Genetically Modified Gamma Delta T Cells to Target SIV Reservoirs

转基因 Gamma Delta T 细胞靶向 SIV 储库

• 批准号: 10314034
• 负责人: Namita Rout
• 金额: $ 49.47万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314034
• 关键词: AIDS/HIV problem; Adoptive Transfer; Animals; Antigen Receptors; Antigen-Presenting Cells; Antigens; Autologous; Binding; Biodistribution; Bone Marrow; CAR T cell therapy; CD28 gene; Cells; Clinical; Clinical Trials; Control Groups; Coupled; Cytotoxic T-Lymphocytes; Data; Dependence; Development; Exhibits; Foundations; Generations; Genetic Engineering; Goals; Gut Mucosa; HIV; HIV Entry Inhibitors; HIV Envelope Protein gp120; HIV Fusion Inhibitors; HIV Infections; Homing; Immunotherapy; In Vitro; Individual; Infection; Interruption; Letters; Life; Ligands; Liver; Lung; Lymphocyte Function; Lymphoid Tissue; Macaca; Macaca mulatta; Methods; Modeling; Mucous Membrane; Mutation; Pathogenesis; Persons; Phase; Plasma; Pre-Clinical Model; Production; Property; Research Personnel; Residual state; Resistance; Rhesus; SIV; Safety; Sensitivity Training Groups; Signal Transduction; Spleen; T cell therapy; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapy Evaluation; Tissues; Viral; Viral Load result; Viral Physiology; Viral reservoir; Viremia; Virus; Withdrawal; antibody-dependent cell cytotoxicity; antiretroviral therapy; base; cancer cell; cancer immunotherapy; cell killing; cell transformation; chimeric antigen receptor; chimeric antigen receptor T cells; curative treatments; cytokine; cytotoxicity; gene therapy; in vivo; inhibitor; intestinal epithelium; leukemia/lymphoma; lymph nodes; microbial; microorganism antigen; migration; neoplastic cell; peripheral blood; prevent; receptor; receptor expression; response; simian human immunodeficiency virus; success; targeted treatment; tool; vector; vector control; viral rebound; γδ T cells

Currently there is no cure available for HIV/AIDS. Although antiretroviral therapy (ART) is effective in suppressing circulating HIV levels, it does not eliminate the latent and persistent viral reservoirs and the virus rebounds following ART-interruption. Thus, curative therapies are urgently needed to clear the virus from infected people and eliminate the dependence on lifelong ART. Recent clinical success of Chimeric antigen receptor (CAR) T cells in leukemia and lymphoma have demonstrated that redirecting CTL activity of T cells with specific CAR expression can overcome the limitations of autologous CTL functions. This project aims to redirect the natural cytotoxicity of gamma delta (γδ) T cells against SHIV-infection using CD4-CARs that can recognize infected cells by targeting HIV-Env. The CD4-CAR will be coupled with maC46 expression that will prevent HIV fusion and thereby protect the CAR-γδ T cells from getting infected in vivo. Our data in rhesus macaques show readily available γδ T cells in lymph nodes and bone marrow at levels similar to peripheral blood, and are particularly enriched in gut mucosa, liver, spleen, and lungs, all potential reservoir tissues for residual HIV infection during ART. Based on their unique functional properties, including (i) well-documented CTL activity in immunotherapy of cancer, (ii) tissue migration, (iii) innate anti-HIV/SIV CTL/effector functions, and (iv) continued stimulation through gut microbial ligands; we hypothesize that CAR-γδ T cells will serve as potent anti-HIV CTLs resistant to HIV infection, and migrate to tissues independent of HIV- stimulation to continually target viral reservoirs. In the R21 phase, we will determine the feasibility of autologous CAR-γδ T cell adoptive transfer for migration and persistence in tissues and their in vivo response to SHIV infection in rhesus macaques. In vivo (i) distribution, (ii) proliferation, (iii) persistence; and (iv) ex vivo CTL/cytokine effector functions will be examined in the CD4-CAR-γδ T cell-treated animals and compared with the vector control group that receive vector transduced autologous γδ T cells. In the R33 phase, we will determine the feasibility of CAR-γδ T cell immunotherapy for targeting viral reservoirs in the clinical setting of SHIV-infected macaques on effective ART. The effects of the adoptively transferred CAR-γδ T cells on viral load will be evaluated in lymphoid and mucosal tissue reservoirs. The persistence and homing, CTL activity, selective expansion, and ultimately, the efficacy of adoptive transfer with CD4-CAR-γδ T cells will be compared with vector control group. Since rhesus macaque is an important pre-clinical model for both HIV pathogenesis and gene therapy, the evaluation of CAR-γδ T cell immunotherapy in rhesus/SHIV model has high translational value. The ability of CAR-γδ T cells to control viremia following withdrawal of ART would be a significant advancement in HIV treatment and would strongly promote a new clinical trial for CAR-γδ T cell immunotherapy in HIV/AIDS.

目前尚无治愈艾滋病毒/艾滋病的治愈方法。尽管抗逆转录病毒疗法（ART）在有效 抑制循环的艾滋病毒水平，不会消除潜在的和持续的病毒储存库和病毒 艺术干扰后的篮板。那迫切需要治愈疗法来清除病毒 感染了人们，并消除了对终身艺术的依赖。嵌合抗原的最新临床成功 在白血病和淋巴瘤中的接收器（CAR）T细胞已证明T细胞的CTL活性重定向 使用特定的CAR表达可以克服自体CTL功能的局限性。这个项目旨在 重定向使用CD4-CARS的SHIV感染的伽马三角洲（γδ）T细胞的自然细胞毒性 通过靶向HIV-ENV，公认的感染细胞。 CD4卡车将与MAC46表达式结合 防止HIV融合，从而保护CAR-γδT细胞免受体内感染。我们的数据 猕猴显示淋巴结和骨髓中的γδT细胞在类似于周围的水平 血液，特别富含肠粘膜，肝脏，作为和肺，所有潜在的储层组织 艺术期间残留的艾滋病毒感染。基于它们独特的功能属性，包括（i）有据可查的 CTL在癌症免疫疗法中的活性，（ii）组织迁移，（iii）先天抗HIV/SIV CTL/效应函数， （iv）通过肠道微生物配体持续刺激；我们假设CAR-γδT细胞将使用 作为潜在的抗HIV CTLS对HIV感染具有抗性，并迁移到与HIV-无关的组织 刺激以连续靶向病毒库。 在R21阶段，我们将确定自体CAR-γδT细胞自适应转移的可行性 组织中的迁移和持久性及其对恒河猕猴中SHIV感染的体内反应。体内 （i）分布，（ii）扩散，（iii）持久性； （iv）离体CTL/细胞因子效应子功能将为 在CD4-CAR-γδT细胞处理的动物中进行了检查，并将其与接收的载体对照组进行了比较 载体翻译自体γδT细胞。 在R33阶段，我们将确定CAR-γδT细胞免疫疗法靶向病毒的可行性 在有效艺术的Shiv感染猕猴临床环境中的储层。适当的影响 在病毒载荷上转移的CAR-γδT细胞将在淋巴机和粘膜组织储层中进行评估。这 持久性和归宿，CTL活性，选择性扩展，最终是自适应转移的效率 CD4-CAR-γδT细胞将与载体对照组进行比较。 由于猕猴是HIV发病机理和基因治疗的重要临床前模型，因此 在恒河猴/SHIV模型中CAR-γδT细胞免疫疗法的评估具有很高的翻译价值。能力 CAR-γδT细胞以控制ART后控制病毒血症将是HIV的显着进步 治疗并将强烈促进HIV/AIDS中CAR-γδT细胞免疫疗法的新临床试验。