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

描述(申请人提供)：肝癌是世界上第五大常见癌症(每年748,000例)和第三大癌症死亡原因(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，但作为最常见的肝癌类型，肝细胞癌的发病率在过去20年里几乎增加了两倍，达到每年约20,000例。尽管乙肝疫苗在预防新的乙肝病毒感染方面取得了成功，但现有的大量乙肝病毒(3.5亿)和丙型肝炎病毒(1.7亿)患者，以及最近认识到肥胖/糖尿病成为美国肝癌的主要风险因素，表明未来几十年肝癌发病率将继续上升。不幸的是，肝癌的治疗选择有限，导致令人沮丧的17%的三年存活率。肝脏切除和移植是治疗小肿瘤的有效方法。但是，术后辅助治疗的缺失是肝切除成功的关键障碍。 结果5年内复发率约为70%。因此，迫切需要开发治疗肝细胞癌的新方法。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测，从而防止肝癌在高危人群中复发或从头发展。大约84%的肝细胞癌(但不是正常肝细胞)表达甲胎蛋白(AFP)和/或GPC3，使它们成为良好的免疫靶点。然而，它们是自身/肿瘤抗原，免疫原性较弱，不能有效地激活免疫细胞产生显著的抗肿瘤作用。在此应用程序中，我们 建议利用小鼠原位模型验证以下假设：创新的抗原工程方法将提高肝癌相关自身/肿瘤抗原AFP和GPC3的免疫原性，以创造有效的肝癌疫苗；利用基因工程肝癌疫苗的新免疫策略将诱导强大且高反应性的记忆T细胞，进行免疫监视，以预防原位肝癌。其目标是1)创造免疫原性肝癌疫苗，2)建立有效的免疫策略，3)预防自体肝癌。其结果将是有效地激活免疫系统以预防原发肝癌，并产生关键的临床前数据，这将有助于人类肝癌疫苗的开发，最终导致新的治疗方法来填补肝癌手术后处理的空白。这将极大地有利于接受肝切除术的肝癌患者，防止复发，并提供一个有吸引力的选择，以防止在生活在发展肝癌恐惧中的高危人群中发生肝癌从头开始发展。这将带来一个激进的 改变肝癌的管理方式，将癌症疫苗研究的重点从治疗转移到预防，这是疫苗最擅长的。

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.