Nivolumab reaches brain lesions in patients with recurrent glioblastoma and induces T-cell activity and upregulation of checkpoint pathways.

Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis. Although immunotherapy is being explored as a potential treatment option for patients with GBM, it is unclear whether systemic immunotherapy can reach and modify the tumor microenvironment in the brain. We evaluated immune characteristics in patients receiving the anti-PD1 immune checkpoint inhibitor Nivolumab one week prior to surgery, compared to control patients receiving salvage resection without prior Nivolumab treatment. We observed saturating levels of Nivolumab bound to intratumorally- and tissue-resident T cells in the brain, implicating saturating levels of Nivolumab reaching brain tumors. Following Nivolumab treatment, significant changes in T-cell activation and proliferation were observed in the tumor resident T-cell population, and peripheral T cells upregulated chemokine receptors related to brain homing. A strong Nivolumab-driven upregulation in compensatory checkpoint inhibition molecules, TIGIT, LAG-3, TIM-3 and CTLA-4 was observed, potentially counteracting the treatment effect. Finally, tumor-reactive tumor-infiltrating lymphocytes (TILs) were found in a subset of Nivolumab-treated patients with prolonged survival, and neoantigen-reactive T cells were identified in both TILs and blood. This indicates a systemic response towards GBM in a subset of patients, which was further boosted by Nivolumab, with T-cell responses towards tumor-derived neoantigens. Our study demonstrates that Nivolumab does reach the GBM tumor lesion and enhances antitumor T-cell responses both intratumorally and systemically. However, various anti-inflammatory mechanisms mitigate the clinical efficacy of the anti-PD1 treatment.