Engineering HIV-resistant CAR T cells for a functional HIV cure

工程设计抗 HIV CAR T 细胞以实现功能性 HIV 治愈

基本信息

批准号：
10686941
负责人：
Daniel Thomas Claiborne
金额：
$ 22.52万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-19 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10686941
关键词：
Ablation Activities of Daily Living Address Anti-Retroviral Agents Antigens Appearance Attenuated Biological Models Blood Cells CAR T cell therapy CCR5 gene CD28 gene CD3 Antigens CD4 Positive T Lymphocytes CD8B1 gene CRISPR/Cas technology CXCR4 gene Cell Therapy Cell physiology Cells Chronic Clinic Cytolysis Cytotoxic T-Lymphocytes Data Engineering Exhibits Functional disorder Generations Genetic Engineering Goals HIV HIV Infections HIV resistance HIV therapy Hematopoietic Neoplasms Human immunodeficiency virus test Immune System Diseases Immune response Immunity Immunotherapy Infection Intervention Kinetics Mediating Modality Morbidity - disease rate Mutation Pharmaceutical Preparations Plasma Predisposition Preventive vaccine Public Health Resistance System T cell therapy T-Cell Depletion T-Cell Development T-Lymphocyte Testing Tissues Translating Translations Up-Regulation Viral Viral Load result Viremia Virus Virus Replication antiretroviral therapy cancer cell chimeric antigen receptor chimeric antigen receptor T cells combinatorial cytotoxic efficacy testing engineered T cells exhaustion genetic signature humanized mouse immune activation improved in vivo in vivo Model inhibitor latent HIV reservoir mortality mouse model novel preservation prevent programmed cell death protein 1 receptor transcription factor transcriptomics

项目摘要

Project Summary/Abstract The human immunodeficiency virus (HIV) promptly subverts the host cellular immune response through rapid viral escape, as well as high antigen loads leading to chronic immune activation, T cell exhaustion, and immune dysfunction. The advent of potent antiretroviral therapy (ART) capable of fully suppressing viral replication has drastically reduced the morbidity and mortality of HIV infection. However, ART must be taken indefinitely as HIV persists in long-lived stable reservoirs and thus presents a significant public health burden that can only be alleviated with a preventative vaccine and more potent cure approaches. Given that HIV effectively evades the cellular immune response, and the latent HIV reservoir is preferentially seeded with virus harboring relevant cytotoxic T lymphocyte (CTL)-escape mutations, genetic engineering modalities may offer a potent alternative to intrinsic immunity. Chimeric antigen receptor (CAR) T cells have shown impressive efficacy in eliminating blood cell cancers in the clinic, and CAR T cells re-engineered to target HIV using the CD4 ectodomain (CD4-CAR T) represent a potent escape-resistant cellular therapy demonstrated to have enhanced cytotoxic function over traditional cytotoxic T lymphocytes. We have recently described the creation of a significantly enhanced dual costimulatory domain CAR T cell product (Dual CARs), which significantly outperformed 3rd generation CAR T cells in vivo. Importantly, these studies identified at least two additional hurdles to CD4-CAR T cell efficacy in vivo, which likely informs translation to the clinic. First, CD4-CAR T cells rapidly upregulate multiple inhibitory receptors, express transcription factors associated with exhaustion, and display attenuated function ex vivo. Secondly, our studies definitively show that suppression of plasma viral load requires protection of the CAR T cell product from HIV infection. This proposal seeks to address these deficits in CD4-ectodomain CAR T cell therapy by 1) defining the mechanism(s) by which chronic HIV exposure attenuates T cell function, and 2) developing novel combinatorial strategies to fully protect CD4-CAR T cells from HIV infection, with the ultimate goal of creating a T cell immunotherapy exhibiting enhanced efficacy in the clinic.

项目概要/摘要人类免疫缺陷病毒（HIV）通过快速的免疫反应迅速破坏宿主的细胞免疫反应。病毒逃逸以及高抗原负荷导致慢性免疫激活、T 细胞耗竭和免疫功能障碍。能够完全抑制病毒复制的有效抗逆转录病毒疗法（ART）的出现大大降低了艾滋病毒感染的发病率和死亡率。然而，ART 必须像 HIV 一样无限期地服用持续存在于长期稳定的水库中，因此造成了重大的公共卫生负担，只能通过通过预防性疫苗和更有效的治疗方法可以缓解。鉴于HIV有效地逃避细胞免疫反应，并且潜伏的HIV储存库优先接种含有相关细胞毒性 T 淋巴细胞 (CTL) 逃逸突变的病毒，基因工程方式可能提供内在免疫的有效替代方案。嵌合抗原受体 (CAR) T 细胞在临床上显示出消除血细胞癌的令人印象深刻的功效，并且 CAR T 细胞经过重新设计以靶向使用 CD4 胞外域 (CD4-CAR T) 的 HIV 代表了一种有效的抗逃逸细胞疗法与传统的细胞毒性T淋巴细胞相比，具有增强的细胞毒性功能。我们最近描述了显着增强的双共刺激域 CAR T 细胞的创建产品（双CAR），其体内性能显着优于第三代CAR T细胞。重要的是，这些研究发现 CD4-CAR T 细胞体内功效至少存在两个额外障碍，这可能为翻译提供信息到诊所。首先，CD4-CAR T细胞快速上调多种抑制性受体，表达转录因子与衰竭有关，并表现出离体功能减弱。其次，我们的研究明确表明抑制血浆病毒载量需要保护 CAR T 细胞产品免受 HIV 感染。这个提议寻求通过以下方式解决 CD4 胞外域 CAR T 细胞疗法中的这些缺陷： 1) 定义机制长期暴露于 HIV 会削弱 T 细胞功能，2) 开发新的组合策略以充分保护来自 HIV 感染的 CD4-CAR T 细胞，最终目标是创造一种 T 细胞免疫疗法提高临床疗效。