Aging, immunosenescence and glioblastoma

衰老、免疫衰老和胶质母细胞瘤

基本信息

批准号：
10403678
负责人：
Derek Alan Wainwright
金额：
$ 14.49万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10403678
关键词：
Address Adult Adult Glioblastoma Affect Aftercare Age Aging Animals Bone Marrow Brain Cell Lineage Cell physiology Cells Central Nervous System Neoplasms Clinical Treatment Clinical Trials Combined Modality Therapy Data Dendritic Cells Diagnosis Dioxygenases Disease Effectiveness Elderly Enrollment Enzyme Inhibition Enzyme Inhibitor Drugs Enzymes Excision Future Gene Expression Glial Fibrillary Acidic Protein Glioblastoma Goals Human Immune response Immune system Immunocompetent Immunologic Surveillance Immunosuppression Immunotherapeutic agent Immunotherapy Incidence Individual Injections Isocitrate Dehydrogenase Malignant Neoplasms Mediating Metabolic Metabolism Modeling Monoclonal Antibodies Mus Neuraxis Nivolumab Operative Surgical Procedures Patients Phase III Clinical Trials Phenotype Prevention strategy Primary Brain Neoplasms Prognosis Radiation therapy Reporter Research Scientist Sentinel Signal Transduction Source Study models T-Lymphocyte Tamoxifen Therapeutic Effect Time Training Transgenic Mice Tumor Tissue Wild Type Mouse Work age group age related anti-CTLA4 anti-PD-1 base chemotherapy enzyme activity experience human old age (65+)immunosenescence improved indoleamine juvenile animal mortality neoplastic cell novel peripheral blood prevent programmed cell death protein 1 programs response standard of care success temozolomide transcriptome sequencing tumor tumor growth

项目摘要

PROJECT SUMMARY Advanced aging is the primary factor associated with an adult diagnosis of glioblastoma (GBM) with wild-type isocitrate dehydrogenase; constituting 90% of all GBM diagnoses and the most commonly aggressive primary brain tumor of the central nervous system (CNS). Adult GBM is associated with a median overall survival (OS) of 15 months and the prognosis significantly decreases with progressive aging. Since standard of care treatment including maximal surgical resection, radiotherapy, and chemotherapy with temozolomide (TMZ) inevitably leads to a 100% mortality rate, immunotherapy has been proposed as a potential future approach for GBM patients, based on its success in treating patients with other aggressive cancers. However, in contrast to the growing list of end-stage malignancies that respond beneficially to anti-PD-1 mAb and/or anti-CTLA-4 mAb treatment, patients diagnosed with GBM and treated with immunotherapy have thus far failed to demonstrate an improved survival among all phase III clinical trials to-date. The goal of my K02 application is therefore to define the advanced aging-dependent increase of immunosuppressive factors that inhibit the anti-GBM immune response, as well as to understand how aging-increased immunosuppressive indoleamine 2,3 dioxygenase 1 (IDO1) non- canonically decreases the response to immunotherapy. Previous work from my group discovered that, advanced aging increases immunosuppressive IDO1 gene expression in the normal human and mouse brain. We also showed that, immunotherapeutic treatment combining radiotherapy (RT) with anti-PD-1 mAb and an IDO1 enzyme inhibitor, leads to a long-term (≥150 days) survival benefit in 6-12 week old immunocompetent mice with intracranial GBM. Strikingly, the treatment was made significantly less effective at improving survival in older subjects when engrafted the exact same tumor cells. My working hypothesis is that, advanced aging increases immunosuppression in the CNS that limits immunosurveillance mechanisms responsible for preventing GBM cell outgrowth and suppressing immune system responsiveness to immunotherapy. The protected time during K02 support will allow for comprehensive aging-specific training, high-level interactions with an expert committee of scientists that have broad experience exploring the interactions between aging, cancer, and/or the immune response, and will provide me with the necessary time to develop competitive R01 applications to support a future program of research focused on aging in the setting of GBM; a disease that remains incurable.

项目摘要高级衰老是与具有意志型胶质母细胞瘤（GBM）的成人诊断有关的主要因素等脱水酶占所有GBM诊断的90％中心神经系统的脑肿瘤（CNS）。自护理标准以来，有15个月的预测会显着降低。包括最大手术切除，放疗和替莫唑胺（TMZ）的化学疗法不可避免的铅以100％的死亡率，免疫疗法被证明是GBM患者的潜在未来方法，基于其成功治疗其他侵略性癌的患者。对抗PD-1 MAB ANT/或抗CTLA-4 MAB治疗的终端恶性肿瘤有益地反应诊断为GBM并接受免疫疗法治疗的患者未能证明改善迄今为止，我的K02应用程序的所有临床试验的生存是定义的免疫抑制因子的高级衰老衰老增加，抑制抗GBM免疫反应，以及了解衰老的免疫抑制剂氨基氨酸2,3二氧酶1（IDO1）非 - 典型地减少了对我小组先前工作的反应。衰老增加了正常人和小鼠大脑中的免疫性IDO1基因表达表明，将放疗（RT）与PD-1 MAB和IDO1结合的免疫治疗治疗酶抑制剂，导致6-12周大的免疫能力小鼠长期（≥150天）的生存益处颅内GBM令人惊讶的是，该处理的较小程度较小当我的工作假设时，受试者是高级衰老中枢神经系统中的免疫选择限制了预防免疫监视机制的反应 GBM细胞的生长和抑制免疫系统对免疫疗法的反应在K02支持期间的时间将全面的特定于衰老的培训，与专家的高级互动广泛经验的科学家委员会，癌症和/或免疫反应，并将为我提供时间开发有竞争力的R01应用程序支持未来的研究计划，重点是在GBM的环境下衰老；