Immune checkpoint blockade as a potential therapeutic target: surveying CNS malignancies.

Journal Article (Journal Article)

Background

Expression of programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) across glioma grades is undocumented, and their interactions with commonly expressed genetic and epigenetic alterations are undefined but nonetheless highly relevant to combinatorial treatments.

Methods

Patients with CNS malignancies were profiled by Caris Life Sciences from 2009 to 2016. Immunohistochemistry findings for PD-1 on tumor-infiltrating lymphocytes (TIL) and PD-L1 on tumor cells were available for 347 cases. Next-generation sequencing, pyrosequencing, immunohistochemistry, fragment analysis, and fluorescence in situ hybridization were used to determine isocitrate dehydrogenase 1 (IDH1), phosphatase and tensin homolog (PTEN), and tumor protein 53 mutational status, O(6)-DNA methylguanine-methyltransferase promoter methylation (MGMT-Me) status, PTEN expression, plus epidermal growth factor receptor variant III and 1p/19q codeletion status.

Results

PD-1+ TIL expression and grade IV gliomas were significantly positively correlated (odds ratio [OR]: 6.363; 95% CI: 1.263, 96.236)-especially in gliosarcomas compared with glioblastoma multiforme (P = .014). PD-L1 expression was significantly correlated with tumor grade with all PD-L1+ cases (n = 21) being associated with grade IV gliomas. PD-1+ TIL expression and PD-L1 expression were significantly correlated (OR: 5.209; 95% CI: 1.555, 20.144). Mutations of PTEN, tumor protein 53, BRAF, IDH1, and epidermal growth factor receptor or MGMT-Me did not associate with increased intratumoral expression of either PD-1+ TIL or PD-L1 in glioblastoma multiforme even before false discovery rate correction for multiple comparison.

Conclusions

Targeting immune checkpoints in combination with other therapeutics based on positive biomarker selection will require screening of large patient cohorts.

Full Text

Duke Authors

Cited Authors

  • Garber, ST; Hashimoto, Y; Weathers, S-P; Xiu, J; Gatalica, Z; Verhaak, RGW; Zhou, S; Fuller, GN; Khasraw, M; de Groot, J; Reddy, SK; Spetzler, D; Heimberger, AB

Published Date

  • October 2016

Published In

Volume / Issue

  • 18 / 10

Start / End Page

  • 1357 - 1366

PubMed ID

  • 27370400

Pubmed Central ID

  • PMC5035527

Electronic International Standard Serial Number (EISSN)

  • 1523-5866

International Standard Serial Number (ISSN)

  • 1522-8517

Digital Object Identifier (DOI)

  • 10.1093/neuonc/now132

Language

  • eng