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)，HIV-1 仍然造成相当大的医疗和经济负担，并且仍然迫切需要治愈 HIV-1。该计划的目标是建立一个免疫系统，能够抵抗 HIV-1 感染，将病毒复制控制在检测限度以下，并在没有 ART 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 T 细胞注入 HIV 感染者体内，这些 T 细胞对 HIV 感染具有抵抗力，并且可以通过嵌合抗原受体 (CAR) 识别 HIV 感染者。该联盟的主要目标是制定改善这些 T 细胞的效应功能、运输和持久性的策略。我们提案的要素是：1) 改造 HIV 特异性 T 细胞，使其具有改善的功能和持久性（项目 1，John Wherry）。该项目将使用特征良好的动物模型来寻找增强 T 细胞功能和慢性感染持续性的因素或途径。 2) 在非人类灵长类动物中模拟 HIV CAR T 细胞的运输和持久性（项目 2，Hans-Peter Kiem、Chris Peterson 和 Mike Betts）。该项目旨在了解 CAR T 细胞如何在体内运输，并探索改变这种运输以有利于 HIV 清除的方法。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) 在小鼠模型中建立 HIV 治愈联合免疫疗法模型（项目 3，Jim Riley 和 Todd Allen）。在这里，我们将探讨多种免疫治疗方法如何协同作用，促进 T 细胞对 HIV 复制的控制。4) 开发 HIV 治愈研究以测试工程化 T 细胞的临床试验引擎（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 HIV 感染者中制造工程化 T 细胞，然后采用项目 1-3 开发的最有前途的方法来进行 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，我们的计划利用现有的医学院和 CFAR 核心来促进成本分摊并避免资源重复。