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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

基本信息

批准号：
9891737
负责人：
James L Riley
金额：
$ 99.66万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/9891737
关键词：
B-Lymphocytes BLR1 gene BLT mice 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 Immunity Immunotherapeutic agent Immunotherapy Individual Infection Interruption Life 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 base 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/antagonist insight integration site interest latent HIV reservoir mortality mouse model next generation novel novel strategies prevent programmed cell death protein 1 success tool trafficking tumor viral rebound

项目摘要

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CD 4 CAR T细胞的特异性修饰是否可以增强其抑制HIV的能力并减少潜伏的HIV储存库。这些修饰包括保护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CD 19 B细胞特异性CAR T协同作用，共同靶向HIV和B细胞癌症。具体而言，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，以初步数据为基础，证明CD 4 CAR T细胞在体内抑制HIV的能力。我们将利用人源化小鼠模型在体内测试这些概念，该模型从控制良好的HIV感染个体中注入T细胞，以实现以下目标：目的1：确定保护CD 4 CAR T细胞免受体内功能障碍的方法。目的2：确定提高体内CD 4 CAR T细胞频率和组织分布的方法。目的3：确定CAR T细胞共靶向HIV储库和CD 19+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CD 4 CAR T细胞将能够控制HIV并靶向HIV储库，从而深入了解实现功能性HIV治愈所需的机制。