Development of a treatment for durable remission of HIV using transposon engineered CAR-T and NK cells

使用转座子工程 CAR-T 和 NK 细胞开发持久缓解 HIV 的治疗方法

基本信息

批准号：
10599604
负责人：
Maria Constance Athanasiou
金额：
$ 30.65万
依托单位：
MARPAM PHARMA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-07 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10599604
关键词：
Address Alleles Allogenic Animal Model Animals Anti-Retroviral Agents Antibody Formation Antigens Apoptosis Autologous B-Lymphocytes BLR1 gene Blood Cells CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CXCL13 gene Cancer Patient Cell physiology Cells Cellular immunotherapy Chronic Clinical Trials Development Devices Disease Disease remission Effectiveness Engineering Female Flow Cytometry Gammaretrovirus HIV HIV Infections HIV therapy HIV-1 Homing Human Immune Immune Targeting Individual Infusion procedures Investigation Ligands Lymphoid Lymphoid Tissue Macaca Macaca mulatta Mediating Methods NK cell therapy Natural Killer Cells Patients Pharmaceutical Preparations Phase Phenotype Pilot Projects Primates Production Proteins RNA SIV T cell response T cell therapy T-Lymphocyte Therapeutic Toxic effect Umbilical Cord Blood Viral Viral Load result Viral Physiology Viral reservoir Virus Virus Diseases Virus Replication antiretroviral therapy cellular transduction chemokine receptor chimeric antigen receptor chimeric antigen receptor T cells chronic infection cytokine release syndrome fighting improved in vivo individualized medicine knock-down male migration novel protein expression receptor response safety assessment simian human immunodeficiency virus treatment strategy vector

项目摘要

Project Summary MarPam Pharma aims to develop a one-time treatment for achieving durable remission of human immunodeficiency virus (HIV), after which patients will no longer need to take antiretroviral therapy. Our treatment is an autologous HIV-specific chimeric antigen receptor (CAR) immune cell therapy that employs the CXCR5 chemokine receptor as a homing device to direct either anti-HIV T cells or anti-HIV natural killer (NK) cells into immune-protected “hidden” viral reservoirs in lymphoid B cell follicles, where most virus-producing cells are located during chronic infection. Virus-specific CD8 T cells exert potent antiviral activity against HIV-1 and Simian immunodeficiency virus (SIV), an animal model of HIV. Nevertheless, despite abundant CD8 T cell responses in HIV-1-infected humans and SIV-infected macaques, these cells do not fully suppress virus replication, likely because the majority of HIV-1 and SIV replication occurs in CD4+ T cells concentrated within B cell follicles in secondary lymphoid tissues, where surprisingly few virus-specific CD8 T cells reside in infected individuals. In fact, we found 40-fold lower levels of in vivo effector CTL to target viral (v)RNA+ cells (E:T) inside compared to outside of B cell follicles, likely explained by the fact that very few virus-specific CD8 T cells express the follicular homing molecule CXCR5. These findings suggest that the inability of HIV-specific CD8 T cells to fully suppress virus replication may be due to a deficiency of virus-specific CD8 T cells in B cell follicles. As the vast majority of virus-producing cells are CD4 T cells located in secondary lymphoid tissue and concentrated in follicles during chronic HIV and SIV infections, we targeted these infected cells by infusing autologous antiviral CAR/CXCR5-T cells in chronically SIV-infected rhesus macaques. The treated animals showed successful homing of CAR/CXCR5-T cells to B cell follicles, evidence of direct contact of the CAR/CXCR5-T cells with vRNA+ infected cells and decreased viral loads in treated animals compared to untreated animals. Our pilot study showed that the treatment was safe and effective. These findings have prompted us to further refine our promising targeted CAR/CXCR5-T cell therapy by enhancing its efficacy and to investigate whether this targeted immune cell therapy could be developed using NK cells. CAR-T and CAR-NK cell therapies are individualized therapies that modify a patient’s own immune cells to fight disease; NK cell therapies also have the potential to function as off-the-shelf treatments using allogenic cells. This proposal seeks to optimize the effectiveness of our CAR/CXCR5 immune cell therapy. In addition, we aim to generate and evaluate optimized Car/CXCR5-T and -NK cells using less expensive production methods. Successful completion of the proposed studies will lead to Phase II IND-enabling primate studies to assess the safety and efficacy of the T cell and NK cell therapies for durable HIV remission.

项目概要 MarPam Pharma 旨在开发一种一次性治疗方法，以实现人类持久缓解免疫缺陷病毒（HIV），之后患者将不再需要接受我们的抗逆转录病毒治疗。治疗是一种自体 HIV 特异性嵌合抗原受体 (CAR) 免疫细胞疗法，采用 CXCR5 趋化因子受体作为归巢装置来引导抗 HIV T 细胞或抗 HIV 自然杀伤细胞 (NK) 细胞进入淋巴 B 细胞滤泡中受免疫保护的“隐藏”病毒库，其中大多数病毒产生细胞位于慢性感染期间，病毒特异性 CD8 T 细胞对 HIV-1 和 HIV-1 发挥有效的抗病毒活性。尽管有丰富的 CD8 T 细胞，但猿猴免疫缺陷病毒 (SIV) 是一种 HIV 动物模型。感染 HIV-1 的人类和感染 SIV 的猕猴的反应，这些细胞不能完全抑制病毒复制，可能是因为大多数 HIV-1 和 SIV 复制发生在 CD4+ T 细胞中，集中在次级淋巴组织中的 B 细胞滤泡，感染者体内几乎没有病毒特异性 CD8 T 细胞事实上，我们发现体内针对病毒 (v)RNA+ 细胞 (E:T) 的效应 CTL 水平降低了 40 倍。与 B 细胞滤泡外相比，这可能是因为很少有病毒特异性 CD8 T 细胞表达这些发现表明，HIV 特异性 CD8 T 细胞无法识别滤泡归巢分子 CXCR5。完全抑制病毒复制可能是由于 B 细胞滤泡中病毒特异性 CD8 T 细胞的缺乏。绝大多数产病毒细胞是位于次级淋巴组织中的 CD4 T 细胞，集中在在慢性 HIV 和 SIV 感染期间的卵泡中，我们通过注入自体抗病毒药物来针对这些受感染的细胞长期感染 SIV 的恒河猴中的 CAR/CXCR5-T 细胞显示出成功的治疗效果。 CAR/CXCR5-T 细胞归巢至 B 细胞滤泡，CAR/CXCR5-T 细胞与 B 细胞滤泡直接接触的证据与未经治疗的动物相比，经过治疗的动物受到 vRNA+ 感染的细胞和病毒载量降低。研究表明该治疗是安全有效的，这些发现促使我们进一步完善。我们有前途的靶向 CAR/CXCR5-T 细胞疗法，通过增强其功效并研究这是否可以使用 NK 细胞开发靶向免疫细胞疗法和 CAR-NK 细胞疗法。修改患者自身免疫细胞以对抗疾病的个体化疗法；该提案旨在优化使用同种异体细胞的现成治疗方法。此外，我们的目标是生成和评估优化的 CAR/CXCR5 免疫细胞疗法。 Car/CXCR5-T 和-NK 细胞使用较便宜的生产方法成功完成。研究将导致灵长类动物第二阶段 IND 研究，以评估 T 细胞和 NK 的安全性和有效性细胞疗法可实现艾滋病毒的持久缓解。