BACKGROUND Intra-operative intracerebral (iCE) administration of ipilimumab (IPI) and nivolumab (NIVO) after resection of rGB is safe and resulted in encouraging survival (NCT03233152J; Duerinck et al. JITC 2021). METHODS Eligible patients (pts) underwent a maximal safe resection followed by iCE administration of 5 mg IPI plus 10 mg NIVO and implantation of an Ommaya reservoir through which NIVO (10 mg) and IPI (cohort defined doses of 1-, 5- and 10 mg of IPI) were administered intracavitary (iCA) in combination with NIVO (10 mg) intravenously pre- and postoperatively and Q2w thereafter for up to 24w. RESULTS 20 pts (13 male; median age 58y) were enrolled. One patient was excluded due to an intra-operatively diagnosed epidural bacterial infection. Respectively 4 pts were treated at the 1-, 4 pts at the 5-, and 11 pts at the 10 mg iCA IPI dose level. Median number and range of postoperative iCA administrations of IPI/NIVO was 2 (0-4) at the 1 mg dose level, 5 (1-10) at the 5 mg dose level, and pending for the 10 mg dose level. Most important treatment related adverse events were symptomatic aseptic neutrophilic pleocytosis (3 pts, all treated at the 10 mg IPI dose level), subacute cerebral edema necessitating corticosteroid treatment (5 pts), and bacterial colonization of the Ommaya reservoir (3 pts). There were no G5 AE. Nine pts have progressed and 4 pts died from progressive disease. Molecular-genetic characterization of rGB tissues, analysis of cellular and cytokine content, and NIVO/IPI concentrations in CSV samples are ongoing. CONCLUSION Repeated iCA administration of 10 mg NIVO plus 10 mg IPI resulted in treatment limiting aseptic neutrophilic pleocytosis. Safety of the presumed MTD of repeated 10 mg NIVO plus 5 mg IPI iCA will be further investigated.