerated, highly active and produced marked delays in the growth of human pancreatic xenograft tumors relative to either agent alone. Our results strongly suggest that combination of AdEgr.TNF.11D and gemcitabine may be a potentially useful therapeutic approach for the improved treatment of pancreatic cancer.