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：
8046329
负责人：
David E Kaplan
金额：
$ 15.95万
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/8046329
关键词：
Activated Lymphocyte Address Adult Animals Antibodies Antigen Receptors Antigens BAY 54-9085 Biological Models CD19 gene 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 prevent public health relevance research clinical testing 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）：肝细胞癌是全世界癌症死亡的第三主要原因，死亡率每年大于60万人。 Glypican-3是一种通常在成年肝脏中沉默的膜相关硫酸乙酰肝素糖蛋白，在大约70％的肝细胞癌中被重新表达。 Glypican-3的细胞外结构域通过抗体识别，可以潜在地使用Glypican-3特异性抗体。使用单链可变片段（SCFV）的T体构建体，来自与T细胞受体复合物的细胞内信号传导结构域相关的抗体，已用于激活针对肿瘤表面抗原（如间硫蛋白和MUC1）的淋巴细胞。在该提案中，我们建议验证具有T-Bodies的工程淋巴细胞的效应能力，该淋巴细胞利用了我们实验室中开发的新型Glypican-3-特异性SCFV，并为这些工程淋巴细胞的临床前测试建立必要的模型。提出的实验将（1）验证嵌合抗原受体本身，以及其在体外具有有效抗原特异性效应的功能的肝细胞癌患者中浸泡淋巴细胞的能力，并且（2）建立了In VIVO测试所需的异种移植模型。这些研究将针对这种新型方法进行研究的早期概念阶段，以治疗和/或预防肝细胞癌，阐明将嵌合抗原受体技术应用于该疾病的潜在实用性，并优先考虑将未来的研究用于该技术的临床发展，以治疗肝细胞癌的治疗。公共卫生相关性：肝细胞癌是全球癌症死亡的第三大主要原因，死亡率每年大于60万人。对于无法选择肝移植的患者，肝细胞癌的治疗选择仍然极为有限。我们建议启动对以前未应用于肝细胞癌的相对新型免疫治疗技术的验证。