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Engineered lymphocytes for the treatment of hepatocellular carcinoma

用于治疗肝细胞癌的工程化淋巴细胞

基本信息

批准号：
7874043
负责人：
David E Kaplan
金额：
$ 13.7万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7874043
关键词：
Activated Lymphocyte Address Adult Animals Antibodies Antigen Receptors Antigens BAY 54-9085 Biological Models CD8B1 gene Cancer Etiology Cell Line Cells Cessation of life Chimera organism Chronic Hepatitis C Cirrhosis Clinical Collaborations Complementary DNA Complex Cytolysis Death Rate Development Disease Effector Cell Engineering Extracellular Domain Future Glycoproteins Growth Heparan Sulfate Proteoglycan Heparitin Sulfate Hepatocyte Human Immunotherapeutic agent Immunotherapy In Vitro Incidence Individual Infection Injection of therapeutic agent Kinetics Laboratories Link Liver Liver diseases Lymphocyte Malignant Epithelial Cell Measurement Measures Membrane Memory Modeling Mucin-1 Staining Method Mus Natural Killer Cells Palliative Care Patients Pennsylvania Persons Plasmids Population Pre-Clinical Model Preclinical Testing Primary carcinoma of the liver cells Relative (related person)Research Signal Transduction Staging Surface Surface Antigens System T memory cell T-Cell Receptor Technology Testing Therapeutic Uses Transfection Treatment Efficacy United States Universities Validation Xenograft Model Xenograft procedure antigen binding autologous lymphocytes cellular transduction glypican 3 in vivo in vivo Model kinase inhibitor liver transplantation mesothelin nonalcoholic steatohepatitis novel novel strategies pre-clinical prevent public health relevance research study technology development transduction efficiency tumor tumor growth vector

项目摘要

DESCRIPTION (provided by applicant): Hepatocellular carcinoma is the third leading cause of cancer death worldwide with a death rate greater than 600,000 persons annually. Glypican-3, a membrane-associated heparan sulfate glycoprotein normally silenced in the adult liver, is re-expressed in approximately 70% of hepatocellular carcinomas. The extracellular domain of glypican-3 is recognized by antibodies, allowing for a potential therapeutic use of glypican-3-specific antibodies. T-body constructs that use single-chain variable fragments (scFv) from antibodies linked to the intracellular signaling domains of the T-cell receptor complex have been used to activate lymphocytes against surface antigens of tumors such as mesothelin and MUC1. In this proposal, we propose to validate the effector capacity of engineered lymphocytes harboring T-bodies that utilize a novel glypican-3- specific scFv developed in our laboratory and to establish the requisite models for preclinical testing of these engineered lymphocytes. The proposed experiments will (1) validate the chimeric antigen receptor itself and its capacity to imbue lymphocytes from hepatocellular carcinoma patients with potent antigen-specific effector function in vitro and (2) establish the xenograft model required for in vivo testing. These studies will address early conceptual stages of research into this novel approach to treat and/or prevent hepatocellular carcinoma, clarify the potential utility of applying chimeric antigen receptor technology for this disease, and prioritize future studies geared toward clinical development of this technology for the treatment of hepatocellular carcinoma. PUBLIC HEALTH RELEVANCE: Hepatocellular carcinoma is the third leading cause of cancer death worldwide with a death rate greater than 600,000 persons annually. Treatment options for hepatocellular carcinoma remain extremely limited for patients in whom liver transplantation is not an option. We propose to initiate the validation of a relatively novel immunotherapeutic technology not previously applied to hepatocellular carcinoma.

描述（由申请人提供）：肝细胞癌是全球癌症死亡的第三大原因，每年死亡率超过60万人。磷脂酰肌醇蛋白聚糖-3是一种膜相关硫酸乙酰肝素糖蛋白，通常在成人肝脏中沉默，在大约70%的肝细胞癌中重新表达。磷脂酰肌醇蛋白聚糖-3的胞外域可被抗体识别，从而允许磷脂酰肌醇蛋白聚糖-3特异性抗体的潜在治疗用途。使用来自与T细胞受体复合物的胞内信号传导结构域连接的抗体的单链可变片段（scFv）的T体构建体已被用于活化针对肿瘤表面抗原（如间皮素和MUC 1）的淋巴细胞。在该提案中，我们建议验证工程化淋巴细胞的效应能力，该工程化淋巴细胞携带T-体，其利用我们实验室开发的新型磷脂酰肌醇蛋白聚糖-3特异性scFv，并建立用于这些工程化淋巴细胞的临床前测试的必要模型。拟定的实验将（1）验证嵌合抗原受体本身及其在体外向肝细胞癌患者淋巴细胞灌输有效抗原特异性效应子功能的能力，以及（2）建立体内试验所需的异种移植模型。这些研究将解决这种治疗和/或预防肝细胞癌的新方法研究的早期概念阶段，阐明应用嵌合抗原受体技术治疗这种疾病的潜在效用，并优先考虑未来的研究，面向这种技术治疗肝细胞癌的临床开发。公共卫生相关性：肝细胞癌是世界范围内癌症死亡的第三大原因，每年死亡率超过60万人。肝细胞癌的治疗选择仍然非常有限的患者，肝移植是不是一个选择。我们建议启动一个相对新颖的免疫技术以前没有应用于肝细胞癌的验证。