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)

项目摘要免疫疗法（例如免疫抑制剂）对癌症患者产生了深远的影响生存和生活质量。但是，临床数据现在正在出现，免疫检查点抑制剂可能只能受益于具有高突变负荷，T细胞浸润，PD-L1表达的患者的子集，DNA中的缺陷不匹配修复和微卫星不稳定性。全面的分析表明，这些有利诱发因素在胶质母细胞瘤中并不常见。胶质母细胞瘤代表了一个典型的例子一种“免疫学上的冷”肿瘤。但是，在某些孤立区域中，CD8 T细胞存在于胶质母细胞瘤微环境，但我们不知道是什么引起了这些免疫热点反应性。该提案将决定什么是触发局灶性适应性免疫回报。到现在为止，大多数研究集中在肿瘤内的免疫反应上。基于一系列炎症的观察在肿瘤浸润的大脑边缘的反应，我们现在专注于对抗肿瘤的更详细评估该界面的免疫反应可能与肿瘤质量本身的免疫反应不同。这种差异是可能会错过有关潜在反应和缺少关键的生物标志物的科学界对于抗肿瘤免疫监视和放射性很重要的途径和机制。在情况下中枢神经系统中的癌症，相邻的大脑被“损坏”或压力，从而上调免疫趋化因子。值得注意的是，我们正在进一步进行几个步骤，并创建地形肿瘤-INS界面的免疫地图集，以便更充分地了解控制的局部性免疫反应性。我们将有可能就充实的许多观察结果肿瘤景观内的免疫反应性可能会在其他器官部位保持真实，但我们也怀疑将会有真正独特的CNS特定观察结果。此外，为了我们优先考虑可用的免疫理论策略，该提议还将分析免疫系统免疫抑制的常见操作机制。触发T细胞泛滥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。 sting是一个广泛表达的传感器细胞应激，特别是在细胞质中存在DNA，桥接了先天性和适应性免疫通过触发干扰释放和通过顺式激活髓样细胞的系统。与大多数不同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性M1表型，可以逆转髓样衍生的抑制剂的抑制作用表型细胞。来自我们实验室的临床前数据表明，刺痛的激动剂具有治疗活性建立的鼠神经胶质瘤模型。最终，我们计划将激动剂推向临床试验，可以使用我们独特的放射线纹理MRI评估来监测T细胞浸润。 PHS 398（Rev. 06/09）