Enhancing HSPC CAR-mediated immunity in vivo

增强 HSPC CAR 介导的体内免疫

基本信息

批准号：
10160820
负责人：
SCOTT G KITCHEN
金额：
$ 45.67万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2020-05-07 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10160820
关键词：
Aftercare Anatomy Animal Model Animals Anti-Retroviral Agents Antibody Therapy Antigens Antiviral Agents Autologous B-Lymphocytes BLT mice Biological Assay Blood CD4 Positive T Lymphocytes Cell Therapy Cells Cellular Immunity Clinical Collaborations Combined Modality Therapy Consultations Cytomegalovirus Cytoprotection Development Disease remission Engraftment Environment Flow Cytometry Gene Transduction Agent Generations Genes Genetic Genetic Engineering HIV HIV Infections HIV-1 Hematopoietic stem cells Human Humoral Immunities Immune Immune response Immune system Immunity Immunohistochemistry Immunologic Memory Immunology Immunotherapy In Situ Individual Infection Investigational Drugs Lead Libraries Lymphoid Tissue Macaca Macaca nemestrina Malignant Neoplasms Mediating Memory Methods Modeling Modification Monkeys Pathogenesis Patients Performance Peripheral Pharmaceutical Preparations Phase I Clinical Trials Play Receptor Cell Recovery Rest Role Safety Sampling Site Structure of germinal center of lymph node System T cell differentiation T-Cell Proliferation T-Cell Receptor T-Lymphocyte Targeted Research Testing Thymus Gland Tissues Transplantation Viral Viral Load result Viral reservoir Virus Virus Diseases Virus Replication Withdrawal antiretroviral therapy autoreactive T cell base cell killing chimeric antigen receptor chimeric antigen receptor T cells co-infection cohort combination gene therapy drug development effector T cell experimental arm gene therapy humanized mouse improved improved functioning in vivo inhibitor/antagonist insight latent HIV reservoir lymph nodes mouse model nonhuman primate novel pre-clinical receptor expression response safety and feasibility simian human immunodeficiency virus success therapy design trafficking vector viral DNA viral RNA virology

项目摘要

Project 1: Summary/Abstract The proposed research targets an HIV-1 cure strategy that attempts to increase and optimize anti-HIV cellular immune responses, which play a critical role in the control of HIV replication in the body. Due to the durability and persistence of reservoirs of HIV infected cells, combined antiretroviral treatment (ART) is insufficient in eradicating HIV-1 from the body and the patients have to remain on treatment for the rest of their lives. Achieving HIV-1 cure or remission without ART treatment will require the enhancement and persistence of effective antiviral immune responses. Most current efforts primarily focus on enhancing immunity via genetic modification of peripheral T cells while we aim at creating lifelong anti-HIV responses by modifying autologous Hematopoietic Stem/Progenitor Cells (HSPCs) with an optimized anti-HIV Chimeric Antigen Receptor (CAR) molecule. In addition, the gene therapy vector expressing this CAR molecule also contains anti-HIV genes, which protect the newly developed, vector-containing T cells from infection. We will also explore immune and gene combination therapies to improve the safety, performance, and efficacy of the CAR HSPC-based therapy. We will use a mouse model with a surrogate system that recapitulates the human immune system and HIV pathogenesis, to select for the best CAR vector and best combination therapy design to maximize the in vivo functionality of CAR cells. We will evaluate our lead CAR candidates and combination therapy in SHIV+ infected, anti-retroviral drug-treated non-human primates (NHPs) to best mimic the human clinical setting. Our proposed study will provide crucial insights and pave the way for investigational new drug (IND) development of numerous HSPC-based CAR immunotherapies.

项目1：摘要/摘要拟议的研究针对HIV-1治疗策略，该策略试图增加和优化抗HIV细胞免疫反应，这在控制体内HIV复制中起着至关重要的作用。由于HIV感染细胞的储存剂的持久性和持久性，抗逆转录病毒治疗（ART）的组合在根除体内的HIV-1方面不足，并且患者必须在其余生中继续进行治疗。实现HIV-1治疗或无艺术治疗的缓解将需要增强和持久有效的抗病毒免疫反应。目前的大多数努力主要集中于通过对外围T细胞的遗传修饰增强免疫力，同时我们旨在通过使用优化的抗HIV抗HIV嵌合抗原受体（CAR）分子来修饰自体造血干细胞/祖细胞（HSPC）来创造终身抗HIV反应。此外，表达该CAR分子的基因治疗载体还包含抗HIV基因，可保护新开发的含量的T细胞免受感染。我们还将探索免疫和基因组合疗法，以提高基于HSPC的疗法的安全性，性能和功效。我们将使用具有替代系统的小鼠模型，该模型概括了人类免疫系统和HIV发病机理，以选择最佳的CAR矢量和最佳组合疗法设计，以最大程度地提高汽车细胞的体内功能。我们将评估我们在SHIV+感染的，抗逆转录病毒药物治疗的非人类灵长类动物（NHP）中的候选车和组合疗法，以最好地模仿人类的临床环境。我们提出的研究将为研究新药物（IND）开发众多基于HSPC的汽车免疫疗法的开发铺平道路。