Abstract
Immunotherapy has failed to improve the overall survival (OS) of adults with GBM in all phase III clinical trials to-date. Somewhat less appreciated is that, de novo GBM is a disease associated with a median age of diagnosis at 64 years old. Because of the strong association between advanced aging and human subjects presenting with GBM, we further investigated our previously described observation of a higher mortality rate in elderly C57BL/6 wild-type (WT) mice with intracranial GL261 as compared to young counterparts after treatment with radiotherapy (RT) and anti-PD-1 (PD1)/IDO1 enzyme inhibitor (IDO1i) (Ladomersky et al., 2018; Clinical Cancer Research). Since immunosuppressive IDO1 expression significantly increases in both the mouse and human brain during advanced aging (Ladomersky et al., 2019; Frontiers in Pharm.), we decided to study how IDO1 and aging interact during immunotherapy of GBM. We found that the pretreatment effects of an IDO1 enzyme inhibitor improve OS in young but not elderly WT mice with intracranial GL261 (n=12–15/group; p< 0.05). Strikingly, in the setting of advanced aging, IDO1(-/-) mice with GBM show improved OS as compared with WT mice (p< 0.01) independent of treatment with an IDO1 enzyme inhibitor. Similarly stunning, 74–80 week old IDO1(-/-) mice with GBM treated at 14 days post-ic. with RT and PD1/IDO1i survive significantly longer as compared to elderly WT mice administered the same treatment (n=20–22/group; p< 0.05). These results collectively suggest that, the therapeutic effects of IDO1 enzyme inhibition is less effective in the setting of old age, and provides rationale for the development of new approaches that inhibit IDO1-mediated immunosuppression independent of its association with enzyme activity for eventually improving immunotherapeutic efficacy in human subjects with malignant glioma.