Systemic IFN-β gene therapy results in long-term survival in mice with established colorectal liver metastases

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Abstract

Most patients succumbing to colorectal cancer fail with liver-predominant metastases. To make a clinical impact in this disease, a systemic or whole-liver therapy may be required, whereas most cancer gene therapy approaches are limited in their ability to treat beyond local disease. As a preclinical model for cancer gene therapy, recombinant adenovirus containing the human IFN-β (hIFN-β) cDNA was delivered systemically in nude mouse xenograft models of human colorectal cancer liver metastases. The vector targeted hepatocytes that produced high levels of hIFN-β in the liver, resulting in a profound apoptotic response in the tumors and significant tumor regression. hIFN-β gene therapy not only resulted in improved survival and long-term cure in a micrometastatic model, but provided similar benefits in a clinically relevant gross disease model. A similar recombinant adenovirus containing the murine IFN-β (mIFN-β) cDNA also resulted in a therapeutic response and improved survival in syngeneic mouse models of colorectal cancer liver metastases. Depletion studies demonstrate a contribution of natural killer cells to this therapeutic response. The toxicity of an adenoviral vector expressing murine IFN-β in a syngeneic model is also presented. These encouraging results warrant further investigation of the use of cancer gene therapy for targeting metastatic disease.

Authors

Hiroomi Tada, David J. Maron, Eugene A. Choi, James Barsoum, Hanqin Lei, Qing Xie, Wenbiao Liu, Lee Ellis, A. David Moscioni, John Tazelaar, Stephen Fawell, Xiao Qin, Kathleen J. Propert, Alan Davis, Douglas L. Fraker, James M. Wilson, Francis R. Spitz