Lentivirus-based Immunogene Therapy for HIV Infection

基于慢病毒的 HIV 感染免疫基因疗法

• 批准号: 7113712
• 负责人: CARL H. JUNE
• 金额: $ 193.64万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7113712
• 关键词: Lentivirus; based; Immunogene; Therapy; HIV

DESCRIPTION (provided by applicant): The central theme of the proposal is to continue testing lentiviral engineered T cells for safety and efficacy in HIV infection. This proposal continues the progress made recent years by our group in developing immune restoration for HIV using adoptive T cell transfer and the development of lentiviral vectors to engineer intrinsic HIV resistance. We have recently completed the world's first pilot test of lentiviral gene transfer in humans. Results from the first five subjects are encouraging and warrant formal study to optimize the approach under this RFA. This proposal represents a strong and productive interaction between academia and the private sector that is highly motivated in bringing lentiviral vector technology, in general, and T cell gene transfer therapy in particular, to the bedside, and to do this in a safe and rigorous fashion. The overall goal is to carefully establish the safety or our innovative clinical trials by testing laboratory-based hypotheses, while pursuing additional basic investigation of lentiviral engineering for subsequent immunogene transfer trials for HIV/AIDS. The elements of this proposal are as follows:  Clinical Trials Engine: Lentiviral Engineered T Cells for HIV (Project 1, C. June and P. Tebas). This project will test first and second generation lentiviral vectors that express anti-sense HIV for safety and efficacy and trafficking in phase l/ll trials. Effects of lentiviral engineered CD4 T cells on the host virus relationship will be determined using unique patient samples.  Lentiviral Vector Integration in the Clinic (Project 2, F. Bushman): A comprehensive evaluation of lentiviral integration will be done to predict long term safety of lentiviral engineered T cells.  Engineering Innate T Cell Resistance to HIV Infection (Project 3, J. Riley and R. Doms): Improved lentiviral vectors will be developed by targeting TRIMSa and other novel targets using zinc finger nucleases, and a SCID-hu model will be used to select an optimized vector for clinical testing. The program is supported by 3 cores: Core A, the Lentiviral GLP and GMP Vector Core; Core B, the Cell Engineering Core, and Core C, the Administrative and Biostatistics Core. Private sector interactions are established with ViRxSYS Corp. and Sangamo BioSciences, Inc. Together these studies will provide a comprehensive evaluation of the safety and antiviral efficacy of lentiviral vectors for HIIV/AIDS, and they will move the field forward by providing critical safety data for this new and exciting class of vectors. PROJECT 1: Clinical trials engine: lentiviral engineered T cells for HIV (June, C. H.) DESCRIPTION (provided by applicant): The principle that adoptively transferred T lymphocytes have therapeutic promise for HIV infection is well established. Our long range goals are to establish the safety of infusions of lentiviral engineered T cells, and to test second generation transgenes for safety and improved antiviral efficacy. Our long range objective is to obviate the need to take daily antiviral medications in patients with HIV infection. In a recently completed phase I pilot study, we have demonstrated the safety and feasibility of a single infusion of lentiviral engineered autologous CD4 T cells when administered to HIV infected subjects with late-stage, HAART resistant HIV infection. To date, there is no evidence of insert ional mutagenesis, and one subject has experienced a reduction in viral load. The engraftment and persistence of the gene-modified T cells is satisfactory and suggests that the VSV-G pseudotyped HIV-based lentiviral vector system is nonimmunogenic. Based on our previous studies of costimulated CD4 T cells, we now hypothesize that multiple infusions of lentiviral engineered autologous CD4 T cells that express the VRX496 antisense env transgene will lead to a sustained and higher level engraftment. We further hypothesize that the transgene will confer antiviral effects. Two clinical trials are proposed to test these hypotheses. First, we will perform a multiple dose phase l/ll study in patients whose viral replication is suppressed on HAART. Structured treatment interruption will be carried out to assess antiviral efficacy, and lymphoid biopsies will be used to determine tissue trafficking of the engineered CD4 T cells. In trial #2 we will test a lentiviral vector developed in project 3 that expresses a more potent antiviral product. We will compare the relative survival of the T cells transduced with the second generation vector to cells transduced with the original VRX496 vector tested in trial #1. Together, these trials will represent the first formal efficacy tests of lentiviral engineered T cells for their potential to serve as a potent antiviral therapy for treatment of HIV-1 infection. This project interacts with projects 2, and 3, and the project relies on Cores A and B for cGMP lentiviral vector manufacturing and for clinical grade T cell expansion and transduction technology.

描述（由申请人提供）：该提案的中心主题是继续测试慢病毒工程T细胞在HIV感染中的安全性和有效性。这一建议延续了近年来我们小组在利用过继性T细胞转移和慢病毒载体开发HIV内在抗性方面取得的进展。我们最近完成了世界上第一个慢病毒基因在人体内转移的试点试验。前五名受试者的结果令人鼓舞，值得正式研究以优化该RFA下的方法。这一提议代表了学术界和私营部门之间强有力的、富有成效的互动，这一互动在将慢病毒载体技术，特别是T细胞基因转移治疗，以安全和严格的方式带到床边方面有着很高的动力。总体目标是通过测试实验室假设，仔细建立我们的创新临床试验的安全性，同时为后续的HIV/AIDS免疫基因转移试验进行慢病毒工程的额外基础研究。该提案的内容如下：临床试验引擎：慢病毒工程T细胞HIV（项目1，C. June和P. Tebas）。该项目将在1 / 11期试验中测试第一代和第二代表达反义艾滋病毒的慢病毒载体的安全性、有效性和贩运情况。慢病毒工程CD4 T细胞对宿主病毒关系的影响将使用独特的患者样本来确定。慢病毒载体在临床中的整合（项目2，F. Bushman）：将对慢病毒整合进行全面评估，以预测慢病毒工程T细胞的长期安全性。工程先天T细胞抵抗HIV感染（项目3，J. Riley和R. Doms）：将利用锌指核酸酶靶向TRIMSa和其他新靶点，开发改进的慢病毒载体，并利用SCID-hu模型选择优化的载体进行临床试验。该程序由3个核心支持：核心A，慢病毒GLP和GMP载体核心；核心B是细胞工程核心，核心C是行政和生物统计学核心。私营部门与ViRxSYS公司和Sangamo生物科学公司建立了互动。这些研究将对慢病毒载体治疗艾滋病毒/艾滋病的安全性和抗病毒效果进行全面评估，并将通过为这类令人兴奋的新型载体提供关键的安全性数据，推动该领域向前发展。