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Genetically Modified NKT Cells to Target Viral Reservoirs

转基因 NKT 细胞靶向病毒库

基本信息

批准号：
9908047
负责人：
Stephen Edward Braun
金额：
$ 17万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-08 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908047
关键词：
Adipose tissue Adoptive Transfer Allogenic Applications Grants Autologous Autopsy Binding Biodistribution Blood CD28 gene Cell Maturation Cells Chimeric Proteins Cytotoxic T-Lymphocytes Data Dendritic Cells Exclusion Extracellular Domain Flow Cytometry Foundations Frequencies Generations Genetic Genetic Engineering Goals Gut Mucosa HIV Human Immune Immunotherapeutic agent In Vitro Infection Inflammation Infusion procedures Investigation Life Cycle Stages Link Macaca Macaca fascicularis Macaca mulatta Membrane Modification Molecular Analysis Monitor Monoclonal Antibodies Mucous Membrane Production Property Retroviral Vector SIV Signal Transduction Site Specificity T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Tissue Harvesting Tissues Viral Viral Load result Viral reservoir Viremia Virus Virus Replication antigen binding antiretroviral therapy cell killing cellular transduction chimeric antigen receptor chimeric antigen receptor T cells clinical efficacy cytokine experimental study extracellular humanized monoclonal antibodies immune activation in vivo inhibitor/antagonist lymph nodes macrophage mucosal site neoplasm immunotherapy nonhuman primate novel prevent rectal simian human immunodeficiency virus success therapeutic evaluation tool vector vector control

项目摘要

PROJECT SUMMARY HIV persistence despite long-term administration of potent viral-suppressive antiretroviral therapy (ART) remains a major impediment to HIV eradication and cure. Immunotherapeutic tools such as genetically modified T cells with chimeric antigen receptors (CAR) offer a new and potentially promising in vivo approach to specifically target and kill HIV-infected cells. The goal of this proposal is to genetically engineer anti-HIV CARs to invariant natural killer T (NKT) cells, with the aim of harnessing the immunotherapeutic potential of this unique innate T cell subset to target HIV-infected cells at tissue reservoir sites. Our specific aims are: SA#1. To evaluate in vitro expansion, signaling, and CTL activity of macaque NKT cells when transduced with CD4-CAR vectors containing Tc-specific intracellular signaling domains (NKT-CAR); and SA#2. To evaluate in vivo biodistribution, and persistence of adoptively transferred anti-HIV NKT-CARs and control Tc-CARs in macaques before and after SHIV infection.

项目总结尽管长期使用有效的病毒抑制抗逆转录病毒疗法(ART)，艾滋病毒仍持续存在仍然是根除和治愈艾滋病毒的主要障碍。免疫治疗工具，如基因携带嵌合抗原受体(CAR)的修饰T细胞提供了一种新的、有潜力的体内治疗方法专门针对和杀死感染艾滋病毒的细胞。这项提议的目标是通过基因工程来对抗艾滋病毒。 Cars到不变的自然杀伤T(NKT)细胞，目的是利用Cars的免疫治疗潜力这种独特的先天T细胞亚群以组织储存部位的HIV感染细胞为靶点。我们的具体目标是： SA#1.评价转基因猕猴NKT细胞的体外扩增、信号传递和CTL活性含有TC特异性细胞内信号域的CD4-CAR载体(NKT-CAR)；和SA#2。过继转导的抗HIV-NKT-CARS和对照TC-CARS在体内的生物分布和持久性 SIV感染前后的猕猴。