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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)

项目总结