Fgl-2 targeted therapy for reversing multi-modality immune suppression

Fgl-2靶向治疗逆转多模式免疫抑制

• 批准号: 9152967
• 负责人: Amy Beth Heimberger
• 金额: $ 36.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9152967
• 关键词: ADORA2A gene; Adenosine; Adenosine A2B Receptor; Antibodies; Autologous; Biological; Biological Assay; Biological Markers; Blocking Antibodies; Blood; CD3 Antigens; CD80 gene; Cd68; Cell Line; Cell Maturation; Cells; Cessation of life; Complex; Cytotoxic T-Lymphocyte-Associated Protein 4; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Detection; Development; Endothelial Cells; Engineering; Family; Fibrinogen; Future; Gene Expression; Gene Expression Profiling; Generations; Genetic Engineering; Glioma; Goals; Growth; Health; Human; ITGAX gene; Immune; Immune response; Immunologic Surveillance; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Knockout Mice; Lead; Longevity; Lymphocyte Activation; MHC Class II Genes; Malignant Neoplasms; Mediating; Messenger RNA; Modality; Molecular; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Myelogenous; Neuraxis; Neurologic; Normal tissue morphology; PDCD1LG1 gene; PECAM1 gene; Pathway interactions; Patients; Peptides; Play; Population; Proteins; Publishing; Regulation; Reporter Genes; Role; Serum; Solid Neoplasm; Suppressor-Effector T-Lymphocytes; System; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Tissues; Transforming Growth Factor beta; Treatment Failure; base; chemotherapy; clinical application; cytokine; liquid biopsy; mRNA Expression; macrophage; melanoma; mouse model; neoplastic cell; novel; overexpression; polyclonal antibody; response; standard of care; targeted treatment; temozolomide; treatment response; tumor; tumor growth

Our goal of this application is to test the hypothesis that blocking the newly identified immune suppressive regulator fibrinogen-like protein 2 (Fgl2) in GBM will comprehensively reverse tumor-mediated immune suppression thereby allowing immunological clearance of gliomas within the central nervous system. We have discovered that Fgl2 is highly expressed in GBM tissues(recently published by JNCI). Patients with GBM tumors that have high levels of Fgl2 expression have a statistically shorter overall survival time relative to those with low expression levels. As further proof of concept, Fgl2-engineered GBM tumors progressed rapidly with neurological sequela and death when compared to the reporter gene-GFP-engineered GBM cells in syngeneic mice. Our data shows that Fgl2 is a key immune suppressive hub that correlates with immune checkpoint family expression (PD-L1, PD-1, and CTLA-4), immune suppressive cytokines (TGF-β), and glioma-infiltrating, of immunosuppressive immune populations such as myeloid-derived suppressor cells (MDSCs), Tregs and M2 macrophages. One underlying mechanism for this observation is Fgl2 induced CD39 and CD73 in T cells. The CD39 protein converts ATP to ADP and AMP, which is then converted to adenosine by CD73. Adenosine is an immunosuppressive metabolite that then suppresses T lymphocyte activation and effector function. Furthermore, the CD39/CD73 complex enhances the conversion of M1 into tumor-promoting M2 to promote tumor growth. Based on these data, we have created a first generation antibody that blocks Fgl2 immune suppressive activity and increases median survival in murine models with established intracerebral gliomas. To test our central hypothesis for this application, the following aims are proposed: Aim 1: Determine the association of Fgl2 expression with immune suppression in human GBM and investigate the mechanism of CD39/CD73 expression in different types of immune cells in GBM; Aim 2: Select the most therapeutically efficacious cross-species Fgl2 mAb that promotes antitumor immune response. Impact: This study will yield a therapeutic candidate – a Fgl2 blocking antibody that may reverse tumor- mediated immune suppression and the number of immune suppressive cells in GBM. Considering that Fgl2 can be detected in almost all GBMs, with most having very high levels, such a candidate therapeutic will be important. This study will also further mechanistically elucidate how Fgl2 regulates immune suppressive gene expression in immune suppressive cells and within effector immune populations. Finally, this study will show whether detection of Fgl2 in circulating GBM tumor cells (CTC) using our newly invented universal CTC capture technology (PCT/US2014/020615) will correlate with the level of GBM tumor Fgl2 expression as a biomarker for guiding blocking therapy in the future. This type of assay would also be highly significant as a longitudinal liquid biopsy for gene expression analysis that could be used in the context of multiple clinical applications such as early progression/treatment failure and response to treatment.

我们此应用的目标是测试阻断新发现的免疫抑制的假设 GBM 中的调节纤维蛋白原样蛋白 2 (Fgl2) 将全面逆转肿瘤介导的免疫 抑制，从而允许中枢神经系统内的神经胶质瘤的免疫清除。我们有 发现Fgl2在GBM组织中高表达（最近由JNCI发表）。 GBM患者 与那些具有高水平 Fgl2 表达的肿瘤相比，具有高水平 Fgl2 表达的肿瘤具有统计学上更短的总生存时间。 表达水平低。作为概念的进一步证明，Fgl2 工程化的 GBM 肿瘤随着 与同基因中报告基因 GFP 工程化的 GBM 细胞相比，神经系统后遗症和死亡 老鼠。我们的数据显示 Fgl2 是与免疫检查点相关的关键免疫抑制中枢 家族表达（PD-L1、PD-1 和 CTLA-4）、免疫抑制细胞因子 (TGF-β) 和神经胶质瘤浸润， 免疫抑制性免疫群体，例如骨髓源性抑制细胞 (MDSC)、Treg 和 M2 巨噬细胞。这一观察结果的一个潜在机制是 Fgl2 在 T 细胞中诱导 CD39 和 CD73。这 CD39 蛋白将 ATP 转化为 ADP 和 AMP，然后由 CD73 转化为腺苷。腺苷是一种 免疫抑制代谢物，然后抑制 T 淋巴细胞活化和效应功能。 此外，CD39/CD73复合物增强M1向肿瘤促进M2的转化，从而促进 肿瘤生长。基于这些数据，我们创建了第一代阻断 Fgl2 免疫的抗体 抑制活性并增加已建立脑内神经胶质瘤的小鼠模型的中位生存期。 为了检验我们对此应用的中心假设，提出了以下目标： 目标 1：确定 人 GBM 中 Fgl2 表达与免疫抑制的关系并探讨其机制 GBM中不同类型免疫细胞中CD39/CD73的表达；目标2：选择最有治疗效果的 有效的跨物种 Fgl2 mAb，可促进抗肿瘤免疫反应。 影响：这项研究将产生一种治疗候选药物——一种可能逆转肿瘤的 Fgl2 阻断抗体 介导的免疫抑制和 GBM 中免疫抑制细胞的数量。考虑到Fgl2 几乎可以在所有 GBM 中检测到，其中大多数具有非常高的水平，这样的候选疗法将是 重要的。本研究也将进一步从机制上阐明Fgl2如何调控免疫抑制基因 在免疫抑制细胞和效应免疫群体中表达。最后，这项研究将表明 是否使用我们新发明的通用 CTC 检测循环 GBM 肿瘤细胞 (CTC) 中的 Fgl2 捕获技术 (PCT/US2014/020615) 将与 GBM 肿瘤 Fgl2 表达水平相关联，作为 指导未来阻断治疗的生物标志物。这种类型的测定也非常重要，因为 用于基因表达分析的纵向液体活检可用于多种临床 应用，例如早期进展/治疗失败和对治疗的反应。