Background: We sought to ascertain the immune effector function of pembrolizumab within the glioblastoma (GBM) microenvironment during the therapeutic window. Methods: In an open-label, single-center, single-arm phase II “window-of-opportunity” trial in 15 patients with recurrent (operable) GBM receiving up to 2 pembrolizumab doses before surgery and every 3 weeks afterward until disease progression or unacceptable toxicities occurred, immune responses were evaluated within the tumor. Results: No treatment-related deaths occurred. Overall median follow-up time was 50 months. Of 14 patients monitored, 10 had progressive disease, 3 had a partial response, and 1 had stable disease. Median progression-free survival (PFS) was 4.5 months (95% CI: 2.27, 6.83), and the 6-month PFS rate was 40%. Median overall survival (OS) was 20 months, with an estimated 1-year OS rate of 63%. GBM patients’ recurrent tumors contained few T cells that demonstrated a paucity of immune activation markers, but the tumor microenvironment was markedly enriched for CD68+ macrophages. Conclusions: Immune analyses indicated that pembrolizumab anti–programmed cell death 1 (PD-1) monotherapy alone can’t induce effector immunologic response in most GBM patients, probably owing to a scarcity of T cells within the tumor microenvironment and a CD68+ macrophage preponderance.

Recent efforts in brain tumor research have been directed towards the modulation of the immune system for therapeutic interventions. Several human cancers, including gliomas, are infiltrated with immune cell types—including neutrophils and myeloid-derived suppressor cells—that contribute to tumor progression, invasiveness, and treatment resistance. The role of tumor-associated neutrophils and myeloid-derived suppressor cells in cancer biology remains elusive, as these cells can exert a multitude of pro-tumor and antitumor effects. In this review, we provide the current understanding and novel insights on the role of neutrophils and myeloid-derived suppressor cells in glioma progression and treatment resistance, as well as the mechanisms of pleiotropic behaviors in these cells during disease progression, with an emphasis on possible strategies to reprogram these cells towards their antitumor actions.

Isocitrate dehydrogenase (IDH) mutation status and grade define subgroups of diffuse gliomas differing based on age, tumor location, presentation, and prognosis. While some biologic differences between IDH mutated (IDH mut) and wild-type (IDH wt) gliomas are clear, the distinct alterations associated with progression of the two subtypes to glioblastoma (GBM, Grade IV) have not been well described. We analyzed copy number alterations (CNAs) across grades (Grade II–III and GBM) in both IDH mut and IDH wt infiltrating gliomas using molecular inversion probe arrays. Ninety four patient samples were divided into four groups: Grade II–III IDH wt (n = 17), Grade II–III IDH mut (n = 28), GBM IDH wt (n = 25), and GBM IDH mut (n = 24). We validated prior observations that IDH wt GBM have a high frequency of chromosome 7 gain (including EGFR) and chromosome 10 loss (including PTEN) compared with IDH mut GBM. Hierarchical clustering of IDH mut gliomas demonstrated distinct CNA patterns distinguishing lower grade gliomas versus GBM. However, similar hierarchical clustering of IDH wt gliomas demonstrated no CNA distinction between lower grade glioma and GBM. Functional analyses showed that IDH wt gliomas had more chromosome gains in regions containing receptor tyrosine kinase pathways. In contrast, IDH mut gliomas more commonly demonstrated amplification of cyclins and cyclin dependent kinase genes. One of the most common alterations associated with transformation of lower grade to GBM IDH mut gliomas was the loss of chromosomal regions surrounding PTEN. IDH mut GBM tumors demonstrated significantly higher levels of overall CNAs compared to lower grade IDH mut tumors and all grades of IDH wt tumors, and IDH mut GBMs also demonstrated significant increase in incidence of chromothripsis. Taken together, these analyses demonstrate distinct molecular ontogeny between IDH wt and IDH mut gliomas. Our data also support the novel findings that malignant progression of IDH mut gliomas to GBM involves increased genomic instability and genomic catastrophe, while IDH wt lower grade tumors are virtually identical to GBMs at the level of DNA copy number alterations.