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）：由于年龄的进展，感染持续时间以及乙型肝炎感染的个体的疾病阶段，美国肝细胞癌的医疗负担继续增加。肝细胞癌已显示出表达潜在的免疫原性蛋白，例如α-五蛋白蛋白和Glypican-3。但是，很少有人在病理上或周围检测到任何T细胞，这表明特有的T细胞的抗原识别，扩张，归巢和/或效应子功能已在体内受到抑制。我们假设具有完整能力的肿瘤抗原特异性CD8+ T细胞，可在肝硬化患者中增殖和发挥多种效应功能，但自然而然地发展为肝细胞癌，由于抑制性肿瘤微环境而导致肝细胞癌的自然进展。 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.我们将首先通过检查肿瘤消融对HCC患者的肿瘤抗原特异性CD8+ T细胞的作用来解决这一假设。通过研究抑制性共刺激阻滞对肿瘤浸润的T细胞和肿瘤内消融对肿瘤特异性T细胞的纵向作用，我们将精确定义参与HCC中肿瘤诱导的T细胞抑制的关键机制。其次，我们将尝试证明，靶向肿瘤抗原的高功能性细胞溶液CD8+效应T细胞可以从外周血血液淋巴细胞中扩展，这些患者的肝硬化患者有可能未来的肝细胞癌的风险，但癌症尚未发育。最后，我们将评估一个基于细胞的疫苗平台来刺激肝癌特异性T细胞，作为开发新型预防性疫苗的平台。这些研究的最终目的是开发临床前验证，以支持将基于细胞的疫苗接种转化为人类临床试验的翻译，以防止或延迟肝硬化中肝细胞癌的发展。