Aging, immunosenescence and glioblastoma

衰老、免疫衰老和胶质母细胞瘤

基本信息

批准号：
10227148
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 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10227148
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.

项目概要晚期衰老是与野生型胶质母细胞瘤（GBM）成人诊断相关的主要因素异柠檬酸脱氢酶；占所有 GBM 诊断的 90%，也是最常见的侵袭性原发性疾病中枢神经系统 (CNS) 的脑肿瘤与中位总生存期 (OS) 相关。 15 个月后，随着标准护理治疗的进展，预后显着下降。包括最大程度的手术切除、放疗和替莫唑胺（TMZ）化疗不可避免地会导致为了实现 100% 的死亡率，免疫疗法已被提议作为 GBM 患者未来潜在的治疗方法，基于其在治疗其他侵袭性癌症患者方面的成功，然而，与不断增长的名单相反。对抗 PD-1 mAb 和/或抗 CTLA-4 mAb 治疗有有益反应的终末期恶性肿瘤，迄今为止，诊断为 GBM 并接受免疫疗法治疗的患者未能表现出病情改善因此，我的 K02 应用程序的目标是定义迄今为止所有 III 期临床试验中的生存率。抑制抗 GBM 免疫反应的免疫抑制因子随年龄增长而增加，以及了解衰老增加的免疫抑制吲哚胺 2,3 双加氧酶 1 (IDO1) 如何非我的团队之前的工作发现，典型地降低了对免疫疗法的反应。衰老会增加正常人和小鼠大脑中免疫抑制 IDO1 基因的表达。表明，将放射疗法 (RT) 与抗 PD-1 mAb 和 IDO1 相结合的免疫治疗酶抑制剂，可导致 6-12 周龄免疫功能正常的小鼠长期（≥150 天）生存获益令人惊讶的是，这种治疗在改善老年人生存方面的效果明显较差。当移植完全相同的肿瘤细胞时，受试者的衰老速度会加快。中枢神经系统中的免疫抑制限制了负责预防的免疫监视机制 GBM 细胞生长并抑制免疫系统对免疫治疗的反应。 K02 支持期间的时间将允许进行全面的针对老龄化的培训以及与专家的高水平互动由具有丰富经验的科学家组成的委员会，探索衰老、癌症和/或免疫反应，并将为我提供必要的时间来开发有竞争力的 R01 应用程序支持未来的一项研究计划，重点关注 GBM 这种仍无法治愈的疾病中的衰老问题。