Genetically Modified Gamma Delta T Cells to Target SIV Reservoirs

转基因 Gamma Delta T 细胞靶向 SIV 储库

基本信息

批准号：
10077819
负责人：
Namita Rout
金额：
$ 50.28万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
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/10077819
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

项目摘要

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.

尽管抗逆转录病毒疗法（ART）对艾滋病毒/艾滋病有效，但目前尚无治愈方法。抑制艾滋病毒循环水平，但并不能消除潜伏且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。嵌合抗原最近在临床上取得了成功，从而消除了感染者对终生 ART 的依赖。白血病和淋巴瘤中的 CAR 受体 (CAR) T 细胞已证明可以重定向 T 细胞的 CTL 活性具有特定的CAR表达可以克服自体CTL功能的局限性。使用 CD4-CAR 重定向 γδ (γδ) T 细胞针对 SHIV 感染的天然细胞毒性， CD4-CAR 将与 maC46 表达相结合，从而识别受感染的细胞。防止 HIV 融合，从而保护 CAR-γδ T 细胞免受恒河猴体内感染。猕猴在淋巴结和骨髓中显示出容易获得的 γδ T 细胞，其水平与外周血相似血液中，特别富含于肠粘膜、肝、脾和肺，这些都是潜在的储存组织 ART 期间残留的 HIV 感染基于其独特的功能特性，包括 (i) 有据可查。癌症免疫治疗中的 CTL 活性，(ii) 组织迁移，(iii) 先天抗 HIV/SIV CTL/效应子功能， (iv) 通过肠道微生物配体持续刺激；我们追求 CAR-γδ T 细胞将发挥作用；作为有效的抗 HIV CTL，能够抵抗 HIV 感染，并迁移到独立于 HIV 的组织中刺激持续瞄准病毒库。在R21阶段，我们将确定自体CAR-γδT细胞过继转移的可行性组织中的迁移和持久性及其对恒河猴体内 SHIV 感染的体内反应。 (i) 分布、(ii) 增殖、(iii) 持久性和 (iv) 离体 CTL/细胞因子效应功能；在 CD4-CAR-γδ T 细胞治疗的动物中进行检查，并与接受载体对照组进行比较载体转导自体 γδ T 细胞。在R33阶段，我们将确定CAR-γδT细胞免疫疗法针对病毒的可行性感染 SHIV 的猕猴的临床环境中的储存库对有效 ART 的影响。转移的 CAR-γδ T 细胞的病毒载量将在淋巴和粘膜组织储存库中进行评估。持久性和归巢、CTL 活性、选择性扩增以及最终的过继转移的功效 CD4-CAR-γδ T细胞将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， CAR-γδT细胞免疫治疗在恒河猴/SHIV模型中的评价具有较高的转化价值。 CAR-γδ T 细胞控制 ART 退出后的病毒血症将是 HIV 治疗的重大进步治疗，并将大力推动针对艾滋病毒/艾滋病的 CAR-γδ T 细胞免疫疗法的新临床试验。