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.

抽象的 病毒特异性的CD8 T细胞在体外和IN都对HIV-1和SIV发挥有效的抗病毒活性 体内。然而，尽管HIV-1感染的人类和SIV-中的CD8 T细胞反应丰富，并且 被感染的猕猴，他们无法完全抑制病毒复制。这可能是由于 大多数HIV-1和SIV复制发生在集中在B细胞卵泡中的CD4+ T细胞中 在继发性淋巴组织中；病毒特异性CD8 T细胞的数量相对较少。在 事实，我们发现体内效应病毒特异性CD8 T细胞靶向SIV RNA+细胞比率（E：T） SIV期间与B细胞卵泡外部相比，内部的内部低于40倍以上 猕猴感染。这些发现表明B细胞卵泡是一种免疫特权 病毒特异性CD8 T细胞允许持续的病毒复制的部位。此外， 我们发现，大多数病毒特异性CD8 T细胞无法表达卵泡归巢 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 监视B细胞卵泡。总之，这些数据表明HIV和SIV-无法 特定的CD8 T细胞完全抑制病毒复制可能是由于病毒特异性的缺乏 B细胞卵泡中的CD8 T细胞。这些发现使我们提出了中心假设 将HIV特异性T细胞靶向B细胞卵泡将导致HIV持久缓解 感染。为了支持这一假设，我们在SIV感染了猕猴中表明了 B细胞卵泡中病毒特异性CD8 T细胞的水平增加与较低的病毒载量有关。 为了检验这一假设，我们建议评估针对病毒的T细胞免疫疗法产物 特定的CD8 T细胞至B细胞卵泡。我们称此产品CD4-MBL-CAR/CXCR5 T细胞 免疫疗法。我们的长期目标是制定一种将导致持久缓解的干预措施 艾滋病毒感染。为了检验这一中心假设，我们提出以下两个特定目标。 1）到 确定自体CD4-MBL的体内定位，持久性和抗病毒功效 CAR/CXCR5 T细胞注入抗逆转录病毒药物（ART）之前抑制了猕猴 并在治疗后中断。 2）确定是否使用CD20抗体进行预处理 （而不是环磷酰胺）提高了丰度，持久性或抗病毒功效 自体汽车/CXCR5转导的CD8 T细胞被注入ART抑制猕猴 治疗前后中断。我们提出的针对病毒特异性汽车T细胞的研究 卵泡将通过提供对细胞贩运的见解，对该领域产生广泛的影响， 免疫疗法方法的持久性和预先调节方案。最重要的是， 这些研究可能导致有效的策略，以诱导长期持续的艾滋病毒缓解。