Tumor antigen-specific T-cells and hepatocellular carcinoma

描述（由申请人提供）：由于丙型肝炎感染个体的年龄、感染持续时间以及疾病阶段的进展，美国肝细胞癌的医疗负担持续增加。肝细胞癌已被证明表达潜在的免疫原性蛋白质，如甲胎蛋白和磷脂酰肌醇蛋白聚糖-3。然而，在HCC中或其周围病理学上几乎检测不到任何T细胞，表明对这些抗原特异性的T细胞的抗原识别、扩增、归巢和/或效应子功能在体内受到抑制。我们假设，肿瘤抗原特异性CD 8 + T细胞具有完整的增殖能力，并发挥多种效应功能存在于肝细胞癌患者中，但在自然进展为肝细胞癌时，由于抑制性肿瘤微环境而发生严重的功能障碍。我们的目标是证明，我们可以有效地扩大多功能的肿瘤抗原特异性的CD 8 + T细胞从外周血淋巴细胞从非肿瘤荷瘤患者的意图，最终证明，启动和扩大这些T细胞之前，HCC的发病可能会延迟或防止肝细胞癌的发病。我们将首先通过研究肿瘤消融对HCC患者肿瘤抗原特异性CD 8 + T细胞的作用来探讨这一假设。通过研究抑制性共刺激阻断对肿瘤浸润性T细胞的影响， 为了研究肿瘤内消融对肿瘤特异性T细胞的纵向影响，我们将精确地定义HCC中肿瘤诱导的T细胞抑制中涉及的关键机制。其次，我们将试图证明，高功能的细胞溶解性CD 8+效应T细胞靶向肿瘤抗原，可以扩大从外周血淋巴细胞的肝细胞癌患者的风险，未来的肝细胞癌，但在他们的癌症尚未发展。 最后，我们将评估一种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，以预防或延迟肝硬化中肝细胞癌的发展。

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.