IMMU-46. GLIOBLASTOMA PATIENT DIAGNOSES AND IMMUNOSUPPRESSION ARE MAXIMAL DURING OLD AGE: A RANDOM COINCIDENCE, OR CAUSE AND EFFECT?

Abstract

INTRODUCTION: Immunotherapy fails to improve overall survival (OS) of adults with glioblastoma (GBM) according to recent Phase III clinical trial outcomes. Though immune checkpoint blockade improves OS among patients diagnosed with other, end-stage, non-CNS cancers (ie. melanoma, renal, etc.), there now exists a question of whether immunebased therapies hold promise for GBM. Somewhat under-appreciated is that, de novo GBM is a disease that primarily affects the elderly, with a median age of diagnosis at 64 years old. Strikingly, we recently discovered a higher mortality rate in elderly C57BL/6 mice with syngeneic, intracranial GL261, as compared to young, 6-8-week-old counterparts, after simultaneous treatment with radiotherapy and PD-1/IDO1 inhibitors (Ladomersky et al., 2018; CCR). METHODS: To follow-up the striking age-dependent decrease of immunotherapeutic efficacy, preclinically, we investigated the: (i) Surveillance, Epidemiology, and End Results (SEER) database; (ii) Broad Institute's GTex portal; and (iii) 10k Immunomes repository, to understand the relationship(s) between human GBM, human immunology and aging. RESULTS: GBM patient incidence is 3.4× higher among individuals ≥65 years old, as compared to those <65 (n=7155; P<0.0001). Unexpectedly, the rate of mortality among GBM patients ≥65 years old, is 7× higher, as compared to GBM patients <65 (n=9761; P<0.0001). Strikingly, immunosuppressive IDO1 levels increase in the normal human brain with advanced age, and is maximal among individuals aged 60-69 years old (n=1152; P<0.05). There is also a maximal incidence of circulating immunosuppressive Tregs among normal individuals aged 65-74 years old (n=578; P<0.05). CONCLUSIONS: The elderly population has a cumulative peak for indicators of immunosuppression, at the same age range as the maximal incidence of GBM patient diagnoses. We are currently pursuing how old age enhances immunosuppression, is associated with the maximal incidence of GBM diagnoses, and detracts from immunotherapy for malignant glioma, which is a clinicallyrelevant priority.