Stinging the Glioma Immune Landscape

刺痛神经胶质瘤免疫景观

基本信息

批准号：
10395149
负责人：
Amy Beth Heimberger
金额：
$ 34.11万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10395149
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 Hot Spot Human Hypoxia Immune Immune checkpoint inhibitor Immune response Immune system Immunobiology Immunocompetent Immunohistochemistry Immunologic Surveillance Immunologics Immunosuppression Immunotherapy Inflammatory Inflammatory Response Innate Immune System Interferons Journals Laboratories Lead Ligands Location 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 Quality of life Science Series Site Specimen Steroids Stimulator of Interferon Genes Sting Injury Stress T-Lymphocyte Testing Texture Therapeutic Therapeutic Effect Tumor-infiltrating immune cells VTCN1 gene adaptive immune response anti-tumor immune response arm base chemokine combinatorial directed attention effector T cell immune checkpoint immunosuppressed immunotherapy clinical trials ipilimumab lead candidate macrophage melanoma mouse model neoplastic cell novel 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 treatment strategy tumor tumor microenvironment

项目摘要

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然而，现在的临床数据表明，免疫检查点抑制剂可能只会影响生存率和生活质量。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的综合分析表明这些有利。诱发因素在胶质母细胞瘤中并不常见。胶质母细胞瘤是典型的例子。然而，CD8 T 细胞存在于一些孤立的区域。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到目前为止，该提议将确定是什么触发了局灶性适应性免疫反应。基于对炎症的一系列观察，研究重点关注肿瘤内的免疫反应。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的免疫反应可能与肿瘤块本身的免疫反应不同。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在这种情况下，对于抗肿瘤免疫监视和根除很重要的途径和机制。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，从而上调值得注意的是，我们正在将这一观察进一步推进并创建拓扑。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我们可能会进行有关富集的许多观察。肿瘤景观中的免疫反应可能也适用于其他器官部位，但我们也怀疑此外，为了让我们优先考虑可用的中枢神经系统，将会有真正独特的观察结果。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引发大量 T 细胞。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，它是一种广泛表达的干扰素传感器。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 的存在与大多数系统不同，它通过触发干扰素释放和顺式激活骨髓细胞来实现。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我们实验室的临床前数据表明，STING 激动剂具有治疗活性。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）