Targeting virus-specific CAR T cells to lymphoid follicles to achieve durable HIV suppression

将病毒特异性 CAR T 细胞靶向淋巴滤泡以实现持久的 HIV 抑制

• 批准号: 10284935
• 负责人: PAMELA J SKINNER
• 金额: $ 71.49万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-13 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284935
• 关键词: Aftercare; Animals; Anti-Retroviral Agents; Antibodies; Autologous; B-Lymphocytes; BLR1 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Control Animal; Cyclophosphamide; Data; Disease remission; Goals; HIV; HIV Infections; HIV-1; Homing; Human; Immune; Immunotherapy; In Vitro; Infection; Interruption; Intervention; Lymphoid Follicle; Lymphoid Tissue; MS4A1 gene; Macaca; Macaca mulatta; Patients; Pharmaceutical Preparations; RNA; Regimen; SIV; Site; T cell response; T-Lymphocyte; Testing; Time; Viral; Viral Load result; Viral reservoir; Viremia; Virus; Virus Replication; anti-viral efficacy; chimeric antigen receptor T cells; improved; in vivo; insight; novel; preconditioning; trafficking; treatment strategy; viral rebound

Abstract Virus-specific CD8 T cells exert potent antiviral activity against HIV-1 and SIV both in vitro and in vivo. Nevertheless, despite abundant CD8 T cell responses in HIV-1-infected humans and SIV- infected macaques, they are unable to fully suppress virus replication. This is likely due to the majority of HIV-1 and SIV replication occurring in CD4+ T cells concentrated within B-cell follicles in secondary lymphoid tissues; where virus-specific CD8 T cells are relatively few in number. In fact, we found that in vivo effector virus-specific CD8 T cell to target SIV RNA+ cell ratios (E:T) were over 40-fold lower inside compared to outside of B cell follicles in lymphoid tissues during SIV infection in rhesus macaques. These findings indicate that B cell follicles are an immune privileged site in which low levels of virus-specific CD8 T cells permit ongoing viral replication. Furthermore, we found that the majority of virus-specific CD8 T cells fail to express the follicular homing molecule CXCR5, likely explaining low levels of virus-specific CD8 T cells localizing to and surveilling B cell follicles. Taken together 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. These findings have led us to our central hypothesis that targeting HIV-specific T cells to B cell follicles will lead to durable remission of HIV infection. In support of this hypothesis we have shown, in SIV-infected rhesus macaques, that increased levels of virus-specific CD8 T cells in B cell follicles is associated with lower viral loads. To test this hypothesis, we propose to evaluate a T cell immunotherapy product that targets virus- specific CD8 T cells to B cell follicles. We are calling this product CD4-MBL-CAR/CXCR5 T cell immunotherapy. Our long-term goal is to develop an intervention that will lead to durable remission of HIV infection. To test this central hypothesis, we propose the following two specific aims. 1) To determine the in vivo localization, persistence and antiviral efficacy of autologous CD4-MBL- CAR/CXCR5 T cells infused into antiretroviral drug (ART) suppressed rhesus macaques before and after treatment interruption. 2) To determine whether preconditioning with CD20 antibodies (instead of cyclophosphamide) improves the abundance, persistence, or antiviral efficacy of autologous CAR/CXCR5-transduced CD8 T cells infused into ART suppressed rhesus macaques before and after treatment interruption. Our proposed studies targeting virus-specific CAR T cells to follicles will have a broad impact on the field by providing insights into cell trafficking, persistence, and pre-conditioning regimens for immunotherapy approaches. Most importantly, these studies could result in an effective strategy to induce long-term sustained remission of HIV.

摘要 病毒特异性CD8T细胞在体外和体外对HIV-1和SIV具有强大的抗病毒活性 活着。然而，尽管HIV-1感染者和SIV-1患者体内存在丰富的CD8 T细胞反应， 被感染的猕猴，它们无法完全抑制病毒复制。这很可能是由于 大部分HIV-1和SIV复制发生在集中在B细胞滤泡内的CD4+T细胞中 在次级淋巴组织中，病毒特异性CD8T细胞数量相对较少。在……里面 事实上，我们发现在体内效应病毒特异性CD8 T细胞与靶SIV RNA+细胞的比率(E：T) 在SIV期间，淋巴组织中B细胞滤泡的内部比外部低40多倍 恒河猴的感染。这些发现表明B细胞滤泡是一种免疫特权 低水平的病毒特异性CD8 T细胞允许病毒持续复制的位置。此外， 我们发现大多数病毒特异性CD8T细胞不表达卵泡归巢 分子CXCR5，可能解释了低水平的病毒特异性CD8 T细胞定位于和 监测B细胞滤泡。综上所述，这些数据表明，艾滋病毒-和SIV- 特异性CD8T细胞完全抑制病毒复制可能是由于缺乏病毒特异性 B细胞滤泡中的CD8T细胞。这些发现使我们得出了我们的核心假设 将HIV特异性T细胞靶向B细胞滤泡将导致HIV的持久缓解 感染。为了支持这一假设，我们在感染了SIV的恒河猴身上证明了 B细胞滤泡中病毒特异性CD8T细胞水平的增加与病毒载量的降低有关。 为了验证这一假设，我们建议评估一种针对病毒的T细胞免疫疗法产品- 特异性CD8T细胞转化为B细胞滤泡。我们将这种产品称为CD4-MBL-CAR/CXCR5 T细胞 免疫疗法。我们的长期目标是发展一种可导致持久缓解的干预措施。 艾滋病毒感染的可能性。为了验证这一中心假设，我们提出了以下两个具体目标。1)至 检测自体CD4-MBL-的体内定位、持久性和抗病毒效果 CAR/CXCR5 T细胞注入抗逆转录病毒药物(ART)对恒河猴的抑制作用 治疗中断后。2)确定CD20抗体预适应 (而不是环磷酰胺)可提高药物的丰度、持久性或抗病毒效果 自体CAR/CXCR5转导的CD8 T细胞注入ART抑制的恒河猴 治疗中断前后。我们建议的针对病毒特异性CAR T细胞的研究 通过提供对细胞贩运的洞察，毛囊将在该领域产生广泛的影响， 持续性，以及免疫治疗的预适应方案。最重要的是， 这些研究可能导致一种有效的战略，以诱导艾滋病毒的长期持续缓解。