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: 10054164
• 负责人: PAMELA J SKINNER
• 金额: $ 79.35万
• 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/10054164
• 关键词: Aftercare; Animals; Anti-Retroviral Agents; Antibodies; Antiviral Agents; 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CD 8 T细胞在体外和体内均对HIV-1和SIV发挥有效的抗病毒活性。 vivo.然而，尽管HIV-1感染者和SIV-1感染者中存在大量的CD 8 T细胞应答， 感染的猕猴，他们无法完全抑制病毒的复制。这可能是由于 大多数HIV-1和SIV复制发生在B细胞滤泡内的CD 4 + T细胞中 在次级淋巴组织中;其中病毒特异性CD 8 T细胞数量相对较少。在 事实上，我们发现体内效应病毒特异性CD 8 T细胞与靶SIV RNA+细胞的比例（E：T） 在SIV期间，淋巴组织中B细胞滤泡内部比外部低40倍以上 感染恒河猴。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CD 8 T细胞允许病毒持续复制的位点。此外，委员会认为， 我们发现大多数病毒特异性CD 8 T细胞不能表达滤泡归巢， 分子CXCR 5，可能解释了低水平的病毒特异性CD 8 T细胞定位于 监视B细胞滤泡。综合这些数据表明，艾滋病毒和SIV- 特异性CD 8 T细胞完全抑制病毒复制可能是由于缺乏病毒特异性T细胞， B细胞滤泡中的CD 8 T细胞。这些发现使我们得出了一个中心假设， 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SIV感染的恒河猴中发现， B细胞滤泡中病毒特异性CD 8 T细胞水平的增加与较低的病毒载量有关。 为了验证这一假设，我们建议评估一种靶向病毒的T细胞免疫治疗产品， 特异性CD 8 T细胞与B细胞滤泡结合。我们将该产品称为CD 4-MBL-CAR/CXCR 5 T细胞 免疫疗法我们的长期目标是开发一种干预措施， 艾滋病毒感染。为了检验这个中心假设，我们提出了以下两个具体目标。1)到 确定自体CD 4-MBL-1的体内定位、持久性和抗病毒功效。 CAR/CXCR 5 T细胞输注到抗逆转录病毒药物（ART）中抑制了恒河猴， 治疗中断后。2)为了确定用CD 20抗体预处理是否 （代替环磷酰胺）提高了抗病毒药物的丰度、持久性或抗病毒功效。 自体CAR/CXCR 5转导的CD 8 T细胞输注到ART抑制的恒河猴中 治疗中断前后。我们提出的针对病毒特异性CAR T细胞的研究 通过提供对细胞贩运的见解， 持久性和免疫治疗方法的预处理方案。最重要的是， 这些研究可能会导致一种有效的策略，以诱导长期持续缓解艾滋病毒。