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Development of a treatment for the durable remission of HIV using autologous human CAR T cells that target B cell follicles

使用靶向 B 细胞滤泡的自体人类 CAR T 细胞开发艾滋病毒持久缓解疗法

基本信息

批准号：
10326301
负责人：
Maria Constance Athanasiou
金额：
$ 101.9万
依托单位：
MARPAM PHARMA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-18 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10326301
关键词：
Address Adherence Animals Antiviral Agents Autologous Award B-Lymphocytes BLR1 gene CAR T cell therapy CD8-Positive T-Lymphocytes Caring Cells Communicable Diseases Control Animal Cytotoxic T-Lymphocytes Data Development Devices Disease Disease remission Expenditure Fatigue Funding Gammaretrovirus Genetic Engineering Grant HIV HIV Seropositivity HIV resistance HIV therapy HIV-1 Homing Human Immune In Vitro Individual Insurance Integrase Inhibitors Interruption Laboratories Lead Ligands Lymphoid Lymphoid Tissue Macaca Macaca mulatta Malignant Neoplasms Medical Memory Methods Minnesota Modeling Morbidity - disease rate Oral Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phenotype Physicians Pilot Projects Primates Process Production Protease Inhibitor Regimen Research Research Methodology Reverse Transcriptase Inhibitors SIV Safety Site Small Business Technology Transfer Research Statistical Study Study models T-Lymphocyte Technology Therapeutic Time United States Universities Viral Viral Load result Viral Physiology Viral Vector Viral reservoir Virus Virus Replication antiretroviral therapy base cellular transduction chemokine receptor chimeric antigen receptor chimeric antigen receptor T cells clinical development conventional therapy cost design improved in vivo lymph nodes mortality non-nucleoside reverse transcriptase inhibitors novel nucleoside analog phase 1 study phase 2 study placebo controlled study pre-clinical preclinical study side effect simian human immunodeficiency virus standard of care treatment adherence treatment strategy vector viral RNA viral rebound

项目摘要

ABSTRACT MarPam Pharma is developing a one-time treatment for durable remission of human immunodeficiency virus (HIV) for patients treated with antiretroviral therapy (ART). This treatment is an autologous HIV-specific chimeric antigen receptor (CAR; specifically, CD4-MBL-CAR) T cell therapy that employs the CXCR5 chemokine receptor as a homing device to direct anti-HIV killer T cells into “hidden” viral reservoirs located in lymphoid follicles1,2. B cell follicles are an immune protected site where the majority of viral replication can occur relatively unabated in CD4+ T cells3-7, likely due to a markedly lower presence of virus-specific CD8 T cells inside compared to outside of B cell follicles in lymphoid tissue8-11. In fact, few virus-specific CD8 T cells express the follicular homing molecule CXCR510, possibly explaining the 40-fold lower in vivo effector CTL to target vRNA+ cell levels inside compared to outside of B cell follicles10. 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. Importantly, pilot studies of this CAR-T cell treatment showed safety in animals and also successful homing of CAR-T cells to B cell follicles, evidence of direct contact of the CAR-T cells with viral RNA+ infected cells, and decreased viral loads in ART-suppressed rhesus macaques infected with simian immunodeficiency virus (SIV), a model of HIV. Here, we propose to conduct an IND-enabling preclinical study to assess the safety and efficacy of autologous CAR-T cells transduced with the human CAR construct in a study statistically powered to demonstrate efficacy in a rhesus macaque simian-human immunodeficiency virus (SHIV) model of HIV. In our recent STTR Phase 1 studies, we successfully produced human CAR-T cells using a small-scale research method. Here, we propose to develop a scalable method for GMP production of gammaretrovirus and CAR/CXR5-T cells. These proposed studies will move our product from the current preclinical stage of development into clinical development.

摘要 MarPam Pharma正在开发一种用于持久缓解人类免疫缺陷病毒的一次性治疗方法 (HIV)接受抗逆转录病毒治疗（ART）的患者。这种治疗是一种自体HIV特异性嵌合抗原受体（CAR;特别是CD 4-MBL-CAR）采用CXCR 5趋化因子受体的T细胞疗法作为引导抗HIV杀伤T细胞进入位于淋巴滤泡中的“隐藏”病毒库的归巢装置1，2。B 细胞滤泡是一个免疫保护部位，在那里大多数病毒复制可以相对不减弱地发生， CD 4 + T细胞3 -7，可能是由于与外部相比，内部病毒特异性CD 8 T细胞的存在显著降低淋巴组织中的B细胞滤泡8 -11。事实上，很少有病毒特异性CD 8 T细胞表达滤泡归巢，分子CXCR 510，可能解释了体内效应CTL对靶向vRNA+细胞水平的40倍低，与B细胞滤泡外相比10.这些发现表明，HIV特异性CD 8 T细胞不能完全抑制病毒复制可能是由于B细胞滤泡中缺乏病毒特异性CD 8 T细胞。重要的是，这种CAR-T细胞治疗的初步研究显示了在动物中的安全性，并且还成功地将CAR-T细胞归巢。 CAR-T细胞至B细胞滤泡，CAR-T细胞与病毒RNA+感染细胞直接接触的证据，以及在感染猴免疫缺陷病毒（SIV）的ART抑制恒河猴中降低病毒载量，艾滋病病毒的模型。在这里，我们建议进行一项IND使能临床前研究，以评估安全性和有效性在一项统计学上有把握的研究中，在HIV的恒河猴猴-人免疫缺陷病毒（SHIV）模型中显示出有效性。在我们在最近的STTR第1阶段研究中，我们使用小规模研究成功地生产了人类CAR-T细胞。法在这里，我们提出开发一种用于GMP生产γ逆转录病毒的可扩展方法， CAR/CXR 5-T细胞。这些拟议的研究将使我们的产品从目前的临床前阶段，发展到临床开发。