Aging, immunosenescence and glioblastoma

项目摘要 晚期衰老是与成人诊断为具有野生型胶质母细胞瘤（GBM）相关的主要因素。 异柠檬酸脱氢酶;占所有GBM诊断的90%，是最常见的侵袭性原发性 中枢神经系统（CNS）的脑肿瘤。成人GBM与中位总生存期（OS）相关 15个月，随着年龄的增长，预后显著下降。因为标准治疗 包括最大限度的手术切除、放疗和替莫唑胺（TMZ）化疗， 对于100%的死亡率，免疫疗法已被提出作为GBM患者的潜在未来方法， 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比， 对抗PD-1 mAb和/或抗CTLA-4 mAb治疗有有益应答的终末期恶性肿瘤， 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改善的 迄今为止，所有III期临床试验中的生存率。因此，我的K 02应用程序的目标是定义 抑制抗GBM免疫应答的免疫抑制因子的晚期衰老依赖性增加， 以及了解衰老如何增加免疫抑制性吲哚胺2，3双加氧酶1（IDO 1）非 会降低对免疫疗法的反应我的团队以前的工作发现， 衰老增加了正常人和小鼠脑中免疫抑制IDO 1基因的表达。我们也 显示，免疫治疗结合放射治疗（RT）与抗PD-1 mAb和IDO 1 酶抑制剂，导致6-12周龄免疫活性小鼠的长期（≥150天）生存获益， 颅内GBM。令人惊讶的是，治疗在改善老年人的生存率方面明显不那么有效。 当移植完全相同的肿瘤细胞时。我的工作假设是， CNS中的免疫抑制，限制了负责预防的免疫监视机制 GBM细胞生长和抑制免疫系统对免疫疗法的反应。受保护 K 02支持期间的时间将允许进行全面的针对老化的培训，与专家进行高层次的互动 科学家委员会有广泛的经验，探索衰老，癌症和/或癌症之间的相互作用， 免疫反应，并将为我提供必要的时间来开发有竞争力的R 01应用程序， 支持未来的研究计划，重点是在GBM的设置老化;一种疾病，仍然无法治愈。

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.