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：
10738349
负责人：
Maria Constance Athanasiou
金额：
$ 11.85万
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10738349
关键词：
Address Adherence Animals Autologous Award B-Lymphocytes BLR1 gene CAR T cell therapy CD4 Positive T Lymphocytes 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 Ligands Lymphoid Follicle 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 United States Universities Viral Viral Load result Viral Physiology Viral Vector Viral reservoir Virus Virus Replication antiretroviral therapy cellular transduction chemokine receptor chimeric antigen receptor chimeric antigen receptor T cells clinical development conventional therapy cost design improved in vivo lymph nodes migration mortality non-nucleoside reverse transcriptase inhibitors novel novel therapeutic intervention nucleoside analog phase 1 study phase 2 study placebo controlled study pre-clinical preclinical study safety assessment side effect simian human immunodeficiency virus standard of care treatment adherence 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.

抽象的 MarPam Pharma 正在开发一种一次性治疗方法，用于人类免疫缺陷病毒的持久缓解 (HIV) 用于接受抗逆转录病毒治疗 (ART) 的患者这种治疗是一种自体 HIV 特异性嵌合体。使用 CXCR5 趋化因子受体的抗原受体（CAR；具体为 CD4-MBL-CAR）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。细胞滤泡是一个免疫保护部位，大多数病毒复制可以相对不减弱地发生在其中 CD4+ T 细胞3-7，可能是由于内部病毒特异性 CD8 T 细胞的存在量明显低于外部淋巴组织中 B 细胞滤泡的数量8-11 事实上，很少有病毒特异性 CD8 T 细胞表达滤泡归巢。分子 CXCR510，可能解释了体内靶向 vRNA+ 细胞水平低 40 倍的效应器 CTL 与 B 细胞滤泡外相比，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细胞滤泡中病毒特异性CD8 T细胞的缺乏。重要的是，这种 CAR-T 细胞治疗的试点研究表明在动物中是安全的，并且成功归巢 CAR-T 细胞与 B 细胞滤泡的结合，CAR-T 细胞与病毒 RNA+ 感染细胞直接接触的证据，以及感染猿猴免疫缺陷病毒（SIV）的 ART 抑制的恒河猴中的病毒载量下降，在这里，我们建议进行一项支持 IND 的临床前研究来评估安全性和有效性。心理学家在一项研究中展示了用人类 CAR 结构转导的自体 CAR-T 细胞在我们的恒河猴-人类免疫缺陷病毒（SHIV）HIV模型中证明了功效。最近的 STTR 第一阶段研究，我们通过小规模研究成功生产了人类 CAR-T 细胞在这里，我们建议开发一种可扩展的方法来生产 γ 逆转录病毒和 CAR/CXR5-T 细胞。这些拟议的研究将使我们的产品脱离当前的临床前阶段。开发进入临床开发。