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

Abstract

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-a) with current front-line therapy. Human TNF-a 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-a, AdEgr.TNF.11D (TNFerade), to increase local concentrations of hTNF-a 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-a 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.

Carcinoma pancreas

“…A better understanding of tumor biology resulting in new targeted agents including monoclonal antibodies targeting cell-membrane proteins like MK 0646, AMG 479, and CS 1008; small-molecule inhibitors of oncogenes like Masitinib, AZD 6244 and Sarilasib; and gene therapy with TNFerade are under various phases of trial. 26 It is important to realize that tumor microenvironment and cancer stem cells are critical components of carcinoma pancreas and need to be attacked. Pilot studies are currently under way to study pancreatic cancer stem cells.…”

Effects of Low Intensity Continuous Ultrasound (LICU) on Mouse Pancreatic Tumor Explants

“…However, the role of TNF in pancreatic tumor progression still remains controversial. While some studies demonstrated anti-tumorigenic properties of TNF [35,36], others have shown the opposite results [37,38]. The 17-fold increase, in TNF-α following LICU thus remains to be further explored.…”

Current Perspectives and Future Trends of Systemic Therapy in Advanced Pancreatic Carcinoma

“…AdEgr.TNF.11D (TNFerade) is a gene delivery strategy to increase local peritumoral TNF concentrations through intratumoral injections of an adenoviral vector expressing hTNF, in an attempt to improve local activity while minimizing systemic effects. Effectiveness in combination with gemcitabine has been demonstrated in human pancreatic xenografts (Murugesan et al, 2009). A phase III trial is currently evaluating the addition of TNFerade to 5-FU plus radiotherapy in unresectable pancreatic cancer (Stathis & Moore, 2010).…”