Immune Response Modification for Treatment of Hepatocellular Carcinoma

肝细胞癌治疗的免疫反应调节

基本信息

批准号：
7479565
负责人：
Jeff C Fairman
金额：
$ 25.55万
依托单位：
JUVARIS BIOTHERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-25 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7479565
关键词：
Alcohols Antineoplastic Agents Antiviral Agents Appearance Cancer Etiology Cells Cessation of life Cholesterol Chronic Cirrhosis Clinic Complex Condition DNA Data Development Disease regression Effector Cell Etiology Evaluation Event Goals Guanosine Monophosphate Hepatic Hepatitis B Virus Hepatitis C virus Hepatitis Viruses Hepatocarcinogenesis High Pressure Liquid Chromatography Hour Human Image Immune Immune response Immune system Immunity Immunotherapy Individual Infection Injury Instruction Kinetics Lamivudine Link Lipids Liver Liver diseases Liver neoplasms Malignant Neoplasms Measurement Mediating Modification Monitor Mus Natural Immunity Natural Killer Cells Nucleosides Operative Surgical Procedures Particle Size Patients Pegylated Interferon Alfa Phase Placebos Primary carcinoma of the liver cells Production Public Health Purpose Rate Research Research Personnel Rodent Route Serological Simian B disease Staging Symptoms Temperature Testing Therapeutic Therapeutic Intervention Time Toxicology Translating Translations Tumor Burden Tumor Volume Ultrasonography United States United States Food and Drug Administration Viral Viral Load result Viremia Woodchuck Woodchuck Hepatitis B Virus X-Ray Computed Tomography adefovir base complex IV cytokine entecavir in vivo intravenous administration mRNA Expression macrophage mortality neoplastic cell novel therapeutics nucleotide analog peripheral blood physical property reconstitution research study tumor tumor growth

项目摘要

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.

描述（由申请人提供）：全世界大约有 3.5 亿人是乙型肝炎病毒 (HBV) 的慢性携带者，全世界一半以上的肝细胞癌 (HCC) 病例归因于慢性 HBV 感染。由于HCC的死亡率很高，并且目前的治疗选择非常有限，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有效地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 的施用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 免疫反应；促进肿瘤生长的停止或消退。将监测接受 CLDC 治疗的慢性感染土拨鼠肿瘤生长的变化，这将通过超声检查和计算机断层扫描来确定。 HCC 抗肿瘤作用也与 HBV 病毒载量的动态变化相关。免疫增强有望减少肝脏 WHV 的产生，从而减少慢性肝病并提高接受治疗的土拨鼠的存活率。具体目标是 (1) 通过小鼠静脉注射（存在足够的免疫标记物）确定 CLDC 的稳定性特征和产品释放规格，以及 (2) 将啮齿动物信息转化为治疗 WBV 诱导的土拨鼠的肝癌。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) 诱发的 HCC 的可行治疗选择。这种治疗方法有望激活抗肿瘤 TH1 免疫反应；促进肿瘤生长的停止或消退。