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A novel CAR-T cell therapy for the one-time treatment of chronic HIV infection in patients who are not ART suppressed

一种新型 CAR-T 细胞疗法，用于一次性治疗未接受 ART 抑制的慢性 HIV 感染患者

基本信息

批准号：
10547203
负责人：
Maria Constance Athanasiou
金额：
$ 30万
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：
2022-07-05 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10547203
关键词：
Address Adherence Affinity Animal Model Animals Autologous B-Lymphocytes BLR1 gene Binding CAR T cell therapy CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CXCL13 gene Caring Cells Chronic Communicable Diseases Control Animal Cytotoxic T-Lymphocytes DNA Data Devices Disease Disease remission Fatigue Genetic Engineering HIV HIV Infections HIV resistance HIV therapy HIV-1 Homing Human Immune Individual Interruption Investigation Lead Lymphoid Lymphoid Cell Lymphoid Tissue Macaca Macaca mulatta Memory Methods Modeling Morbidity - disease rate Patients Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Phase Phase I Clinical Trials Phenotype Physicians Pilot Projects Public Health Regimen Reporting Resistance SIV Safety Site T cell response T-Lymphocyte Time United States Viral Viral Load result Viral reservoir Virus Virus Diseases Virus Replication antiretroviral therapy base chemokine receptor chimeric antigen receptor chimeric antigen receptor T cells chronic infection clinical development first-in-human improved in vitro Assay in vivo migration mortality non-compliance novel phase 2 study pre-clinical preclinical development preclinical study side effect success therapy resistant treatment adherence treatment strategy viral RNA

项目摘要

ABSTRACT We aim to develop a one-time treatment for durable remission of human immunodeficiency virus (HIV) for patients who are not suppressed by antiretroviral therapy (ART), including patients who are ART naïve or ART non-compliant. Our treatment is an autologous HIV-specific chimeric antigen receptor (CAR)-T cell therapy that employs the CXCR5 chemokine receptor as a homing device to direct anti-HIV killer T cells into immune- protected “hidden” viral reservoirs in lymphoid B cell follicles, where most virus-producing cells are located during chronic infections. 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 few virus-specific CD8 T cells reside. In fact, we showed that the ratio of in vivo effector virus-specific CD8 T cells to target SIV RNA+ cells is >40-fold lower inside compared to outside of B cell follicles in lymphoid tissues in SIV-infected macaques. Furthermore, the majority of virus-specific CD8 T cells fail to express the follicular homing molecule CXCR5, likely explaining low levels of virus-spcific CD8 T cells localizing to and surveilling B cell follicles. These data suggest that the inability of HIV- and SIV-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 during chronic HIV and SIV infections, we targeted lymphoid cells by autologously infusing anti-viral CAR (specifically CAR/CXCR5) T cells into chronically SIV-infected rhesus macaques. The treated animals showed CAR/CXCR5- T cell localization to B cell follicles and decreased virus replication in the follicles compared to control animals. In addition, this product showed safety and efficacy in a pilot preclinical study of ART-suppressed SIV-infected macaques. Based on these findings and the success of our preclinical studies in ART-suppressed macaques, we propose to: (Phase 1, Aim 1) modify our current CAR/CXCR5 construct by producing and characterizing an optimized (opt) CAR/CXCR5 construct that contains a tri-specific HIV binding domain, an alternate co-stimulatory domain, and an HIV resistance domain; (Phase 2, Aim 2) develop a GMP-scalable method to produce CAR-T cells using the optCAR/CXCR5 construct and PBMCs from a) SIV-infected non-ART-treated rhesus macaques for use in an IND-enabling preclinical study; and b) HIV-infected non-ART treated individuals to prepare for the first-in-human Phase 1 clinical trial; and (Phase 2, Aim 3) assess the safety and efficacy of CAR-T cells produced with the human optCAR/CXCR5 construct in a simian/human HIV (SHIV) model of chronic HIV infection. Successful completion of the proposed studies will be IND-enabling, moving the optCAR/CXCR5-T cell product from the preclinical stage into clinical development.

摘要我们的目标是开发一种一次性治疗方法，用于持久缓解人类免疫缺陷病毒（HIV），未被抗逆转录病毒治疗（ART）抑制的患者，包括ART初治或ART 不符合我们的治疗是自体HIV特异性嵌合抗原受体（CAR）-T细胞疗法，使用CXCR 5趋化因子受体作为归巢装置，将抗HIV杀伤T细胞导向免疫系统，保护淋巴B细胞滤泡中的“隐藏的”病毒库，其中大多数产生病毒的细胞位于淋巴滤泡中，慢性感染病毒特异性CD 8 T细胞对HIV-1和猿猴发挥有效的抗病毒活性免疫缺陷病毒（SIV），HIV的动物模型。尽管如此，尽管存在丰富的CD 8 T细胞应答， HIV-1感染的人类和SIV感染的猕猴，这些细胞不能完全抑制病毒复制，因为HIV-1和SIV的大部分复制发生在聚集在B细胞滤泡内的CD 4 + T细胞中，次级淋巴组织，其中很少存在病毒特异性CD 8 T细胞。事实上，我们发现，靶向SIV RNA+细胞的体内效应病毒特异性CD 8 T细胞比体外低>40倍。 SIV感染猕猴淋巴组织中的B细胞滤泡。此外，大多数病毒特异性CD 8 T细胞细胞未能表达滤泡归巢分子CXCR 5，这可能解释了病毒特异性CD 8 T细胞水平低的原因定位并监视B细胞滤泡。这些数据表明，HIV和SIV特异性CD 8 T细胞的功能不全，细胞完全抑制病毒复制可能是由于B细胞滤泡中病毒特异性CD 8 T细胞的缺乏。由于绝大多数的病毒产生细胞是CD 4 T细胞，其位于慢性炎症期间的次级淋巴组织中。在HIV和SIV感染中，我们通过自体输注抗病毒CAR（特别是 CAR/CXCR 5）T细胞植入慢性SIV感染的恒河猴中。治疗的动物显示CAR/CXCR 5- 与对照动物相比，T细胞定位于B细胞卵泡，并减少了卵泡中的病毒复制。此外，该产品在ART抑制的SIV感染的临床前试验中显示了安全性和有效性。猕猴基于这些发现和我们在ART抑制猕猴中的临床前研究的成功，我们建议：（第1阶段，目标1）通过产生和表征CAR/CXCR 5，优化的（opt）CAR/CXCR 5构建体，其含有三特异性HIV结合结构域、替代的共刺激结构域、以及三特异性HIV结合结构域。结构域和HIV抗性结构域;（第2阶段，目标2）开发GMP可扩展的方法来生产CAR-T 使用optCAR/CXCR 5构建体的细胞和来自a）SIV感染的非ART处理的恒河猴的PBMC 用于IND-使能临床前研究;和B）HIV感染的非ART治疗的个体，以准备首次人体I期临床试验;和（II期，目标3）评估产生的CAR-T细胞的安全性和有效性与人optCAR/CXCR 5构建体在慢性HIV感染的猿猴/人HIV（SHIV）模型中的作用。成功完成拟议的研究将使IND成为可能，将optCAR/CXCR 5-T细胞产品从临床前阶段进入临床开发阶段。