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JNCI Journal of the National Cancer Institute 2001 93(6):472-479; doi:10.1093/jnci/93.6.472
© 2001 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 93, No. 6, 472-479, March 21, 2001
© 2001 Oxford University Press

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Large Nontransplanted Hepatocellular Carcinoma in Woodchucks: Treatment With Adenovirus-Mediated Delivery of Interleukin 12/B7.1 Genes

Brigitte M. Pützer, Thorsten Stiewe, Florian Rödicker, Oliver Schildgen, Stefan Rühm, Olaf Dirsch, Melanie Fiedler, Uta Damen, Bud Tennant, Caren Scherer, Frank L. Graham, Michael Roggendorf

Affiliations of authors: B. M. Pützer, T. Stiewe, F. Rödicker, C. Scherer (Department of Molecular Biology [Cancer Research]), O. Schildgen, M. Fiedler, M. Roggendorf (Department of Virology), S. Rühm (Department of Diagnostic Radiology), O. Dirsch (Department of Pathology), U. Damen (Department of Experimental Surgery), University of Essen Medical School, Germany; B. Tennant, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY; F. L. Graham, Department of Biology and Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.

Correspondence to: Brigitte M. Pützer, M.D., Ph.D., Centre for Cancer Research and Cancer Therapy, Institute of Molecular Biology, University of Essen, Hufelandstr. 55, D-45122 Essen, Germany (e-mail: brigitte.puetzer{at}uni-essen.de)

Background: Cytokine-based gene therapy strategies efficiently stimulate immune responses against many established transplanted tumors, leading to rejection of the tumor. In this study, we investigated the therapeutic potential of cancer immunotherapy in a clinically more relevant model, woodchucks with primary hepatocellular carcinomas induced by woodchuck hepatitis virus. Methods: Large (2–5 cm), established intrahepatic tumors were given an injection once with 1 x 109 plaque-forming units of AdIL-12/B7.1, an adenovirus vector carrying genes for murine interleukin 12 and B7.1, or of AdEGFP, the control virus, and regression of the tumors was then monitored. Five animals were used in total. Results: In four tumor-bearing animals, the antitumor response was assessed by autopsy and histologic analysis within 1–2 weeks after treatment. In all animals treated with AdIL-12/B7.1 therapy versus AdEGFP therapy, we observed substantial tumor regression (P = .006; two-sided unpaired Student's t test) accompanied by a massive infiltration of T lymphocytes. These tumors also contained increased levels of CD4+ and CD8+ T cells and interferon gamma (IFN {gamma}). In continuously growing tumor nodules given an injection of the control virus or in nontumoral liver, no such effects (i.e., tumor regression and increased levels of CD4+ and CD8+ T cells and IFN {gamma}) were detected. In the fifth animal, monitored for long-term antitumor efficacy by magnetic resonance imaging (MRI) after intratumoral vector administration by MRI guidance, the tumor was almost completely eliminated (>=95%) 7 weeks after treatment. Conclusion: Adenovirus vector-based immunotherapy appears to be an effective treatment of large nontransplanted (orthotopic) tumors that acquire malignant characteristics in a stepwise process, reflecting the real-world scenario of hepatocellular carcinoma in humans.


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