'Arresting' bone marrow T cell sequestration in patients with GBM

“阻止”GBM 患者的骨髓 T 细胞隔离

• 批准号: 10705243
• 负责人: Peter Fecci
• 金额: $ 25.24万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-24 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10705243
• 关键词: Acquired Immunodeficiency Syndrome; Antitumor Response; Area; Biological Assay; Biological Markers; Blood; Bone Marrow; CD4 Lymphocyte Count; Cell Count; Cell surface; Cells; Chemistry; Circulation; Clathrin; Clinical; Contracts; Cytoplasm; Data; Endocytosis; Excision; Exhibits; Foundations; G-Protein-Coupled Receptors; Glioblastoma; Goals; Human; Immune System Diseases; Immunotherapeutic agent; Immunotherapy; Implant; In Vitro; Intervention; Investigation; Knock-in; Knock-in Mouse; Knockout Mice; Licensing; Ligands; Lung; Lymphopenia; Malignant - descriptor; Malignant neoplasm of brain; Marrow; Mediating; Methods; Mus; Newly Diagnosed; Nobel Prize; Patients; Phenotype; Plasma; Primary Brain Neoplasms; Process; Radiation; Recurrence; Research Personnel; Resistance; Serine; Sphingosine-1-Phosphate Receptor; Spleen; Surface; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Variant; Wild Type Mouse; Work; beta-arrestin; biomarker identification; combinatorial; design; efficacy study; improved; inhibitor; lymphoid organ; malignant breast neoplasm; melanoma; mouse model; novel; novel strategies; patient population; pharmacologic; predictive marker; prevent; receptor; receptor internalization; recruit; small molecule; small molecule inhibitor; success; temozolomide; transcriptome sequencing; translatable strategy; tumor; uptake

ABSTRACT – Project 2 Glioblastoma (GBM) elicits severe local and systemic immune dysfunction, including T cell lymphopenia, which has remained unexplained and unaddressed for nearly 40 years. Foundational studies characterizing T cell disappearance from the blood and lymphoid organs of both patients and mice with GBM reveal AIDS-level CD4 counts (< 200 cells/μl), substantial reductions in spleen volume (mean of 30%), and up to 5-fold increases in naïve T cell counts in bone marrow. Additional work has connected these observations to the loss of sphingosine 1-phosphate receptor 1 (S1P1) from the T cell surface. Specifically, loss of S1P1 results in sequestration of T cells preferentially in the bone marrow in the context of regressing lymphoid organs such as spleen. In mice, however, S1P1 can be stabilized on T cells by knocking in a receptor with disrupted cytoplasmic serines to prevent β-arrestin recruitment, an early step toward receptor internalization. Importantly, β-arrestin-inhibited, S1P1-stabilized mice implanted with GBM exhibit long-term survival when administered T cell-activating therapies that were previously ineffective. Likewise β-arrestin2 knockout mice, specifically, prove resistant to T cell sequestration in the setting of GBM. Building on these findings, Project 2 proposes to set the groundwork for designing translatable strategies to inhibit β-arrestin2 and stabilize S1P1 as a novel anti-tumor platform. Likewise the project has an early focus on elucidating biomarkers that correctly identify those patients most likely to benefit from intervention and when. The project will test the hypothesis that systemically administered β-arrestin2 small molecule inhibitors developed by the group will effectively hinder S1P1 internalization, stabilize surface T cell S1P1, free T cells from sequestration, and newly license T cell anti-tumor capacities. This hypothesis will be tested by the following Specific Aims: Aim 1: Assess in patients the longitudinal variation in T cell sequestration with tumor resection and treatment and establish predictive biomarkers and contributory mechanisms for T cell S1P1 loss; Aim 2: Establish the relative contribution of β-arrestin2 to S1P1 internalization and screen candidate β-arrestin2 small molecule inhibitors for their ability to stabilize S1P1 and abrogate T cell sequestration; Aim 3. Initiate IND-enabling toxicity and efficacy studies with our leading β-arrestin2 small molecule inhibitor. This study is expected to provide a foundation for therapeutic approaches enabling T cell release, which our data suggest would allow immunotherapies to render a more successful antitumor response.

摘要 - 项目2 胶质母细胞瘤（GBM）引起严重的局部和全身免疫功能障碍，包括T细胞淋巴细胞减少症 近40年来一直保持出乎意料且未经工作。表征T细胞的基础研究 GBM患者和小鼠的血液和淋巴器官消失揭示了AIDS级CD4 计数（<200个单元/μL），脾脏体积的大量减少（平均30％），最多增加了5倍 骨髓中幼稚的T细胞计数。其他工作将这些观察结果与鞘氨醇的丧失联系起来 1-磷酸受体1（S1P1）来自T细胞表面。具体而言，S1P1的丢失导致t 在回归淋巴器官（如脾脏）的背景下，细胞优先在骨髓中。在老鼠中， 但是，可以通过敲击胞质丝氨酸中断的接收器来稳定S1P1在T细胞上稳定 预防β-arrestin募集，这是迈向受体内在化的早期一步。重要的是，β-arrestin抑制， 当施用T细胞激活时，S1P1稳定的小鼠植入了GBM暴露的长期存活率 以前无效的疗法。同样，β-arrestin2基因敲除小鼠，特别是对T的抗性 在GBM环境中的单元格会。在这些发现的基础上，项目2提案为 设计可翻译的策略来抑制β-arrestin2并将S1P1稳定为一种新型的抗肿瘤平台。同样地 该项目早期关注阐明生物标志物，这些生物标志物正确识别最有可能受益的患者 从干预和何时出发。该项目将检验以下假设，即系统地施用β-arrestin2小 该组开发的分子抑制剂将有效地阻碍S1P1内在化，稳定表面T细胞 S1P1，来自隔离的游离T细胞和新许可的T细胞抗肿瘤能力。这个假设将是 通过以下特定目的测试：目标1：在患者中评估T细胞隔离的纵向变化 通过肿瘤切除和治疗，建立了预测性生物标志物和T细胞的促成机制 S1P1损失； AIM 2：建立β-arrestin2对S1P1内在化和筛选候选者的相对贡献 β-arrestin2小分子抑制剂具有稳定S1P1并消除T细胞固醇的能力；目标3。 通过我们的领先β-arrestin2小分子抑制剂进行辅助毒性和效率研究。这项研究 预计将为可以释放T细胞的治疗方法提供基础，我们的数据建议 将允许免疫疗法产生更成功的抗肿瘤反应。