Abstract
BackgroundApproximately 250 million people worldwide are chronically infected with hepatitis B virus (HBV) and more than half of the hepatocellular carcinoma (HCC) cases are attributed to this infection. As HCC has a high mortality rate, and current treatment options are remarkably limited, the development of new therapeutic treatment strategies is warranted.MethodsIn this study, woodchucks infected with woodchuck hepatitis virus (WHV), and with pre-existing liver tumors, were used as a model to investigate if complexes of cationic liposomes and non-coding DNA (JVRS-100) were effective in treatment of HCC.ResultsIt was observed that the high serum viral load that is present in a typical chronic WHV infection (i.e., approximately 100-fold higher than human viral loads) results in immune suppression and resistance to treatment with JVRS-100. Treatment of woodchucks with lower serum viral load that more closely matched with the viral load usually seen in human HBV infection appears a better model for immunotherapeutic development based on the responsiveness to JVRS-100 treatment. In the latter case, marked declines in WHV DNA and WHV surface antigen were determined over the 12-week treatment period and WHV markers stayed suppressed during most time points of the 12-week follow-up period. Even more remarkably, the formation of new liver tumors was not observed in woodchucks treated with a well-tolerated dose of JVRS-100, as compared to several new tumors that developed in vehicle-treated control animals.ConclusionsAlthough there was little decrease in the volumes of the liver tumors existing at the time of treatment, it is generally accepted that preventing the spread and metastasis of almost always fatal cancers such as HCC and thus, reducing it to a chronic and treatable disease can also be a successful therapeutic approach. The results in woodchucks warrant the investigation of JVRS-100 as an intervention to prevent liver cancer in patients chronically infected with HBV and at high risk for HCC development.
Highlights
250 million people worldwide are chronically infected with hepatitis B virus (HBV) and more than half of the hepatocellular carcinoma (HCC) cases are attributed to this infection
Immune responsiveness of woodchucks with increasing viral loads For determining the dependency of responsiveness to immune stimulation on serum woodchuck hepatitis virus (WHV) DNA, cytokine and T cell surface marker mRNA expression was evaluated following dosing of JVRS-100 in four age- and gendermatched chronic WHV carrier woodchucks with low (mean: 2.5 × 1010 genomic equivalents/ml) versus high viral load
Woodchucks were dosed IV once with JVRS-100 and evaluated for mRNA expression of important antiviral cytokines, such as IFN-α, IFN-γ, and Tumor necrosis factor (TNF)-alpha, and for T cell surface markers, such as CD4 and CD8 in peripheral blood mononuclear cells (PBMCs) obtained at eight hours postinjection
Summary
250 million people worldwide are chronically infected with hepatitis B virus (HBV) and more than half of the hepatocellular carcinoma (HCC) cases are attributed to this infection. As HCC has a high mortality rate, and current treatment options are remarkably limited, the development of new therapeutic treatment strategies is warranted. Chronic infection with hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC), which is the fifth most common cancer in the world and the third leading cause of cancer deaths [1, 2]. Infection with HBV is a major public health problem and is responsible for an estimated 1.2 million deaths per year worldwide. Liver cancer is fast becoming an increasing public health threat in the United States and has a five-year survival rate of less than 10%, making it one of the deadliest cancers in this country
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