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.

项目摘要 Marpam Pharma旨在开发一次性治疗，以实现人类的持久缓解免疫缺陷病毒（HIV），此后不再需要接受抗逆转录病毒疗法。我们的治疗是一种自体HIV特异性嵌合抗原受体（CAR）免疫细胞疗法 CXCR5趋化因子接收器作为指导抗HIV T细胞或抗HIV天然杀手（NK）的归巢装置细胞进入淋巴样B细胞中受到免疫保护的“隐藏”病毒储存剂，其中大多数产生病毒的细胞位于慢性感染期间。病毒特异性CD8 T细胞对HIV-1发挥潜在的抗病毒活性， HIV的动物模型，Simian免疫缺陷病毒（SIV）。然而，dospite丰富的CD8 T细胞 HIV-1感染的人和SIV感染的猕猴的反应，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复制发生在集中在CD4+ T细胞中 B细胞膜中的二次淋巴组织中，令人惊讶的是，很少有病毒特异性CD8 T细胞驻留在感染中实际上，我们发现体内效应率CTL的低较低，以靶向病毒（V）RNA+细胞（E：T）与B细胞四囊的外部相比，很少有病毒特异性CD8 T细胞表达的事实可以解释卵泡归巢分子CXCR5。这些发现表明HIV特异性CD8 T细胞无法完全抑制病毒复制可能是由于B细胞中的病毒特异性CD8 T细胞缺乏引起的。作为绝大多数产生病毒的细胞是位于次级淋巴组织中的CD4 T细胞，并集中在慢性艾滋病毒和SIV感染期间的卵泡，我们通过注入自体抗病毒来针对这些感染细胞慢性SIV感染的恒河猕猴中的CAR/CXCR5-T细胞。经过治疗的动物表现成功将CAR/CXCR5-T细胞归为B细胞四聚体，与CAR/CXCR5-T细胞直接接触的证据与未经治疗的动物相比，VRNA+感染的细胞和改善了治疗动物的病毒载量。我们的飞行员研究表明，治疗是安全有效的。这些发现促使我们进一步完善了我们承诺的有针对性的CAR/CXCR5-T细胞疗法通过提高其有效性，并研究是否可以使用NK细胞开发靶向免疫细胞疗法。 CAR-T和CAR-NK细胞疗法是个性化疗法，可以改变患者自己的免疫细胞来抗击疾病； NK细胞疗法也有使用替代细胞作为现成的治疗的潜力。该建议旨在优化我们的汽车/CXCR5免疫细胞疗法的有效性。此外，我们旨在生成和评估优化 CAR/CXCR5 -T和-NK细胞使用较便宜的生产方法。成功完成拟议的研究将导致第二阶段的灵长类动物研究，以评估T细胞和NK的安全性和效率耐用HIV的细胞疗法。