Synergistic effect of reirradiation and PD-1 inhibitors in recurrent high-grade gliomas.

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105 Background: To date, studies of single agent PD-1 or PDL-1 inhibitors in recurrent high-grade gliomas (HGG) have shown infrequent responses ( < 10%) and limited efficacy. Reirradiation is considered one of the standard salvage regimens for selected patients with recurrent gliomas but tumor responses are also infrequent ( < 5%). Radiotherapy counteracts the immunosuppressive tumor microenvironment by increasing MHC class I expression and enhancing tumor neoantigen presentation and has a significant synergistic effect with PD-1 inhibition in preclinical models of glioma. Methods: From December 2014 to June 2016, 20 patients (14 men, 6 women) with recurrent HGG were treated with the combination of reirradiation and PD-1 inhibitors. 18 patients had a glioblastoma, 1 anaplastic astrocytoma and 1 anaplastic oligodendroglioma. The median KPS at the start of this regimen was 70 (50 to 80). The median number of prior treatments for recurrent tumor was 2 (1-4), 100% had prior radaition, 95% prior temozolomide and 55% prior bevacizumab. 8 patients received pembrolizumab (2 mg/Kg every 3 weeks) and 12 patients received nivolumab (3 mg/Kg or 240 mg flat dose every 2 weeks). Median reirradiation dose was 35 Gy (12 Gy to 35 Gy). Results: There were 7 confirmed partial responses (35% objective response rate, ORR), 5 stable disease and 8 progressive disease. The median duration of response was 5 months (2.2 to 10+ months). Median PFS was 4 months and median OS was 10 months. Most common side effects were increased ALT (3 patients) and fatigue (2 patients). There was no obvious case of cerebral edema related to treatment. 5 patients required a mild increase of dexamethasone (2-4 mg) and all other 15 patients had decreased or stable dexamethasone dosage after the reirradiation. Conclusions: PD-1 inhibitors in combination with re-irradiation can be administered safely to patients with recurrent HGG. The ORR of 35% is an early signal of the potential synergist effect of the combination of PD-1 inhibitors with re-irradiation in HGG. This retrospective analysis of a heavily pre-treated population of recurrent HGG showed significantly higher ORR than either PD-1 inhibitors or re-irradiation alone. A clinical trial under development to test this hypothesis.