Lentiviral Vectors for TCR Immunotherapy Targeted to HCV

描述（由申请人提供）：本提案的总体目标是评估使用表达能够识别丙型肝炎（HCV）诱导的肝肿瘤细胞的T细胞受体（TCR）的慢病毒工程化T细胞是否会改善该疾病的免疫治疗疗效的新概念。HCV的慢性感染可导致多种肝脏疾病，包括肝细胞癌和肝硬化。这些肝脏疾病是肝移植的主要指征。IFN-？与利巴韦林联合用于治疗HCV感染，但成功有限。为了降低全球范围内HCV感染和HCV相关疾病的发病率和死亡率，需要对HCV感染患者进行更有效的治疗。在这项提案中，我们将测试的基本假设，即与HCV相关的肝肿瘤细胞的重定向特异性的人T细胞可以通过使用慢病毒载体技术创建，并可以提供一个临床相关的和成功的治疗方法。最终目标是开发一种新的和改进的治疗丙型肝炎病毒相关的恶性肿瘤，一个潜在的主要公共卫生问题，约3%的世界人口。慢病毒载体（LV）已在HIV/AIDS患者的I期临床试验中成功评估，为更广泛地应用该技术治疗其他疾病（包括慢性感染和癌症）提供了可能性。Lentigen的合作者Michael Nishimura博士帮助开拓了过继免疫疗法，作为肝炎的潜在治疗方法。因此，在本提案的目的1中，我们将开发表达能够识别HCV和/或肝肿瘤细胞的TCR的α和β链的自失活（SIN）LV。在目标2中，我们将与Nishimura博士的团队一起测试LVTCR转导的T细胞在预防HCV诱导的肝肿瘤生长和治疗体内已建立的肿瘤中的安全性和有效性。总之，Lentigen Corp.和Nishimura博士的实验室处于独特的位置，可以提供第一个全面评估重定向T细胞方法，以在感染HCV的患者中产生抗HCV诱导的肝肿瘤效应，并将其应用于未来的临床试验中，用于这种危及生命的疾病。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to evaluate the novel concept whether using lentiviral-engineered T cells that express T cell receptor (TCR) capable of recognizing hepatitis C (HCV)-induced liver tumor cells will improve efficacy of immunotherapy for this disease. Chronic infection with HCV can lead to several liver diseases including hepatocellular carcinoma and cirrhosis. These liver diseases are the major indication for liver transplantation. IFN-? in combination with ribavirin is used to treat HCV infections with limited success. In order to reduce the worldwide morbidity and mortality from HCV infection and HCV related diseases more effective treatments for HCV infected patients are necessary. In this proposal we will test the fundamental hypothesis that human T cells with redirected specificity for HCV associated liver tumor cells can be created by using lentiviral vector technology and can offer a clinically relevant and successful therapeutic approach. The ultimate goal is the development of a novel and improved therapy for hepatitis HCV related malignancy, a potentially major public health concerns with approximately 3% of the world's population. Lentiviral vectors (LVs) have been successfully evaluated in Phase l clinical trials in patients with HIV/AIDS, offering the possibility to more broadly apply this technology for the treatment of other diseases, including chronic infections and cancer. Lentigen's collaborator Dr. Michael Nishimura has helped pioneer adoptive immunotherapy as a potential therapeutic approach for hepatitis. Therefore, in Aim 1 of this proposal we will develop self inactivating (SIN) LVs expressing a and ¿ chains of the TCR capable of recognizing the HCV and/or liver tumor cells. In Aim 2, together with Dr. Nishimura's team, we will test safety and efficacy of LVTCR transduced T cells in preventing HCV- induced liver tumor growth and treating established tumors in vivo. In summary, Lentigen Corp. and Dr. Nishimura's laboratory are uniquely positioned to provide the first comprehensive evaluation of the redirected T cell approach to generate anti-HCV induced liver tumor effects in patients infected with HCV and to apply this in a future clinical trial for patients with this life threatening disease.