Modified CMV-specific T cells to Target HIV

修饰 CMV 特异性 T 细胞以靶向 HIV

基本信息

批准号：
9177838
负责人：
Stephen Edward Braun
金额：
$ 8.66万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-19 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9177838
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Adoptive Transfer Animal Model Animals Anti-Retroviral Agents Antigens Back Binding Biodistribution CD28 gene CD4 Positive T Lymphocytes CTL assay Cancer Model Cells Cessation of life Chimeric Proteins Clinic Clinical Clinical Trials Cytomegalovirus Cytomegalovirus Vaccines Data Disease Down-Regulation Effector Cell Extracellular Domain Generations Genes Goals HIV HIV Seropositivity HIV-1 Homing Human Immunologic Monitoring In Vitro Infection Lead Life Life Cycle Stages Link Lymphoid Tissue MHC Class I Genes Macaca mulatta Measures Mediating Membrane Methods Modeling Mutation Neoplasm Metastasis Pathogenesis Pathologic Processes Patients Peripheral Pharmacotherapy Phase Phenotype Plasma Protocols documentation Regimen Residual state Retroviral Vector SIV Signal Transduction Solid Neoplasm Specificity Study models T cell response T-Cell Depletion T-Cell Receptor T-Lymphocyte Therapeutic Therapy Evaluation Tissues Transduction Gene Translating Tumor Antigens Vaccinated Viral Viral Load result Viral Physiology Viral reservoir Viremia Virus Virus Replication antigen binding antiretroviral therapy base cellular transduction chimeric antigen receptor clinically relevant design experience extracellular gene therapy immune function improved in vitro activity in vivo inhibitor/antagonist internal control killings leukemia mouse model novel oncology public health relevance purge research study simian human immunodeficiency virus tumor vector vector-based vaccine viral fitness

项目摘要

DESCRIPTION: Infection with human immunodeficiency virus-1 (HIV-1) results in CD4+ T cell depletion. Antiretroviral therapy (ART), although effective in controlling plasma viremia, does not purge the latent or persistent reservoirs necessary to eliminate the infection. Recently, studies have demonstrated control of viral replication and decreasing viral reservoirs in 50% of rhesus vaccinated with a CMV vaccine vector. They propose that the continuous immuno surveillance of SIV by Tem cells is maintained by the persistent CMV vectors. To mimic the immuno surveillance and increase the HIV-specific CTL activity in vivo, we will genetically modify CMV- specific T cells with a chimeric antigen receptor (CAR) and follow the effects on viral reservoirs in rhesus macaque. The CARs express the CD4 extracellular domain to redirect CTL activity against HIV and intracellular T cell signaling domains to stimulate CTL functions. These "designer T cells" (dTc) target a critical step in the viral life cycle independent of MHC presentation, targeting heterogeneous viruses while avoiding the potential for viral escape. Our preliminary data (and many cancer models) show that CARs with multiple co-stimulatory signals (2nd and/or 3rd generation) have stronger activity than original (1st generation) vectors. Clinical trials with these advanced dTc have been efficacious in reducing metastatic solid tumors and leukemia. Additionally, based our preliminary studies, we will also co-transduce dTc with the potent fusion inhibitor maC46 to protect these dTc from infection. Therefore, we hypothesize that CMV-specific T cells, when co-transduced with CD4-CAR and the fusion inhibitor, will persist in vivo based on their CMV specificity, but will be protected from infection and will targe residual/reactivated HIV+ cells. In the R21 phase, we will determine the feasibility of these experiments by measuring the in vivo anti-HIV activity of CMV-specific dTc in rhesus macaque model. We will follow a clinical scenario and treat animals with ART after SHIV infection. The effects of these CMV-specific dTc on viral load will be measured in lymphoid tissue reservoirs. Therefore, we established these critical milestones: 1) demonstrate efficient co- transduction/gene marking of CMV-specific dTc in vivo, 2) measure the distribution and functional CTL activity in vivo, and 3) measure the effects on plasma and tissue viremia. In the R33 phase, we will expand these studies to measure the effect of CMV-specific dTc expressing CD4- CAR vectors to inhibit viral replication in tissues. We will use an internal control vector as the basis for comparing proliferation and selection of the dTc. The original CD4-CAR vector with only the TCRζ the 2nd generation, and the 3rd generation CD4-CAR adding intracellular signaling domains from CD28 and 4-1BB will redirect the CMV-specific T cells towards HIV, as have been accomplished clinically in oncology. We will compare the persistence and homing, CTL activity, the selective expansion, and ultimately, the efficacy of the different vectors. Since rhesus macaque is an important animal model for HIV pathogenesis and gene therapy, the evaluation of dTc in rhesus/SHIV model will translate quickly into the clinic. The ability of dTc t control viremia in the absence of ART, especially in the rhesus/challenge model, would be a significant advancement in HIV treatment and would strongly promote a new clinical trial for dTc in HIV/AIDS.

描述：人类免疫缺陷病毒1（HIV-1）的感染导致CD4+ T细胞耗竭。抗逆转录病毒疗法（ART）虽然有效控制血浆病毒血症，但没有清除消除感染所需的潜在或持续的储藏。最近，研究表明，用CMV疫苗载体接种疫苗的50％的恒河猴对病毒复制和降低病毒储量的控制。他们认为，TEM细胞对SIV的连续免疫监视是由持续的CMV载体维持的。为了模仿免疫监测并增加体内HIV特异性CTL活性，我们将通常用嵌合抗原受体（CAR）修饰CMV特异性T细胞，并遵循鼠尾草猕猴对病毒储量的影响。汽车将CD4细胞外域表达针对HIV和细胞内T细胞信号传导域的重定向CTL活性，以刺激CTL功能。这些“设计师T细胞”（DTC）针对病毒生命周期中的关键步骤，独立于MHC表现，靶向异质性病毒，同时避免了病毒逃生的潜力。我们的初步数据（以及许多癌症模型）表明，具有多个共同刺激信号（第二代和/或第三代）的汽车比原始载体具有强大的活性。临床这些晚期DTC的试验在减少转移性实体瘤和白血病方面有效。此外，基于我们的初步研究，我们还将与有效的融合抑制剂MAC46共跨DTC，以保护这些DTC免受感染。因此，我们假设CMV特异性T细胞与CD4-车和融合抑制剂共转二个时，将基于其CMV的特异性在体内持续存在，但将受到保护，并免受感染的侵害，并将靶向残留/重新激活的HIV HIV+细胞。在R21阶段，我们将通过测量恒河猕猴模型中CMV特异性DTC的体内抗HIV活性来确定这些实验的可行性。我们将遵循临床方案，并在SHIV感染后用ART治疗动物。这些CMV特异性DTC对病毒负荷的影响将在淋巴组织储层中测量。因此，我们确定了这些关键里程碑：1）证明CMV特异性DTC在体内的有效共透介导/基因标记，2）测量体内的分布和功能性CTL活性，3）测量对血浆和组织病毒的影响。在R33阶段，我们将扩展这些研究，以测量表达CD4-CAR载体抑制组织中病毒复制的CMV特异性DTC的影响。我们将使用内部控制向量作为比较DTC的增殖和选择的基础。仅具有TCRζ的最初的CD4型载体载体，以及第三代CD4-CAR添加了CD28和4-1BB的细胞内信号传导域，将把CMV特异性T细胞重定向到HIV，就像临床上在肿瘤学上所完成的一样。我们将比较持久性和归巢，CTL活性，选择性扩展，最终是不同向量的效率。自从猕猴是HIV发病机理和基因治疗的重要动物模型，恒河类/SHIV模型中DTC的评估将迅速转化为诊所。 DTC T控制病毒血症在没有ART的情况下，尤其是在恒河猴/挑战模型中的能力将是HIV治疗方面的重大进步，并将强烈促进DTC在HIV/AIDS中的新临床试验。