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Updated: Nov 28, 2025
Evaluation of Biomarkers in Glioma by Immunohistochemistry on Paraffin-Embedded 3D Glioma Neurosphere Cultures
Published on: January 9, 2019
What is the Burden of Proof for Tumor Mutational Burden in gliomas?
Mustafa Khasraw1, Kyle M Walsh1, Amy B Heimberger2
1Preston Robert Tisch Brain Tumor Center at Duke, Departments of Neurosurgery, Duke University Medical Center, Durham, NC.
Abstract:
The treatment of patients with a variety of solid tumors has benefitted from immune checkpoint inhibition targeting the anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis. The US Food and Drug Administration (FDA) granted accelerated approval of PD-1 inhibitor pembrolizumab for the treatment of adult and pediatric patients with TMB-high (TMB-H), solid tumors that have progressed following prior treatment and who have no other treatment options, including the extension to tumors of the Central Nervous System (CNS). In general, pan-cancer approvals are viewed positively to empower patients and clinicians. There are subsets (eg, BRAF, NTRK) for which this pathway for approval is appropriate. However, the pan-cancer FDA approval of pembrolizumab raises several concerns regarding the generalizability of the evidence to other tumor types, including managing patients with gliomas and other CNS tumors. The cut off for TMB-H is not well defined. There are intrinsic immunological differences between gliomas and other cancers types, including the immunosuppressive glioma microenvironment, the tumor's effects on systemic immune function, and the transformation of the T cell populations to an exhausted phenotype in glioma. Here we address the caveats with pan-cancer approvals concerning gliomas, complexities of the unique CNS immune environment, and discuss potential predictive biomarkers, including TMB, and explain why the recent approval should be applied with caution in CNS tumors.
Insights
Pembrolizumab shows promise for solid tumors, but its pan-cancer approval warrants caution for brain cancers. Further research is needed to understand its efficacy in the unique CNS immune environment.
Area of Science:
- Oncology
- Immunology
- Neuro-oncology
Background:
- Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis have advanced solid tumor treatment.
- The US Food and Drug Administration (FDA) granted accelerated approval for PD-1 inhibitor pembrolizumab in TMB-high (TMB-H) solid tumors, including Central Nervous System (CNS) tumors, that progressed on prior therapy.
Purpose of the Study:
- To address concerns regarding the generalizability of pan-cancer approvals, specifically pembrolizumab, to gliomas and other CNS tumors.
- To discuss the complexities of the CNS immune environment and its implications for immunotherapy efficacy.
- To evaluate the utility of tumor mutational burden (TMB) as a predictive biomarker in CNS tumors.
Main Methods:
- Review of current literature on immune checkpoint inhibition in solid tumors and CNS cancers.
- Analysis of the immunological differences between gliomas and other cancer types.
- Discussion of potential predictive biomarkers for immunotherapy response in CNS tumors.
Main Results:
- Pan-cancer approvals, while generally positive, raise concerns about applicability to specific tumor types like gliomas due to unique tumor microenvironments and systemic immune effects.
- The definition of TMB-high (TMB-H) is not consistently defined, impacting its utility as a universal biomarker.
- Gliomas exhibit intrinsic immunosuppressive characteristics and T cell exhaustion, potentially limiting pembrolizumab's effectiveness.
Conclusions:
- The pan-cancer approval of pembrolizumab requires cautious application in CNS tumors, particularly gliomas.
- Understanding the unique CNS immune microenvironment is crucial for predicting immunotherapy response.
- Further investigation into predictive biomarkers beyond TMB is necessary for optimizing immunotherapy in brain cancers.
