Tumor antigen-specific T-cells and hepatocellular carcinoma

描述(由申请人提供)：在美国，由于丙型肝炎感染者的年龄、感染持续时间和疾病阶段的增加，肝细胞癌的医疗负担持续增加。肝细胞癌表达潜在的免疫原性蛋白，如甲胎蛋白和GLPICA-3。然而，病理上在肝细胞癌内或肝细胞癌周围几乎没有检测到T细胞，这表明针对这些抗原的T细胞的抗原识别、扩增、归巢和/或效应功能在体内受到了抑制。我们假设，肿瘤抗原特异性CD8+T细胞具有完整的增殖和发挥多种效应功能的能力，但在自然发展为肝细胞癌的过程中，由于肿瘤微环境的抑制，出现了严重的功能障碍。我们的目标是证明我们可以有效地从非肿瘤肝硬变患者的外周血淋巴细胞中扩增多功能肿瘤抗原特异性CD8+T细胞，最终证明在肝细胞癌发生之前启动和扩增这些T细胞可以延缓或预防肝细胞癌的发生。我们将首先通过检测肿瘤消融对肝细胞癌患者肿瘤抗原特异性CD8+T细胞的作用来探讨这一假说。通过研究抑制性共刺激阻断对肿瘤浸润性T细胞的影响及其机制。 在肿瘤内消融对肿瘤特异性T细胞的纵向影响方面，我们将准确地定义在肝癌中肿瘤诱导的T细胞抑制所涉及的关键机制。其次，我们将试图证明，针对肿瘤抗原的高功能细胞溶解CD8+效应T细胞可以从有未来肝细胞癌风险但癌症尚未发展的肝硬变患者的外周血淋巴细胞中扩增。最后，我们将评估一个基于细胞的疫苗平台，以刺激肝癌特异性T细胞，作为开发新型预防性疫苗的平台。这些研究的最终目标是开发临床前验证，以支持将基于细胞的疫苗接种转化为人类临床试验，以预防或延缓肝硬变中肝细胞癌的发展。

DESCRIPTION (provided by applicant): The medical burden of hepatocellular carcinoma continues to increase in the United States as a consequence of the progressing age, duration of infection, and thus disease stage of hepatitis C-infected individuals. Hepatocellular carcinoma has been shown to express potentially immunogenic proteins such as alpha-fetoprotein and glypican-3. However, few if any T-cells can be detected in or around HCC pathologically, suggesting that the antigen recognition, expansion, homing and/or effector function of T-cells specific for these antigens have been suppressed in vivo. We hypothesize that tumor antigen-specific CD8+ T cells with intact capacity to proliferate and exert multiple effector functions exit in cirrhotic patients but in the natural progression to hepatocellular carcinoma develop profound functional impairment due to the suppressive tumor microenvironment. Our goal is to demonstrate that we can efficiently expand polyfunctional tumor antigen-specific CD8+ T-cells from peripheral blood lymphocytes from non-tumor-bearing cirrhotic patients with the intent of ultimately proving that priming and expanding these T-cells prior to the onset of HCC may retard or prevent the onset of hepatocellular carcinoma. We will approach this hypothesis first by examining the role of tumor ablation on tumor antigen-specific CD8+ T-cells from HCC patients. By studying the effects of inhibitory co-stimulation blockade on tumor-infiltrating T-cells and the longitudinal effects of intratumoral ablation on tumor-specific T-cells, we will precisely define te critical mechanisms involved in tumor-induced T-cell suppression in HCC. Secondly, we will attempt to demonstrate that highly functional cytolytic CD8+ effector T-cells targeting tumor antigens can be expanded from peripheral blood lymphocytes of cirrhotic patients at risk for future hepatocellular carcinoma but in whom cancer has yet to develop. Lastly, we will evaluate a cell-based vaccine platform to stimulate hepatoma-specific T-cells, as a platform toward developing a novel, preventive vaccine. The ultimate goal of these studies is to develop pre-clinical validation to support translation of cell-based vaccination into human clinical trials to prevent or delay the development of hepatocellular carcinoma in cirrhosis.