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: 10450651
• 负责人: James L Riley
• 金额: $ 97.41万
• 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/10450651
• 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; 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

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