Current therapuetic modalities for patients with liver metastases are clearly inadequate. To date, virtually all cancer gene therapy research using viruses have focused on replication- incompetent viruses. However, replication-competent herpes simplex virus type 1 (HSV) holds promise as a potentially effective oncolytic agent. The principal anti-tumor activity of replication-competent HSV results from viral replication within tumor cells, resulting in cell destruction, as well as production of progeny virions that can directly infect adjacent tumor cells. In addition, HSV thymidine kinase activation of the prodrug ganciclovir enhances the antitumor activity. The strategy of restricting HSV replication to cancer cells represents a novel paradigm. The hypotheses to be examined are 1) HSV can be genetically modified to restrict its replication to CEA- expressing cells; 2) Treatment of diffuse liver metastases with intrasplenic administration of HSV will result in significant tumor reduction with limited spread of viral infection; and 3) Pre-existing immunity to HSV will limit spread of viral infection without reducing anti-tumor efficacy.
In Specific Aim 1 construction of an HSV mutant (designated HSVceaalpha) will be completed. This vector is engineered such that an immediate-early gene that is critical for HSV replication is regulated by the human CEA promoter, thereby limiting HSVceaalpha replication to CEA-expressing cells. The ability of HSVceaalpha to replicate and cause cytopathic effects will be examined in primary cultures of normal human tissues, CEA- positive and CEA- negative colon carcinomas, and in human skin xenografts.
In Specific Aim 2 the efficacy and toxicity of treating liver metastases with replication-conditional HSV will be examined. Several complementary assays will be used to detect HSV replication in tumor and non-tumor tissues after intrasplenic HSV administration to mice bearing diffuse liver metastases. The effects of viral dose, systemic ganciclovir administration, and initial tumor volume on spread of viral infection and animal surivival will be measured.
In Specific Aim 3 we will analyze the effect of the host immune system on treatment of liver metastases with replication-conditional HSV. We will first examine how pre-existing immunity influences both the spread of HSV infection after treatment of liver metastases and the anti- tumor efficacy. We will subsequently examine the effect of individual components of the immune system on viral spread and anti-tumor efficacy. In concert, these studieds will provide a basis for development of clinical trials with HSV.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076183-03
Application #
6489117
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Welch, Anthony R
Project Start
2000-01-07
Project End
2003-12-31
Budget Start
2002-01-01
Budget End
2003-12-31
Support Year
3
Fiscal Year
2002
Total Cost
$385,142
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Fuchs, Bryan C; Hoshida, Yujin; Tanabe, Kenneth K (2015) Reply: To PMID 24677197. Hepatology 61:729-30
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Fuchs, Bryan C; Hoshida, Yujin; Fujii, Tsutomu et al. (2014) Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma. Hepatology 59:1577-90
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Fujii, Tsutomu; Fuchs, Bryan C; Yamada, Suguru et al. (2010) Mouse model of carbon tetrachloride induced liver fibrosis: Histopathological changes and expression of CD133 and epidermal growth factor. BMC Gastroenterol 10:79
Geevarghese, Sunil K; Geller, David A; de Haan, Hans A et al. (2010) Phase I/II study of oncolytic herpes simplex virus NV1020 in patients with extensively pretreated refractory colorectal cancer metastatic to the liver. Hum Gene Ther 21:1119-28
Kulu, Y; Dorfman, J D; Kuruppu, D et al. (2009) Comparison of intravenous versus intraperitoneal administration of oncolytic herpes simplex virus 1 for peritoneal carcinomatosis in mice. Cancer Gene Ther 16:291-7
Tanabe, Kenneth K; Lemoine, Antoinette; Finkelstein, Dianne M et al. (2008) Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis. JAMA 299:53-60

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