Engineered lymphocytes for the treatment of hepatocellular carcinoma

描述（由申请人提供）：肝细胞癌是全球第三大癌症死亡原因，每年死亡率超过60万人。Glypican-3是一种在成人肝脏中通常沉默的膜相关硫酸肝素糖蛋白，在大约70%的肝细胞癌中重新表达。glypican-3的细胞外结构域被抗体识别，允许glypican-3特异性抗体的潜在治疗用途。使用单链可变片段（scFv）的t小体构建物，来自与t细胞受体复合体胞内信号域相连的抗体，已被用于激活淋巴细胞对抗肿瘤表面抗原，如间皮素和MUC1。在本提案中，我们建议验证利用我们实验室开发的新型glypican-3特异性scFv的工程淋巴细胞携带t体的效应能力，并为这些工程淋巴细胞的临床前测试建立必要的模型。拟进行的实验将(1)在体外验证嵌合抗原受体本身及其向肝癌患者淋巴细胞注入具有强效抗原特异性效应功能的能力；(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的早期概念研究阶段，阐明应用嵌合抗原受体技术治疗这种疾病的潜在效用，并优先考虑面向该技术治疗肝细胞癌的临床发展的未来研究。

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.