Modeling Combination Immunotherapy for HIV Cure in Humanized Mouse Models

在人源化小鼠模型中模拟联合免疫疗法治愈 HIV

• 批准号: 10617364
• 负责人: James L Riley
• 金额: $ 97.8万
• 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/10617364
• 关键词: B-Lymphocytes; BLR1 gene; BLT mice; Binding; CD19 gene; Cardiovascular Diseases; Cells; Combination immunotherapy; Data; Drug or chemical Tissue Distribution; Effectiveness; Frequencies; Functional disorder; Generations; Goals; HIV; HIV Antigens; HIV Infections; HIV-1; Immune; Immune system; Immunity; Immunotherapeutic agent; Immunotherapy; Individual; Infection; Inflammation; Interruption; Learning; Ligands; Malignant Neoplasms; Modeling; Modification; Morbidity - disease rate; Mutation; Patients; Phase I Clinical Trials; Resistance; Shock; Signal Transduction; T-Lymphocyte; Testing; Transforming Growth Factor beta; antiretroviral therapy; cancer cell; chimeric antigen receptor; chimeric antigen receptor T cells; clinical efficacy; cost; design; engineered T cells; exhaustion; genomic locus; humanized mouse; immune activation; improved; in vivo; inhibitor; insight; integration site; interest; latent HIV reservoir; manufacture; mortality; mouse model; next generation; novel; novel strategies; prevent; programmed cell death protein 1; success; synergism; tool; trafficking; tumor; viral rebound

Project 3 - Abstract Project 3 seeks to determine whether specific modifications to CD4 CAR T cells can enhance their ability to suppress HIV and reduce the latent HIV reservoir. These modifications include protecting CAR T cells from T cell exhaustion and infection, improving the frequency and tissue distribution of these cells, and ultimately exploring whether they can synergize with latency reversing agents (LRA) and CD19 B cell-specific CAR Ts to co-target HIV and B cell cancer. Specifically, we will leverage the expertise of Project 1 (prevent or reverse T cell exhaustion), Core B (preferred CAR integration sites), and Project 4 (CAR T manufacturing platform) to build upon our preliminary data demonstrating the ability of CD4 CAR T cells to suppress HIV in vivo. We will test these concepts in vivo utilizing a humanized mouse model that infuses T cells from well-controlled HIV-infected individuals to accomplish the following goals: Aim 1: Identify approaches to protect CD4 CAR T cells from dysfunction in vivo. AIM 2: Identify approaches to enhance the frequency and tissue distribution CD4 CAR T cells in vivo. Aim 3: Determine the in vivo efficacy of CAR T cells to co-target the HIV reservoir and CD19+ tumors. Therefore, utilizing a humanized mouse model of HIV infection, we hypothesize that enhanced CD4 CAR T cells will be capable of controlling HIV and targeting the HIV reservoir, providing insight into the mechanisms required to achieve a functional HIV cure

项目 3 - 摘要 项目 3 旨在确定对 CD4 CAR T 细胞的特定修饰是否可以增强其抑制 HIV 并减少潜在 HIV 储存库的能力。这些修改包括保护 CAR T 细胞免受 T 细胞耗竭和感染，改善这些细胞的频率和组织分布，并最终探索它们是否可以与潜伏期逆转剂 (LRA) 和 CD19 B 细胞特异性 CAR T 协同作用以共同靶向HIV 和 B 细胞癌。具体来说，我们将利用项目 1（预防或逆转 T 细胞耗竭）、核心 B（首选 CAR 整合位点）和项目 4（CAR T 制造平台）的专业知识，以我们证明 CD4 CAR T 能力的初步数据为基础细胞在体内抑制艾滋病毒。我们将利用人源化小鼠模型在体内测试这些概念，该模型注入来自控制良好的 HIV 感染者的 T 细胞，以实现以下目标： 目标 1：确定保护 CD4 CAR T 细胞免受体内功能障碍的方法。目标 2：确定增强 CD4 CAR T 细胞体内频率和组织分布的方法。目标 3：确定 CAR T 细胞共同靶向 HIV 储存库和 CD19+ 肿瘤的体内功效。因此，利用 HIV 感染的人源化小鼠模型，我们假设增强的 CD4 CAR T 细胞将能够控制 HIV 并靶向 HIV 储存库，从而深入了解实现功能性 HIV 治愈所需的机制