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: 10165491
• 负责人: James L Riley
• 金额: $ 280.79万
• 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/10165491
• 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; 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; detection limit; 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.

尽管抗逆转录病毒疗法（ART），HI​​V-1仍会造成相当大的医疗和经济负担，并且对HIV-1治疗的迫切需求继续。该程序的目的是生成一种可以抵抗HIV-1感染的免疫系统，在没有ART的情况下，控制病毒复制以下，以低于检测极限，并在高功能能力下持续存在。我们目前正在进行一项I期临床试验，该试验正在注入100亿T细胞，该试验已使HIV感染具有抗药性，并且可以通过嵌合抗原受体（CAR）识别HIV感染的HIV感染个体。该财团的主要目标是制定改善这些T细胞效应子功能，运输和持久性的策略。我们提案的要素是：1）具有改善功能和持久性的工程HIV特异性T细胞（项目1，John Wherry）。该项目将使用良好的动物模型来寻找增加T细胞功能并持续到慢性感染的因素或途径。 2）对非人类灵长类动物的HIV CAR T细胞运输和持久性进行建模（Project 2，Hans-Peter Kiem，Chris Peterson和Mike Betts）。该项目试图了解汽车T细胞如何在整个人体中流动，并探索改变这种贩运的方法以支持HIV清除。此外，还探索了HIV CAR T细胞成为组织驻留记忆T细胞的能力。 3）在小鼠模型中为HIV治疗的建模组合免疫疗法（Project 3，Jim Riley和Todd Allen）。在这里，我们将探索各种各样的免疫疗法如何协同化以促进HIV复制的T细胞控制。4）临床试验引擎，以开发一项HIV治疗研究以测试工程T细胞（Project 4，Usman Azam，Pablo Tebas和Jim Hoxie）。这个行业领导的项目将开发改进的过程，从艾滋病毒感染的个体中生产工程的T细胞，然后采用项目1-3开发的最有希望的方法来进行I期临床试验。该程序由2个核心支持：核心A是行政核心（PI，Jim Riley）； Core B是基因组工程核心（PI，Rick Bushman）。此外，我们的计划利用现有的医学学院和CFAR核心来促进成本共享并避免重复资源。