Immune Response Modification for Treatment of Hepatocellular Carcinoma

描述（由申请人提供）：全球约有3.5亿人是慢性乙型肝炎病毒（HBV）携带者，全球超过一半的肝细胞癌（HCC）病例归因于慢性HBV感染。由于HCC死亡率高，目前的治疗方案非常有限，因此迫切需要开发新的治疗策略。阳离子脂质- dna复合物（CLDC）可通过多种给药途径广泛刺激先天免疫系统，并作为有效的免疫反应调节剂。先前的体内研究表明，CLDC可能被证明是治疗慢性HBV感染的有效治疗方法，因此是HCC的潜在治疗方法。当前提案的总体目的是确定CLDC诱导先天免疫是否是土拨鼠肝炎病毒（WHV）诱导的HCC的可行治疗选择。这种治疗方法有望激活抗肿瘤th1偏向性免疫反应；促进肿瘤生长的。用CLDC治疗的慢性感染土拔鼠将被监测肿瘤生长的变化，这将由超声检查和计算机断层扫描确定。HCC的抗肿瘤作用也将与HBV病毒载量的动力学变化相关。免疫增强有望减少肝内白喉病毒的产生，从而减少慢性肝病，并提高治疗后土拨鼠的存活率。具体目标是：(1)确定小鼠静脉给药CLDC的稳定性和产品释放规格（存在足够的免疫标记物）；(2)将啮齿动物信息转化为解释治疗wbv诱导的土拨鼠HCC的疗效结果。公共卫生相关性：当前提案的总体目的是确定CLDC诱导先天免疫是否是土拨鼠肝炎病毒（WHV）诱导的HCC的可行治疗选择。这种治疗方法有望激活抗肿瘤th1偏向性免疫反应；促进肿瘤生长的。

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.