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Purpose:To date, there are no systemic treatment options for patients with recurrent or refractory meningioma.Experimental Design:To identify effective drugs, we performed a large-scale drug screening using FDA-approved drugs on several meningioma cell lines. The impact of the top four compounds was assessed on cell viability, proliferation, colony formation, migration, and apoptosis. In addition, the antineoplastic effects of the selected drugs were validated in a heterotopic xenograft mouse model.Results:Analyses of the viability of meningioma cells treated with 119 antineoplastic FDA-approved drugs resulted in categorization into sensitive and resistant drug–response groups based on the mean IC50 values and peak serum concentrations (Cmax) in patients. Eighty drugs, including 15 alkylating agents, 14 antimetabolites, and 13 tyrosine kinase inhibitors, were classified as resistant (IC50 > Cmax). The sensitive drug–response group (n = 29, IC50 < Cmax) included RNA/protein synthesis inhibitors, proteasome inhibitors, topoisomerase, tyrosine-kinase, and partial histone deacetylase and microtubule inhibitors. The IC50 value of the four most effective compounds (carfilzomib, omacetaxine, ixabepilone, and romidepsin) ranged from 0.12 to 9.5 nmol/L. Most of them caused cell-cycle arrest in the G2–M-phase and induced apoptosis. Furthermore, all drugs except romidepsin significantly inhibited tumor growth in vivo. The strongest antineoplastic effect was observed for ixabepilone, which reduced tumor volume by 86%.Conclusions:In summary, a large-scale drug screening provides a comprehensive insight into the anti-meningioma activities of FDA-approved drugs, and identified carfilzomib, omacetaxine, ixabepilone, and romidepsin as novel potent antineoplastic agents for the treatment of aggressive meningiomas. The most pronounced effects were observed with ixabepilone mandating for further clinical investigation.

Supplementary Figures

Drug Screening Data

Fig. S1: Workflow; Fig. S2: Representative gating strategy for TissueFAXS analysis; Fig. S3: Analysis of helper, cytotoxic and regulatory T cell infiltration and the proportion of PD-1-expressing T cells; Fig. S4: Association between the infiltration of T cells and survival; Fig. S5: Levels of tumor-infiltrating T lymphocytes (TILs) in meningiomas, separated by their localization.

Purpose:Clinically aggressive meningiomas (MGMs) are rare but treatment-resistant tumors in need for more effective therapies. Because tumor-infiltrating T lymphocytes (TILs) are essential for successful immunotherapy, we assessed TIL numbers and their activation status in primary (p-) and recurrent (r-) meningiomas and their impact on survival.Experimental Design:Presence of TILs was analyzed in 202 clinically well-annotated cases (n = 123 pMGMs and n = 79 rMGMs) focusing on higher-grade meningiomas [n = 97 World Health Organization (WHO) °II, n = 62 WHO°III]. TILs were quantified by a semiautomated analysis on whole-tissue sections stained by multicolor immunofluorescence for CD3, CD8, FOXP3, and programmed cell death protein 1 (PD-1).Results:Median T-cell infiltration accounted for 0.59% TILs per total cell count. Although there were no significant WHO°-dependent changes regarding helper (CD3+CD8−FOXP3−) and cytotoxic (CD3+CD8+FOXP3−) TILs in pMGMs, higher number of cytotoxic TILs were associated with an improved progression-free survival (PFS) independent of prognostic confounders. rMGMs were characterized by lower numbers of TILs in general, helper, and cytotoxic TILs. The additional analysis of their activation status revealed that a proportion of PD-1+CD8+ TILs within the TIL population was significantly decreased with higher WHO grade and in rMGMs. Furthermore, lower proportions of PD-1+CD8+ TILs were associated with inferior PFS in multivariate analyses, arguing for PD-1 as activation rather than exhaustion marker.Conclusions:We identified higher numbers of CD3+CD8+FOXP3− TILs and proportions of PD-1–expressing CD3+CD8+FOXP3− TILs as novel biomarkers for better survival. These findings might facilitate the selection of patients who may benefit from immunotherapy and argue in favor of an intervention in primary rather than recurrent tumors.

Supplementary Figure Legends

Suppl. Table S1: Impact of cytotoxic T-cells on patient survival; Suppl. Table S2: Impact of PD-1-expressing cytotoxic T-cells on patient survival