Stinging the Glioma Immune Landscape

刺痛神经胶质瘤免疫景观

基本信息

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
项目类别：
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

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)

项目摘要免疫疗法（例如免疫检查点吸入器）对癌症患者产生了深远的影响但是，生存和生活质量。具有高突变负荷，T细胞浸润，PD-L1表达的患者的子集，DNA中的缺陷不匹配的克雷佩尔和微卫星不稳定性。诱发因子在胶质母细胞瘤中并不常见。 “免疫学上”肿瘤。胶质母细胞瘤微环境，但我们不知道是什么诱导了免疫热点反应性。研究集中在肿瘤内的免疫疗法。在肿瘤感染脑边缘的反应，我们现在专注于该界面的免疫反应可能与Thumor质量不同可能会误导科学界关于潜在反应的生物标志物和缺少凯西的生物标志物对于抗肿瘤的免疫监视和消除的途径和机制中枢神经系统中的癌症，相邻的大脑被“损坏”或受到压力，从而上升了表达免疫趋化因子。为了完全了解哪些控制的局部性免疫学反应性。肿瘤景观内的免疫反应性应在其他器官部位保持真实，但我们也怀疑将会有真正的CNS特定观察结果。免疫治疗策略，该提案将愿意与先天和适应性部门免疫系统的免疫作用机制。通过抑制性肿瘤基质的促炎性激活渗透到其他“冷”肿瘤中，我们创造了一种新颖的刺痛（干扰素基因的刺激剂）激动剂。细胞应激，特别是在细胞质中存在DNA，桥接了先天性和适应性免疫触发干扰酶和髓样细胞的Throgh顺式激活其他先天免疫激动剂，刺激激活可以使肿瘤支持M2巨噬细胞重新教育促炎的M1表型，并且可以逆转髓样衍生的抑制剂细胞。建立的鼠神经瘤模型。受监测进行T细胞纹理MRI评估。 PHS 398（Rev. 06/09）