Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy

Matthias Gromeier,Allan H Friedman,Michael C Brown,Eric Lipp ,Smita K Nair,Roger E Mclendon,Nike Beaubier,Frederick S Varn,Katherine B Peters,Henry S Friedman,Andrea Muscat ,Mustafa Khasraw,Dani P Bolognesi,Gao Zhang,Roel Verhaak ,Yiping He,John H Sampson,Frances Mcsherry,Junfei Zhao,Zhi Wei,Annick Desjardins,Darell D Bigner,Hai Yan,James E Herndon,Dina Randazzo,Yeqing Chen,Xiang Lin,David Ashley

doi:10.1038/s41467-020-20469-6

Abstract

Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10–20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.

Highlights

Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10–20% of patients
Some hypermutant gliomas with mismatch repair (MMR) deficiency are less responsive to PD1 blockade than gliomas with lower TMB9, and a non-significant inverse relationship between tumor mutation burden (TMB) and radiographic/histological responses to PD1 blockade was observed in an recurrent GBM (rGBM) patient cohort[10]
Survival differences upon stratification by TMB, time to recurrence, and TP53 mutation status were maintained after excluding patients with IDH1 mutation and/or MGMT promoter methylation (Supplementary Fig. 2); survival differences upon stratification by TMB were observed after exclusion of patients with PTEN mutations (Supplementary Fig. 2k)

Summary

Introduction

Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10–20% of patients. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Subsets of rGBM patients have responded to other virotherapy approaches[4] or immune checkpoint blockade (ICB)[5] Such dichotomous responses have been observed in other indications after ICB therapy[6], inspiring investigation into predictive biomarkers of ICB response[7]. RGBM tumors with lower TMB have enriched inflammatory gene signatures relative to rGBM tumors with higher TMB levels This correlation is not observed in primary GBM tumors, indicating that a relationship between tumor-intrinsic inflammation and TMB develops upon recurrence in GBM

Methods

Results

Conclusion