Hypermutation as a potential predictive biomarker of immunotherapy efficacy in high-grade gliomas: a broken dream?

A high tumor mutational burden and mismatch repair deficiency are observed in 'hypermutated' high-grade gliomas (HGGs); however, the molecular characterization of this distinct subtype and whether it predicts the response to immune checkpoint inhibitors (ICIs) are largely unknown. Pembrolizumab is a valid therapeutic option for the treatment of hypermutated cancers of diverse origin, but only a few clinical trials have explored the activity of ICIs in hypermutated HGGs. HGGs appear to differ from other cancers, likely due to the prevalence of subclonal versus clonal neoantigens, which are unable to elicit an immune response with ICIs. The main aim of this review is to summarize the current knowledge on hypermutation in HGGs, focusing on the broken promises of tumor mutational burden and mismatch repair deficiency as potential biomarkers of response to ICIs. Plain language summary An interesting question arising in neuro-oncology is whether a high mutational load (a condition termed 'hypermutation') can be as immunogenic in high-grade gliomas as in other solid tumors. The most recent literature has raised the question of whether hypermutated high-grade gliomas may be 'insensitive' to immunotherapy, especially in patients pretreated with temozolomide, which is the standard of care for glioma therapy. The purpose of this review is to summarize the available evidence on hypermutated gliomas and their sensitivity to immunotherapy agents.

Automated summary

This review aims to summarize the current knowledge on hypermutation in high-grade gliomas and discusses the limitations of tumor mutational burden and mismatch repair deficiency as biomarkers for the response to immune checkpoint inhibitors.