Immune Response Modification for Treatment of Hepatocellular Carcinoma

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DESCRIPTION (provided by applicant): Approximately 350 million people worldwide are chronic carriers of hepatitis B virus (HBV) and more than half of the hepatocellular carcinoma (HCC) cases worldwide are attributed to chronic HBV infection. As HCC has a high mortality rate and current treatment options are remarkably limited, there is an urgent need for the development of new therapeutic strategies. Cationic lipid-DNA complexes (CLDC) are effective via multiple administration routes in broadly stimulating the innate immune system and serving as potent immune response modifiers. Previous in vivo studies suggest that administration of CLDC may prove to be an effective therapeutic approach for treating chronic HBV infection and hence, a potential treatment for HCC. The overall purpose of the current proposal is to determine if CLDC induction of innate immunity is a viable treatment option for woodchuck hepatitis virus (WHV)-induced HCC. This treatment approach is expected to activate an antitumoral TH1-biased immune response; facilitating arrest or regression of tumor growth. Chronically-infected woodchucks treated with CLDC will be monitored for changes in tumor growth, which will be determined by ultrasonography and computed tomography. The HCC antitumoral effect will also be correlated with kinetic changes in the HBV viral load. Immune enhancement is expected to reduce the hepatic production of WHV leading to diminished chronic liver disease and to increased survival of treated woodchucks. The specific goals are (1) to determine the stability profile and product release specifications of CLDC using intravenous administration in mice (where sufficient immunological markers exist) and (2) to translate the rodent information to interpretation of efficacy results in treatment of WBV-induced HCC in woodchucks. PUBLIC HEALTH RELEVANCE: The overall purpose of the current proposal is to determine if CLDC induction of innate immunity is a viable treatment option for woodchuck hepatitis virus (WHV)-induced HCC. This treatment approach is expected to activate an antitumoral TH1-biased immune response; facilitating arrest or regression of tumor growth.