TCR Gene Transfer for Treating HCV-Associated Malignancies

TCR 基因转移治疗 HCV 相关恶性肿瘤

• 批准号: 9099790
• 负责人: Timothy Spear
• 金额: $ 4.9万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9099790
• 关键词: Affinity; Animal Model; Antigen Targeting; Antigens; Autologous; Avidity; Biology; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Patient; Cells; Cellular Immunity; Chronic; Chronic Hepatitis C; Cirrhosis; Clinical; Clinical Trials; Clone Cells; Code; Collaborations; Development; Disease; Disease Progression; Dose; Engineering; Epitopes; Escape Mutant; Gene Transfer; Gene-Modified; Generations; Genetic Engineering; Goals; Growth; Helper-Inducer T-Lymphocyte; Hepatitis C; Hepatitis C Therapy; Human; Human Cloning; Humoral Immunities; Immune; Immune response; Immune system; Immunity; In Vitro; Individual; Infection; Infection prevention; Interferons; Jurkat Cells; Lead; Liver Cirrhosis; Liver diseases; Malignant Neoplasms; Mediating; Medicine; Memory; Mus; Patients; Peptides; Peripheral Blood Lymphocyte; Peripheral Blood Mononuclear Cell; Phase; Population; Preventive vaccine; Primary carcinoma of the liver cells; Public Health; Retroviral Vector; Ribavirin; Sampling; Specificity; T-Cell Receptor; T-Cell Receptor Genes; T-Lymphocyte; Testing; Therapeutic; Vaccination; Variant; Viral Antigens; Viral Genome; Viral Proteins; Virus; Virus Diseases; Virus Replication; Western World; Xenograft Model; base; burden of illness; cellular engineering; design; effective therapy; improved; in vivo; in vivo Model; killings; liver transplantation; melanoma-associated antigen; mutant; neoplastic cell; novel; novel therapeutics; pathogen; public health relevance; response; success; targeted treatment; therapeutic vaccine; treatment response; tumor; tumor xenograft; vaccine development; virus related cancer

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infects approximately 3% of the world's population, often causing associated diseases including cirrhosis of the liver and hepatocellular carcinoma (HCC). With limited effective therapies and slow vaccine development, alternative approaches for treatment and prevention of infection and its associated diseases is imperative. An immune-based approach for targeted therapy utilizes adoptive T cell transfer to genetically engineer an individual's T cells to become reactive to an antigen of choice. Our lab has previously demonstrated its ability to successfully redirect peripheral blood lymphocyte (PBL)-derived T cells with retroviral vectors in order to recognize target antigens. Studies redirecting T cells to recognize melanoma- associated antigens have led to ongoing Phase I/II clinical trials for treating metastatic disease. We believe this approach can be applied to HCV infections and HCV-associated malignancies. Our lab has cloned and expressed two functional TCRs from PBL-derived T cell clones from humans capable of recognizing HCV peptides NS3:1406-1415 and NS3:1073-1081. Additionally, we have shown that these are high affinity TCRs since they have CD8-independent target cell recognition and can recognize naturally occurring mutant escape variants. We believe the approach to redirect T cells to recognize mutagenic HCV antigens may have benefits in understanding TCR biology as well as producing a clinical therapy for HCV infection and associated diseases. Based on these observations, we hypothesize that the ability of a TCR to have broad reactivity is not unique to such isolated clones and that in patients with resolved HCV infection there may exist a variety of TCRs with the capability of recognizing many epitopes of viral proteins. We also hypothesize that HCV TCR transduced T cells have the ability to recognize and kill tumor cells expressing wild type and mutant HCV antigens in vitro and can mediate regression of HCV+ tumor cells in vivo. Three specific aims have been developed to examine these hypotheses. Aim 1 will test our hypothesis that HCV reactive T cells from patients who resolved their HCV infections but not patients with HCV chronic infections express TCRs that recognize wild type and a broad spectrum of mutant HCV antigens. Aim 2 will test the hypothesis that the TCRs from HCV reactive T cells from patients who resolved their HCV infections can transfer this reactivity against mutant HCV antigens to other T cells. Aim 3 will test the hypothesis that HCV TCR transduced T cells can mediate regression of HCC tumors expressing wild type and mutant HCV antigens in mouse xenograft tumor models in vivo. Overall, this proposal will yield novel information that may lead to a better understanding of the capability of TCRs to recognize multiple mutant HCV epitopes and will aid in the development of novel therapeutics for patients with HCV-associated HCC.

描述（由申请人提供）：丙型肝炎病毒（HCV）感染约3%的世界人口，通常导致相关疾病，包括肝硬化和肝细胞癌（HCC）。由于有效疗法有限，疫苗开发缓慢，治疗和预防感染及其相关疾病的替代方法势在必行。一种基于免疫的靶向治疗方法利用过继性T细胞转移，对个体的T细胞进行基因工程改造，使其对选定的抗原产生反应。我们的实验室之前已经证明了它能够成功地用逆转录病毒载体重新定向外周血淋巴细胞（PBL）衍生的T细胞，以识别目标抗原。重新引导T细胞识别黑色素瘤相关抗原的研究已经导致正在进行的I/II期临床试验用于治疗转移性疾病。我们相信这种方法可以应用于HCV感染和HCV相关的恶性肿瘤。本实验室从人pbl衍生的T细胞克隆中克隆并表达了两种功能性tcr，它们能够识别HCV肽NS3:1406-1415和NS3:1073-1081。此外，我们已经证明这些是高亲和力的tcr，因为它们具有不依赖cd8的靶细胞识别，并且可以识别自然发生的突变逃逸变体。我们相信，引导T细胞识别诱变HCV抗原的方法可能有助于理解TCR生物学，并为HCV感染和相关疾病提供临床治疗。基于这些观察结果，我们假设TCR具有广泛反应性的能力并不是这种分离克隆所独有的，并且在HCV感染解决的患者中可能存在多种具有识别病毒蛋白许多表位能力的TCR。我们还假设HCV TCR转导的T细胞在体外具有识别和杀死表达野生型和突变型HCV抗原的肿瘤细胞的能力，并且可以介导体内HCV+肿瘤细胞的消退。为了检验这些假设，我们提出了三个具体的目标。目的1将验证我们的假设，即来自HCV感染消退患者而非慢性HCV感染患者的HCV反应性T细胞表达识别野生型和广谱突变型HCV抗原的tcr。目的2将检验来自HCV感染解决患者的HCV反应性T细胞的tcr可以将这种针对突变HCV抗原的反应性转移到其他T细胞的假设。目的3将验证HCV TCR转导的T细胞在体内小鼠异种移植肿瘤模型中介导表达野生型和突变型HCV抗原的HCC肿瘤消退的假设。总的来说，这一提议将产生新的信息，可能导致更好地理解tcr识别多种突变HCV表位的能力，并将有助于开发用于HCV相关HCC患者的新疗法。