Engineering T cells to Provide Durable Control of HIV-1 Replication

改造 T 细胞以提供 HIV-1 复制的持久控制

• 批准号: 9891732
• 负责人: James L Riley
• 金额: $ 287.15万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9891732
• 关键词: Adoptive Transfer; Animal Model; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; BLT mice; CAR T cell therapy; CD19 gene; CXCR4 gene; Cell physiology; Cells; Clinic; Clinical Trials; Combination immunotherapy; Competence; Cost Sharing; Data; Detection; Discipline; Economic Burden; Elements; Engineering; FDA approved; Future; Genetic; Genetic Engineering; Genome; Genome engineering; Goals; HIV; HIV Infections; HIV resistance; HIV-1; Hematologic Neoplasms; Highly Active Antiretroviral Therapy; Human; Immune system; Immunotherapy; In complete remission; Individual; Industry; Infection; Infection Control; Infusion procedures; Lead; Lymph; Malignant Neoplasms; Mammals; Mediating; Medical Economics; Modeling; Pathway interactions; Patients; Pattern; Phase I Clinical Trials; Process; Refractory; Research; Research Personnel; Resistance; Resources; Safety; Screening procedure; T cell response; T memory cell; T-Lymphocyte; Technology; Testing; Therapeutic; Tissues; Translating; Translations; Virus Replication; antiretroviral therapy; base; bench to bedside; bioinformatics tool; cancer immunotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; chronic infection; engineered T cells; exhaustion; experience; humanized mouse; improved; improved functioning; inhibitor/antagonist; medical schools; mouse model; nonhuman primate; novel strategies; programs; success; tool; trafficking

Despite anti-retroviral therapies (ART), HIV-1 continues to cause a considerable medical and economic burden, and there continues to be a pressing need for an HIV-1 cure. The goal of this Program is to generate an immune system that can resist HIV-1 infection, control viral replication below the limit of detection and persist at high functional competency in the absence of ART. We are currently performing a Phase I clinical trial that is infusing 10 billion T cells that have been made resistant to HIV infection and can recognize HIV infected via a chimeric antigen receptor (CAR) into HIV infected individuals. A major goal of this consortium to develop strategies that improve the effector function, trafficking and persistence of these T cells. The elements of our proposal are: 1) Engineering HIV-specific T cells that have improved function and persistence (Project 1, John Wherry). This project will use well-characterized animal models to search for factors or pathways that augment T cell function and persistence to chronic infection. 2) Modeling HIV CAR T cell trafficking and persistence in Non-Human Primates (Project 2, Hans-Peter Kiem, Chris Peterson and Mike Betts). This project seeks to understand how CAR T cells traffic throughout the body and explores ways to alter this trafficking to favor HIV clearance. Additionally, the ability of HIV CAR T cells to become tissue resident memory T cells is explored. 3) Modeling combination immunotherapy for HIV Cure in a mouse models (Project 3, Jim Riley and Todd Allen). Here, we will explore how a wide array of immunotherapy approaches synergize to promote T cell control of HIV replication.4) Clinical trials engine to develop an HIV Cure study to test engineered T cells (Project 4, Usman Azam, Pablo Tebas and Jim Hoxie). This industry led project will develop an improved process to manufacture engineered T cells from HIV infected individuals and then take the most promising approaches developed by Projects 1-3 to conduct a Phase I clinical trial. The Program is supported by 2 Cores: Core A is the administrative Core (PI, Jim Riley); Core B is the Genome Engineering Core (PI, Rick Bushman). In addition, our Program takes advantage of existing School of Medicine and CFAR Cores to promote cost sharing and avoid duplication of resources.

尽管有抗逆转录病毒疗法（ART），但艾滋病毒-1继续造成相当大的医疗和经济负担，仍然迫切需要治愈艾滋病毒-1。该计划的目标是产生一种能够抵抗HIV-1感染的免疫系统，将病毒复制控制在检测极限以下，并在没有抗逆转录病毒治疗的情况下保持高功能能力。我们目前正在进行一项I期临床试验，将100亿个抗HIV感染的T细胞注入HIV感染者体内，这些T细胞可以通过嵌合抗原受体（CAR）识别HIV感染。该联盟的主要目标是开发改善这些T细胞的效应功能、运输和持久性的策略。我们建议的要素是：1)设计具有改进功能和持久性的hiv特异性T细胞（项目1，John Wherry）。该项目将使用具有良好特征的动物模型来寻找增强T细胞功能和慢性感染持久性的因素或途径。2)模拟非人类灵长类动物的HIV CAR - T细胞运输和持久性（项目2，Hans-Peter Kiem， Chris Peterson和Mike Betts）。该项目旨在了解CAR - T细胞如何在全身运输，并探索改变这种运输的方法，以有利于清除艾滋病毒。此外，HIV CAR - T细胞成为组织常驻记忆T细胞的能力也被探索。3)在小鼠模型中模拟联合免疫疗法治疗HIV（项目3，Jim Riley和Todd Allen）。在这里，我们将探讨一系列广泛的免疫治疗方法如何协同促进T细胞控制HIV复制。4)临床试验引擎，开发HIV治愈研究，测试工程T细胞（项目4，Usman Azam， Pablo Tebas和Jim Hoxie）。这个行业主导的项目将开发一种改进的工艺，从感染艾滋病毒的个体中制造工程化T细胞，然后采用项目1-3开发的最有希望的方法进行I期临床试验。该计划由2个核心支持：核心A是行政核心（PI, Jim Riley）；核心B是基因组工程核心（PI, Rick Bushman）。此外，我们的项目利用现有的医学院和CFAR核心，促进成本分担，避免资源重复。