Abstract Glioblastoma is immunologically “cold” and resistant to single-agent immune-checkpoint inhibitors (ICI). Our previous study of neoadjuvant pembrolizumab in surgically-accessible recurrent glioblastoma identified a molecular signature of response to ICI and suggested that neoadjuvant pembrolizumab may improve survival. To increase the power of this observation, we performed bulk-RNA seq on resected tumor tissue from an additional 25 patients with recurrent glioblastoma treated with neoadjuvant pembrolizumab. Neoadjuvant pembrolizumab was associated with suppression of cell cycle/cancer proliferation genes and upregulation of T-cell/interferon-related gene expression. This signature was unique to patients treated with neoadjuvant pembrolizumab and was an independent positive risk factor for survival. PF6 for the stage 2 expansion cohort was 0%, while overall survival and progression-free survival were similar to historical controls at 6.8 months and 2.5 months, respectively. Our results demonstrate a clear pharmacodynamic effect of anti-PD1 therapy in glioblastoma and identify pathways that may mediate resistance. However, we did not observe a survival benefit to neoadjuvant pembrolizumab in recurrent glioblastoma in our expansion cohort. Our new data suggests some patients may exhibit innate resistance to pre-surgical ICI and require other concomitant therapies to sensitize effectively.
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