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

• 批准号: 10548551
• 负责人: Daniel Thomas Claiborne
• 金额: $ 27.35万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 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/10548551
• 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; Lead; Mediating; Modality; Morbidity - disease rate; Mutation; Pharmaceutical Preparations; Plasma; 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; receptor function; transcription factor; transcriptomics

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.

项目摘要/摘要 人类免疫缺陷病毒（HIV）迅速通过快速颠覆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细胞疲劳和免疫 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 大幅度降低了HIV感染的发病率和死亡率。但是，必须无限期地将艺术视为艾滋病毒 坚持长寿稳定的水库，因此给出了重大的公共卫生负担，只能是 通过预防性疫苗和更有效的治疗方法缓解。 鉴于HIV有效地逃避了细胞免疫反应，并且潜在的HIV储备优先 用含有相关细胞毒性T淋巴细胞（CTL） - escape突变的病毒播种，基因工程 模式可能提供了内在免疫力的有效替代品。嵌合抗原受体（CAR）T细胞具有 在消除诊所中的血细胞癌中显示出令人印象深刻的功效，而CAR T细胞重新设计为目标 使用CD4胞外域（CD4-CAR t）的HIV代表了有效的逃逸细胞疗法 在传统的细胞毒性T淋巴细胞上增强了细胞毒性功能。 我们最近描述了创建一个显着增强的双重刺激域Car T细胞 产品（双车），在体内表现明显优于第三代汽车T细胞。重要的是，这些 研究确定了在体内至少两个额外的CD4型T细胞功效的障碍，这可能会导致翻译 去诊所。首先，CD4-car T细胞迅速上调多种抑制受体，表达转录因子 与疲惫相关，并在体内显示衰减功能。其次，我们的研究明确表明 血浆病毒载量的抑制需要保护CAR T细胞产物免受HIV感染。这个建议 旨在通过1）定义机制来解决CD4- eTecodobain CAR T细胞疗法中的这些缺陷 慢性艾滋病毒暴露会减弱T细胞功能，2）制定新型组合策略以完全保护 来自HIV感染的CD4型T细胞，其最终目的是创建表现出T细胞免疫疗法 诊所的功效增强。