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：
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
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/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

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并减少潜在的HIV储量的能力。这些修饰包括保护CAR T细胞免受T细胞耗尽和感染的侵害，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 TS与共同推测的HIV和B细胞HIV和B细胞癌协同作用。具体而言，我们将利用项目1（预防或反向T细胞耗尽），Core B（首选汽车集成站点）和项目4（CAR T Manufacturing Platform）的专业知识来构建我们的初步数据，以证明CD4 CAR T细胞在体内抑制HIV的能力。我们将利用人源化的小鼠模型在体内测试这些概念，该模型从受良好控制的HIV感染的个体中注入T细胞来实现以下目标：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：确定在体内增强频率和组织分布CD4 CAR T细胞的方法。 AIM 3：确定CAR T细胞对HIV储层和CD19+肿瘤共同靶向的体内功效。因此，利用人源化的HIV感染小鼠模型，我们假设增强的CD4 CAR T细胞将能够控制HIV和靶向HIV储量，从而深入了解实现功能HIV治疗所需的机制