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慢病毒工程T细胞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）是否会提高这种疾病的免疫治疗效果。慢性丙型肝炎病毒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。干扰素- ?与利巴韦林联合用于治疗丙型肝炎病毒感染，但效果有限。为了降低全球范围内丙型肝炎病毒感染及相关疾病的发病率和死亡率，需要对丙型肝炎病毒感染者进行更有效的治疗。在这个提议中，我们将测试一个基本假设，即使用慢病毒载体技术可以创建具有HCV相关肝肿瘤细胞重定向特异性的人T细胞，并可以提供临床相关和成功的治疗方法。最终目标是开发一种新的和改进的治疗丙型肝炎相关恶性肿瘤的方法，这是一个潜在的主要公共卫生问题，约占世界人口的3%。慢病毒载体（LVs）已在艾滋病毒/艾滋病患者的i期临床试验中得到成功评估，为更广泛地应用这项技术治疗其他疾病，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，在本提案的目标1中，我们将开发表达能够识别HCV和/或肝肿瘤细胞的TCR的a和¿链的自我失活（SIN） lv。在Aim 2中，我们将与Nishimura博士的团队一起，在体内测试LVTCR转导T细胞在预防HCV诱导的肝脏肿瘤生长和治疗已建立肿瘤方面的安全性和有效性。总之，Lentigen Corp.和Nishimura博士的实验室具有独特的优势，可以首次全面评估重定向T细胞方法在HCV感染患者中产生抗HCV诱导的肝肿瘤效应，并将其应用于未来的HCV患者的临床试验中。

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.