Clinical Trials Engine Lentiviral engineered T cells for HIV

过继转移的T淋巴细胞对HIV感染有治疗前景的原理是很好的 确立了习我们的长期目标是建立慢病毒工程T细胞输注的安全性， 测试第二代转基因的安全性和提高抗病毒效果。我们的长远目标是 提醒艾滋病病毒感染者每日服用抗病毒药物的必要性。在最近完成的 在第一阶段的初步研究中，我们已经证明了单次输注慢病毒的安全性和可行性。 当给予患有晚期HAART的HIV感染受试者时， 抵抗艾滋病毒感染。到目前为止，还没有插入突变的证据，有一个受试者 病毒载量减少了基因修饰的T细胞的植入和持久性是 这是令人满意的，并表明VSV-G假型HIV为基础的慢病毒载体系统是非免疫原性的。 基于我们以前对共刺激的CD 4 T细胞的研究，我们现在假设多个 输注表达VRX 496反义env转基因的慢病毒工程化自体CD 4 T细胞 将导致持续和更高水平的植入。我们进一步假设，转基因将赋予 抗病毒作用。两个临床试验，提出了测试这些假设。首先，我们将进行多次给药 在HAART抑制病毒复制的患者中进行的I/II期研究。结构化处理 将进行中断以评估抗病毒疗效，并将使用淋巴活检来确定 工程化的CD 4 T细胞的组织运输。在试验#2中，我们将测试项目中开发的慢病毒载体 3，其表达更有效的抗病毒产物。我们将比较T细胞的相对存活率 将用第二代载体转导的细胞转化至用在 试验#1。总之，这些试验将代表慢病毒工程化T细胞用于 它们作为治疗HIV-1感染的有效抗病毒疗法的潜力。该项目相互作用 项目2和3，该项目依赖于核心A和B进行cGMP慢病毒载体生产， 用于临床级T细胞扩增和转导技术

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 insertional 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 multipledose 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