Aging, immunosenescence and glioblastoma

  • Wainwright, Derek Alan (PD/PI)

Project: Research project

Project Details

Description

Advanced aging is the primary factor associated with a diagnosis of glioblastoma (GBM); the most common and aggressive primary brain tumor of the central nervous system (CNS). Adult GBM is associated with a median overall survival (OS) of 16-18 months and the prognosis significantly decreases during advanced 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 with GBM treated with immunotherapy fail to show an improved survival benefit among all phase III clinical trials to-date. Therefore, this study aims to understand why GBM is enriched during advanced aging and refractive to immunotherapy, with a special emphasis on the disproportionately negative role of advanced aging in the CNS. Previous work from our group discovered that, advanced aging increases immunosuppressive 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 significantly less effective at improving survival against GBM in 72-74 week old mice; similar to the median age of a human GBM patient diagnosis and coincident with maximal immunosuppressive gene expression in the CNS. Therefore, our overall hypothesis is that, advanced aging increases immunosuppression in the brain that limits immunosurveillance mechanisms responsible for preventing GBM cell outgrowth and suppressing immune system responsiveness to immunoth
StatusFinished
Effective start/end date8/1/2012/31/22

Funding

  • National Institute on Aging (5K02AG068617-03 REVISED)

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