Engineered lymphocytes for the treatment of hepatocellular carcinoma

描述(申请人提供)：肝细胞癌是全球第三大癌症死亡原因，每年的死亡率超过60万人。Glypcan-3是一种膜相关的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。Glypcan-3的胞外结构域可被抗体识别，从而允许Glypcan-3特异性抗体的潜在治疗用途。T小体结构使用来自与T细胞受体复合体细胞内信号域相连的抗体的单链可变区(ScFv)，已被用于激活针对肿瘤表面抗原(如Mesothelin和MUC1)的淋巴细胞。在这项建议中，我们建议验证含有T小体的工程淋巴细胞的效应器能力，并建立这些工程淋巴细胞临床前测试所需的模型。这些实验将(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注入强大的抗原特异性效应功能的能力；(2)建立体内测试所需的异种移植模型。这些研究将涉及这种治疗和/或预防肝细胞癌的新方法的早期概念阶段的研究，阐明应用嵌合抗原受体技术治疗这种疾病的潜在效用，并优先考虑未来针对该技术治疗肝细胞癌的临床开发的研究。 公共卫生相关性：肝细胞癌是全球癌症死亡的第三大原因，每年的死亡率超过60万人。对于不能选择肝移植的患者来说，肝细胞癌的治疗选择仍然非常有限。我们建议启动一项相对新颖的免疫治疗技术的验证，该技术以前并未应用于肝细胞癌。

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.