Development of Gamma delta CAR-T cells to target CNS HIV reservoir

开发针对 CNS HIV 储存库的 Gamma delta CAR-T 细胞

• 批准号: 10620021
• 负责人: Namita Rout
• 金额: $ 28.46万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620021
• 关键词: Address; Adoptive Transfer; Autopsy; Bar Codes; Biodistribution; Brain; CAR T cell therapy; CD4 Positive T Lymphocytes; Cell model; Cells; Cellular Stress; Central Nervous System; Data; Development; Engineering; Engraftment; Foundations; Functional disorder; Future; Genes; Genetic Engineering; Goals; Granzyme; HIV; HIV-associated neurocognitive disorder; Hematologic Neoplasms; Immune; Impaired cognition; In Vitro; Infection; Inflammation; Innovative Therapy; Lentivirus Vector; Location; Macaca; Macaca mulatta; Macrophage; Microglia; Modeling; Modernization; Mutation; Myelogenous; Myeloid Cells; Nervous System Trauma; Neurocognitive; Neurocognitive Deficit; Neurons; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Property; Research; Resistance; Retroviral Vector; Rhesus; Risk; SIV; Safety; Site; Specificity; Stress; T-Lymphocyte; Testing; Therapeutic; Tissues; Viral; Virus; Virus Replication; antiretroviral therapy; brain tissue; cancer immunotherapy; cell transformation; chimeric antigen receptor; chimeric antigen receptor T cells; clinically relevant; cytotoxicity; design; feasibility testing; improved; in vitro Assay; in vivo; in vivo evaluation; insight; latent HIV reservoir; lymph nodes; migration; monocyte; neuroAIDS; neuroinflammation; novel; novel strategies; prevent; purge; simian human immunodeficiency virus; transmission process; γδ T cells

PROJECT SUMMARY HIV persistence in reservoir tissues remains a major barrier to achieving a therapeutic cure despite effective antiretroviral therapy (ART). Eradicating HIV-infected cells in the central nervous system (CNS) is particularly challenging since it is a site of immune privilege and is poorly accessible to ART drugs. While cognitive impairment among people living with HIV has significantly reduced in the era of modern HIV treatment, about 30% of ART-suppressed HIV patients still display conditions of HIV-associated neurocognitive disorder (HAND), suggesting that even low levels of HIV persisting in the brain can cause neurological damage. Thus, functional cure strategies that can safely eradicate replicating virus the CNS reservoir are urgently needed. Emerging evidence suggests that myeloid cells, including brain macrophages (Mf), are sanctuaries of HIV persistence in the CNS, and that HIV-infected macrophages are more resistant to CTLs than CD4 T cells. The goal of this project is to develop a universal gamma delta (γδ) CAR-T platform with dual HIVenv/Mf-targeting for HIV- infected myeloid cells in the CNS reservoir. Our central hypothesis is that adding Mf specific CAR to anti-HIV γδ CAR-T cells will enable efficient targeting of HIV-infected cells in the CNS reservoir. Our data in rhesus macaques show enhanced in vitro killing of HIV-infected monocytic cells by γδ CD4-CAR-T cells and greater Granzyme B cytotoxicity, which has been shown to be critical for CTL killing of HIV-infected primary macrophages. Based on the unique functional properties of γδ T cells, including (i) well-documented CTL activity in immunotherapy of cancer, (ii) ability to migrate to sites of neuroinflammation, and (iii) innate anti-HIV/SIV CTL functions; we hypothesize that the dual γδ CAR-T cells will induce more effective targeting of myeloid HIV reservoirs. In Aim 1, we will develop approaches for generating retroviral and lentiviral vector-based γδ CD4- CAR-T cells toward enhanced targeting of SHIV-infected primary Mf and microglial cells. In Aim 2, we will test the in vivo potential of the optimized γδ CAR-T cell to migrate and engraft in the CNS during viremic infection with the novel macrophage-tropic TF SHIV.D model of CNS pathogenesis. The proposed research is significant because its successful completion will lead to the development of a universal γδ CAR-T cell model with enhanced targeting of tissue macrophage reservoirs including the CNS in a clinically relevant model of SHIV.D infected rhesus macaques.

项目摘要 艾滋病毒持续性在研究器组织中仍然是达到治疗性治疗有效性的主要障碍 抗逆转录病毒疗法（ART）。根除中枢神经系统（CNS）中的HIV感染细胞特别是 具有挑战性，因为它是一个免疫特权的场所，而艺术药物则无法获得。同时认知 在现代艾滋病毒治疗时代，艾滋病毒感染者的损害大大减少了 30％的被抑制ART的HIV患者仍显示与HIV相关的神经认知障碍（手）的疾病， 表明即使在大脑中持续存在的艾滋病毒含量也很低也会造成神经系统损害。那，功能 迫切需要治愈可以安全地消除CNS储层复制病毒的策略。新兴 有证据表明，包括脑巨噬细胞（MF）在内的髓样细胞是HIV持久性的庇护所 与CD4 T细胞相比，中枢神经系统和HIV感染的巨噬细胞对CTL的抗性更大。目标的目标 项目将开发一个通用伽马三角洲（γδ）CAR-T平台，具有双Hivenv/MF靶向HIV- 中枢神经系统储层中感染的髓样细胞。我们的中心假设是将MF特异性CAR添加到抗HIVγδ中 CAR-T细胞将有效地靶向CNS储层中的HIV感染细胞。我们的数据 猕猴显示通过γδCD4-CAR-T细胞对HIV感染的单核细胞的体外杀死，并且更大 颗粒酶B细胞毒性，这对于CTL杀死HIV感染的原发性至关重要 巨噬细胞。基于γδT细胞的独特功能特性，包括（i）有据可查的CTL活性 在癌症的免疫疗法中，（ii）迁移到神经炎症部位的能力和（iii）先天性抗HIV/SIV CTL 功能；我们假设双γδCAR-T细胞将诱导髓样HIV的更有效靶向 水库。在AIM 1中，我们将开发用于产生逆转录病毒和慢病毒载体的方法γδCD4- CAR-T细胞朝着增强的Shiv感染的原代MF和小胶质细胞的靶向。在AIM 2中，我们将测试 在病毒感染期间，优化的γδCAR-T细胞在CNS中迁移和植入的体内电位 与新型的巨噬细胞 - 热带TF SHIV.D CNS发病机理的模型。拟议的研究很重要 因为它的成功完成将导致具有增强的通用γδCAR-T细胞模型的发展 靶向组织巨噬细胞储量在内的临床相关模型中的CN. 恒河猕猴。