Stinging the Glioma Immune Landscape

刺痛神经胶质瘤免疫景观

• 批准号: 10532803
• 负责人: Amy Beth Heimberger
• 金额: $ 32.4万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532803
• 关键词: ADORA2A gene; Active Immunotherapy; Adaptive Immune System; Agonist; Antigens; Area; Atlases; Biological Markers; Brain; CD276 gene; CD3 Antigens; CD8-Positive T-Lymphocytes; CTLA4 gene; Cancer Patient; Cell Density; Cellular Stress; Central Nervous System Neoplasms; Clinical Data; Clinical Trials; Communities; Community Clinical Oncology Program; Cytoplasm; DNA; Data; Defect; Dendritic Cells; Development; Disease Progression; Evaluation; Family; Floods; Flow Cytometry; Frequencies; Gene Activation; Genetic; Glioblastoma; Glioma; Heterogeneity; Histology; Human; Hypoxia; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunobiology; Immunocompetent; Immunohistochemistry; Immunologic Surveillance; Immunologics; Immunosuppression; Immunotherapy; Infiltration; Inflammatory; Inflammatory Response; Innate Immune System; Interferons; Invaded; Journals; Laboratories; Lead; Ligands; Location; Macrophage; Magnetic Resonance Imaging; Maintenance; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of lung; Manuscripts; Mediating; Microsatellite Instability; Mismatch Repair; Modeling; Monitor; Mutation; Myeloid Cell Activation; Myeloid-derived suppressor cells; Necrosis; Neurons; OX40; Organ; Outcome; Pathway interactions; Patients; Phenotype; Pre-Clinical Model; Preclinical Testing; Predisposing Factor; Probability; Quality of life; Science; Series; Site; Specimen; Steroids; Stimulator of Interferon Genes; Sting Injury; Stress; T cell infiltration; Testing; Texture; Therapeutic; Therapeutic Effect; VTCN1 gene; adaptive immune response; anti-tumor immune response; arm; candidate identification; chemokine; combinatorial; directed attention; effector T cell; immune cell infiltrate; immune checkpoint; immunosuppressed; immunotherapy clinical trials; ipilimumab; lead candidate; melanoma; mouse model; neoplastic cell; novel; novel therapeutic intervention; patient subsets; phase III trial; pre-clinical; programmed cell death ligand 1; programmed cell death protein 1; prospective; radiomics; response; response biomarker; sensor; standard of care; success; therapeutic candidate; trafficking; tumor; tumor microenvironment

PROJECT SUMMARY Immune therapies such as immune checkpoint inhibitors have had a profound impact on cancer patient survival and quality of life. However, clinical data is now emerging that immune checkpoint inhibitors may only benefit subsets of patients that have high mutational loads, T cell infiltration, PD-L1 expression, defects in DNA mismatch repair, and microsatellite instability. Comprehensive profiling reveals that these favorable predisposing factors are not common within glioblastoma. Glioblastoma represents a prototypical example of an “immunologically cold” tumor. Nonetheless, there are isolated areas in which CD8 T cells are present in the glioblastoma microenvironment but we do not know understand what induces these immune hotspots of reactivity. This proposal will determine what is triggering focal adaptive immune responses. Until now, most studies have focused on immune responses within the tumor. Based on a series of observation of inflammatory responses at the tumor-infiltrative brain edge, we are now focusing on a more detailed evaluation of anti-tumor immune responses at this interface, which likely differs from those in the tumor mass itself. This discrepancy is probably misinforming the scientific community regarding biomarkers of potential response and missing key pathways and mechanisms that are important for antitumor immune surveillance and eradication. In the case of cancer in the CNS, the adjacent brain is “damaged” or stressed, thereby upregulating the expression of immune chemokines. Notably, we are taking this observation several steps further and creating topographical immune atlases of the tumor-CNS interface, in order to more fully understand what controls localized immunological reactivity. Many of the observations that we will potentially make regarding enrichment of immune reactivity within the tumor landscape are likely to hold true for other organ sites, but we also suspect that there will be truly unique CNS-specific observations. Furthermore, in order for us to prioritize available immune therapeutic strategies, this proposal will also be profiling both the innate and adaptive arm of the immune system for common operational mechanisms of immune suppression. To trigger a flood of T cell infiltration into otherwise “cold” tumors through pro-inflammatory activation of suppressive tumor stroma, we have created a novel STING (stimulator of interferon genes) agonist. STING is a widely expressed sensor of cellular stress, specifically the presence of DNA in the cytoplasm that bridges the innate and adaptive immune systems both by triggering interferon release and through cis-activation of myeloid cells. Distinct from most other innate immune agonists, STING activation can re-educate tumor supportive M2 macrophages toward a pro-inflammatory M1 phenotype and can reverse the suppressive phenotype of myeloid-derived suppressor cells. Preclinical data from our laboratory demonstrates that STING agonists have therapeutic activity in established murine models of glioma. Ultimately, we plan to advance STING agonists into clinical trials that can be monitored for T cell infiltration using our unique radiomic textural MRI assessments. PHS 398 (Rev. 06/09)

项目概要 免疫检查点抑制剂等免疫疗法对癌症患者产生了深远的影响 生存和生活质量。然而，现在出现的临床数据表明，免疫检查点抑制剂可能仅 使具有高突变负荷、T 细胞浸润、PD-L1 表达、DNA 缺陷的患者亚群受益 错配修复和微卫星不稳定性。综合分析表明，这些有利的 诱发因素在胶质母细胞瘤中并不常见。胶质母细胞瘤代表了一个典型的例子 “免疫冷”肿瘤。尽管如此，在某些孤立的区域中存在 CD8 T 细胞。 胶质母细胞瘤微环境，但我们不知道是什么诱发了这些免疫热点 反应性。该提案将确定是什么触发了局灶性适应性免疫反应。到目前为止，大多数 研究重点是肿瘤内的免疫反应。基于对炎症的一系列观察 肿瘤浸润脑边缘的反应，我们现在专注于抗肿瘤的更详细的评估 该界面处的免疫反应可能与肿瘤块本身的免疫反应不同。这个差异是 可能会误导科学界有关潜在反应和缺失关键生物标志物的信息 对于抗肿瘤免疫监视和根除很重要的途径和机制。在这种情况下 中枢神经系统中的癌症发生时，邻近的大脑会受到“损害”或受到压力，从而上调 免疫趋化因子。值得注意的是，我们正在将这一观察进一步推进并创建地形 肿瘤-中枢神经系统界面的免疫图谱，以便更全面地了解控制局部的因素 免疫反应性。我们可能会就丰富 肿瘤景观中的免疫反应可能也适用于其他器官部位，但我们也怀疑 将会有真正独特的中枢神经系统特定的观察结果。此外，为了让我们优先考虑可用的 免疫治疗策略，该提案还将分析免疫治疗的先天性和适应性臂 免疫系统常见的免疫抑制运作机制。触发T细胞大量涌入 通过抑制性肿瘤基质的促炎激活渗透到其他“冷”肿瘤中，我们 创造了一种新型 STING（干扰素基因刺激剂）激动剂。 STING 是一种广泛表达的传感器 细胞应激，特别是细胞质中连接先天免疫和适应性免疫的 DNA 的存在 通过触发干扰素释放和通过顺式激活骨髓细胞来调节系统。与大多数人不同 与其他先天免疫激动剂一样，STING 激活可以重新教育肿瘤支持性 M2 巨噬细胞朝向 促炎 M1 表型，并可逆转骨髓源性抑制因子的抑制表型 细胞。我们实验室的临床前数据表明，STING 激动剂具有以下治疗活性： 建立小鼠神经胶质瘤模型。最终，我们计划将 STING 激动剂推进临床试验， 使用我们独特的放射组学纹理 MRI 评估来监测 T 细胞浸润。 PHS 398（修订版 06/09）