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

描述（由申请人提供）：肝癌是世界上第五大最常见的癌症（每年748，000例）和第三大最常见的癌症死亡原因（每年695，000例死亡）。在美国，虽然许多主要癌症的发病率正在下降，但最常见的肝癌类型肝细胞癌（HCC）的发病率在过去二十年中几乎增加了两倍，达到每年约20，000例。尽管HBV疫苗成功地预防了新的HBV感染，但现有的HBV（3.5亿）和HCV（1.7亿）患者的大量人群以及最近认识到肥胖/糖尿病成为美国HCC的主要风险因素，表明HCC发病率将在未来几十年内继续增加。不幸的是，HCC的治疗选择有限，导致3年生存率仅为17%。肝切除和肝移植是治疗小肿瘤的有效方法。但是，术后辅助治疗的缺乏是肝切除术成功的关键障碍， 5年复发率约为70%。因此，迫切需要开发用于HCC的新方法。我们的长期目标是开发肝癌疫苗，以激活患者的免疫系统进行免疫监视，从而防止肝癌复发或在高危人群中重新发展。大约84%的HCC（但不是正常肝细胞）表达甲胎蛋白（AFP），磷脂酰肌醇蛋白聚糖3（GPC 3），或两者兼而有之，使其成为极好的免疫靶点。然而，它们是自身/肿瘤抗原并且免疫原性弱，因此不能有效地激活免疫细胞以产生显著的抗肿瘤作用。在本申请中，我们 提出使用小鼠自体模型来测试以下假设：抗原工程的创新方法将增加HCC相关自身/肿瘤抗原AFP和GPC 3的免疫原性以产生有效的HCC疫苗，并且使用工程化HCC疫苗的新型免疫策略将诱导有效且高度应答的记忆T细胞，其进行免疫监视以预防自体HCC。其目的是1）创建免疫原性HCC疫苗，2）建立有效的免疫策略，3）预防原发性HCC。其结果将是有效激活免疫系统以预防原发性HCC，并产生关键的临床前数据，这将有助于开发人类HCC疫苗，最终导致新的治疗方法，以填补HCC手术后管理的差距。这将极大地受益于肝癌患者谁经历了肝切除术，防止复发，也提供了一个有吸引力的选择，以防止肝癌从头发展的高危人群谁是生活在发展肝癌的恐惧。这将带来一个激进的 HCC管理的变化，将癌症疫苗研究的重点从治疗转移到预防，这是疫苗最好的地方。

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.