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

Abstract:

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.

journal_name

Neuro Oncol

journal_title

Neuro-oncology

authors

Garber ST,Hashimoto Y,Weathers SP,Xiu J,Gatalica Z,Verhaak RG,Zhou S,Fuller GN,Khasraw M,de Groot J,Reddy SK,Spetzler D,Heimberger AB

doi

10.1093/neuonc/now132

subject

Has Abstract

pub_date

2016-10-01 00:00:00

pages

1357-66

issue

10

eissn

1522-8517

issn

1523-5866

pii

now132

journal_volume

18

pub_type

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