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: 10065758
• 负责人: Namita Rout
• 金额: $ 50.87万
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10065758
• 关键词: AIDS/HIV problem; Adoptive Transfer; Animals; Antigen Receptors; Antigen-Presenting Cells; Antigens; Antiviral Agents; 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; 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/antagonist; 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.

目前没有治愈艾滋病毒/艾滋病的方法。虽然抗逆转录病毒治疗（ART）在 抑制循环的HIV水平，它不会消除潜伏和持久的病毒库和病毒 ART中断后反弹。因此，迫切需要治愈性疗法来清除病毒， 嵌合抗原的临床应用 白血病和淋巴瘤中的CAR受体T细胞已经证明， 具有特异性CAR表达的细胞可以克服自体CTL功能的限制。该项目旨在 使用CD 4-汽车重定向γ δ（γδ）T细胞对SHIV感染的天然细胞毒性， 通过靶向HIV-Env识别感染细胞。CD 4-CAR将与maC 46表达偶联， 防止HIV融合，从而保护CAR-γδ T细胞免受体内感染。我们在恒河猴中的数据 猕猴淋巴结和骨髓中的γδ T细胞水平与外周血中的γδ T细胞水平相似， 血液中，特别是在肠粘膜、肝、脾和肺中富集，所有这些都是潜在的储存组织， 基于其独特的功能特性，包括（i）有充分记录的 癌症免疫治疗中的CTL活性，（ii）组织迁移，（iii）先天性抗HIV/SIV CTL/效应子功能， 和（iv）通过肠道微生物配体的持续刺激;我们假设CAR-γδ T细胞将 作为抗HIV感染的强效抗HIV CTL，并迁移至不依赖于HIV的组织- 刺激以持续靶向病毒储库。 在R21阶段，我们将确定自体CAR-γδ T细胞过继转移的可行性， 迁移和持久性的组织和他们在体内的反应，以SHIV感染恒河猴。体内 (i)分布，（ii）增殖，（iii）持久性;和（iv）离体CTL/细胞因子效应子功能。 在CD 4-CAR-γδ T细胞处理的动物中检查，并与接受CD 4-CAR-γδ T细胞的载体对照组进行比较。 载体转导的自体γδ T细胞。 在R33阶段，我们将确定CAR-γδ T细胞免疫治疗靶向病毒的可行性。 在临床环境中的SHIV感染的猕猴对有效的ART的水库。 将在淋巴和粘膜组织储库中评价病毒载量上的转移的CAR-γδ T细胞。的 持久性和归巢，CTL活性，选择性扩增，并最终，过继转移的功效， 将CD 4-CAR-γδ T细胞与载体对照组进行比较。 由于恒河猴是HIV发病机制和基因治疗的重要临床前模型， 在恒河猴/SHIV模型中评估CAR-γδ T细胞免疫疗法具有高转化价值。的能力 CAR-γδ T细胞在ART停药后控制病毒血症将是HIV治疗的重大进展。 这将有力地推动CAR-γδ T细胞免疫疗法在HIV/AIDS中的新临床试验。