Tumor antigen-specific T-cells and hepatocellular carcinoma

肿瘤抗原特异性 T 细胞和肝细胞癌

基本信息

批准号：
8438826
负责人：
David E Kaplan
金额：
$ 33.2万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8438826
关键词：
Ablation Age Antigen-Presenting Cells Antigens B-Lymphocytes CD8B1 gene CTAG1 gene Cancer Etiology Cancer Vaccines Cells Cessation of life Cirrhosis Clinical Clinical Trials Cyclic GMP Data Dendritic Cells Detection Development Disease Funding Future Goals Hepatitis C Homing Human Immune Immunity Immunotherapy In Vitro Incidence Individual Infection Intervention Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of prostate Medical Minority Patients Peptides Peripheral Peripheral Blood Lymphocyte Population Prevention Preventive Primary carcinoma of the liver cells Proliferating Proteins Refractory Regulatory T-Lymphocyte Risk Role Signal Transduction Staging T cell response T-Cell Depletion T-Lymphocyte TNFRSF5 gene Therapeutic Time Translations Tumor Antigens United States Vaccination Vaccines Validation Work alpha-Fetoproteins base cancer prevention clinical effect design functional disability functional restoration glypican 3 hepatoma cell immunogenic in vivo liver transplantation melanoma monocyte neoplastic cell novel pre-clinical prevent prophylactic public health relevance research clinical testing success survivin tumor tumor microenvironment vaccine candidate

项目摘要

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.

描述（由申请人提供）：由于丙型肝炎感染者年龄、感染持续时间以及疾病阶段的不断增长，在美国，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，例如甲胎蛋白和磷脂酰肌醇蛋白聚糖-3。然而，在 HCC 内或周围病理学上几乎无法检测到 T 细胞，这表明对这些抗原具有特异性的 T 细胞的抗原识别、扩增、归巢和/或效应功能在体内已被抑制。我们假设肝硬化患者中存在具有完整增殖能力和发挥多种效应功能的肿瘤抗原特异性 CD8+ T 细胞，但在肝细胞癌的自然进展过程中，由于抑制性肿瘤微环境而出现严重的功能损伤。我们的目标是证明我们可以有效地从非荷瘤肝硬化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，目的是最终证明在疾病发生之前启动并扩增这些 T 细胞。 HCC 可以延缓或预防肝细胞癌的发生。我们将首先通过检查肿瘤消融对 HCC 患者肿瘤抗原特异性 CD8+ 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 T 细胞的影响以及通过瘤内消融对肿瘤特异性 T 细胞的纵向影响，我们将精确定义 HCC 中肿瘤诱导的 T 细胞抑制所涉及的关键机制。其次，我们将尝试证明，针对肿瘤抗原的高功能溶细胞性 CD8+ 效应 T 细胞可以从有未来肝细胞癌风险但尚未发展为癌症的肝硬化患者的外周血淋巴细胞中扩增。最后，我们将评估一种刺激肝癌特异性 T 细胞的细胞疫苗平台，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体临床试验，以预防或延缓肝硬化中肝细胞癌的发展。