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则是好的 已经成立了。我们的长期目标是确定输注慢病毒工程T细胞的安全性，以及 测试第二代转基因的安全性和改善的抗病毒效果。我们的长期目标是 使感染艾滋病毒的患者不必每天服用抗病毒药物。在最近完成的一个 第一阶段的初步研究，我们已经证明了单次输注慢病毒的安全性和可行性。 工程自体CD4T细胞用于晚期HAART患者的HIV感染 抵抗艾滋病毒感染。到目前为止，还没有插入突变的证据，有一名受试者已经 经历病毒载量的减少。转基因T细胞的植入性和持久性 这表明VSV-G伪型HIV慢病毒载体系统是非免疫原性的。 基于我们之前对共刺激的CD4T细胞的研究，我们现在假设 慢病毒工程表达VRX496反义env转基因的自体CD4T细胞的输注 将导致持续和更高水平的嫁接。我们进一步假设转基因将赋予 抗病毒作用。两个临床试验被用来检验这些假说。首先，我们将执行多项承诺 HAART抑制病毒复制的患者的L/11期研究。结构化治疗 将进行阻断以评估抗病毒效果，并将使用淋巴活检来确定 基因工程的CD4T细胞的组织运输。在试验#2中，我们将测试在Project中开发的慢病毒载体 3表达了一种更有效的抗病毒产品。我们将比较T细胞的相对存活率 用第二代载体转导到用原始VRX496载体转导的细胞 试验1。这些试验将代表慢病毒工程T细胞治疗的第一次正式疗效测试。 它们有可能成为治疗HIV-1感染的一种有效的抗病毒疗法。此项目将与 对于项目2和3，该项目依赖于cGMP慢病毒载体制造和cGMP慢病毒载体的核心A和B 用于临床分级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