Engineering alpha fetoprotein and glypican-3 to develop hepatoma (HCC) vaccines

改造甲胎蛋白和磷脂酰肌醇蛋白聚糖 3 以开发肝癌 (HCC) 疫苗

基本信息

批准号：
8827287
负责人：
YUKAI HE
金额：
$ 32万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8827287
关键词：
Adjuvant Adjuvant Therapy Adverse effects Aftercare Animal Model Antigens Autoimmune Hepatitis CD4 Positive T Lymphocytes CD8B1 gene Cancer Etiology Cancer Vaccines Carcinogens Cells Cessation of life Computational algorithm Data Dendritic Cells Development Diabetes Mellitus Diethylnitrosamine Engineering Epitopes Excision Fright Generations Glypican Goals Health Hepatitis B Surface Antigens Hepatitis B Vaccines Hepatitis B Virus Hepatitis C Hepatitis C Prevalence Hepatitis C virus Hepatocyte Human Human Development Immune Immune Targeting Immune Tolerance Immune system Immunization Immunologic Surveillance Incidence Infection Lead Legal patent Life Liver Malignant Neoplasms Malignant neoplasm of liver Modeling Mono-S Mus Obesity Operative Surgical Procedures Outcome Patients Population Prevention Primary carcinoma of the liver cells Proteins Recombinants Recurrence Relapse Risk Factors Survival Rate T cell response T memory cell T-Lymphocyte Testing Tissues Transgenic Organisms Transplantation Tumor Antigens United States Vaccine Research Vaccines Virus-like particle Work alpha-Fetoproteins antitumor effect design exhaustion fighting high risk immunogenic immunogenicity innovation killings melanoma memory CD4 T lymphocyte neoplastic cell novel novel strategies novel vaccines pre-clinical prevent response success tumor vaccine efficacy vaccine evaluation vaccinia virus vector

项目摘要

DESCRIPTION (provided by applicant): Liver cancer is the 5th most common cancer (748,000 cases a year) and the 3rd most common cause of cancer death (695,000 deaths a year) in the world. In the United States, while the incidence of many major cancers is declining, the incidence of hepatocellular carcinoma (HCC), the most common type of liver cancer, has almost tripled over the past two decades to ~20,000 per year. Despite the success of HBV vaccines to prevent new HBV infection, the large pool of existing HBV (350 million) and HCV (170 million) patients and the recent recognition that obesity/diabetes become a major risk factor of HCC in US suggest that HCC incidence will continue increasing over next few decades. Unfortunately, treatment options for HCC are limited, contributing to the dismal 17% 3-year survival rate. Liver resection and transplantation are curative for small tumors. But, the lac of adjuvant treatments after surgery is a critical barrier to the success of liver resection, which results in ~70% 5-year recurrence rate. Thus, there is an urgent need to develop novel approaches for HCC. Our long-term goal is to develop HCC vaccines to activate patient's immune system to conduct immune surveillance and thereby prevent HCC relapse or de novo development in high risk population. Approximately 84% of HCC (but not normal hepatocytes) express alpha fetoprotein (AFP), glypican 3 (GPC3), or both, making them excellent immune targets. However, they are self/tumor antigens and weakly immunogenic, and thus cannot effectively activate immune cells to generate significant antitumor effect. In this application, we propose to use murine autochthonous models to test the hypotheses that innovative approach of antigen engineering will increase the immunogenicity of HCC-associated self/tumor antigens of AFP and GPC3 to create effective HCC vaccines and that novel immunization strategy with the engineered HCC vaccines will induce potent and highly responsive memory T cells that conduct immune surveillance to prevent autochthonous HCC. The objectives are 1) to create immunogenic HCC vaccines, 2) to establish effective immunization strategy, and 3) to prevent autochthonous HCC. The outcomes will be the effective activation of immune system to prevent autochthonous HCC and generation of critical preclinical data that will help development of human HCC vaccine, which eventually lead to new therapy to fill the gap of HCC management after surgery. This will greatly benefit HCC patients who have undergone liver resection by preventing relapse and also offer an attractive option to prevent HCC de novo development in high risk populations who are living in the fear of developing HCC. This will bring about a radical change of HCC management, shifting the focus of cancer vaccine research from therapy to prevention, which is what a vaccine does best.

描述（由申请人提供）：肝癌是世界上最常见的第五个常见癌症（每年748,000例），是世界上癌症死亡的第三个最常见原因（每年695,000例死亡）。在美国，尽管许多主要癌症的发病率正在下降，但在过去的二十年中，肝细胞癌（HCC）的发病率几乎增加了两倍，每年差不多三倍。尽管HBV疫苗在预防新的HBV感染方面取得了成功，但现有的HBV（3.5亿）和HCV（1.7亿）患者的大量库以及最近认识到，肥胖/糖尿病是美国HCC的主要危险因素，这表明HCC发病率将在未来几十年中继续增加。不幸的是，HCC的治疗选择有限，导致了17％的3年生存率。肝切除和移植可治愈小肿瘤。但是，手术后的辅助治疗的乳糖是肝切除成功的关键障碍，这是导致〜70％的5年复发率。因此，迫切需要为HCC开发新颖的方法。我们的长期目标是开发HCC疫苗，以激活患者的免疫系统以进行免疫监测，从而防止高风险人群中HCC复发或从头发展。大约84％的HCC（但不是正常的肝细胞）表达α胎儿蛋白（AFP），Glypican 3（GPC3）或两者兼而有之，使其成为极好的免疫靶标。但是，它们是自我/肿瘤抗原和弱免疫原性，因此无法有效激活免疫细胞以产生明显的抗肿瘤作用。在此应用程序中，我们建议使用鼠自发模型来测试假设，即抗原工程的创新方法将增加AFP和GPC3的HCC相关的自/肿瘤抗原的免疫原性，以创建有效的HCC疫苗，并创建有效的HCC疫苗，并与工程HCC疫苗的新型免疫接种策略可诱导有效的HCCENENCER，以防止有效的HCC造成HCC的耐受性HCC，从而促进了HCC的自动造型。目的是1）创建免疫原性HCC疫苗，2）建立有效的免疫策略，以及3）防止自动HCC。结果将是免疫系统的有效激活，以防止自动HCC和生成关键的临床前数据，这将有助于人类HCC疫苗的开发，这最终导致了新的疗法，以填补手术后HCC管理的空白。这将极大地使HCC患者通过防止复发进行肝切除，并提供有吸引力的选择，以防止生活在害怕发展HCC的高风险人群中的HCC DE NOVO DEVEMATION。这将带来激进的 HCC管理的变化，将癌症疫苗研究的重点从治疗转移到预防，这是疫苗最能做的。