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

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.

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“…We also obtain PD-L1 positivity level and tumor mutational burden (TMB) on all tumors which has implications for immunotherapy (IT) use. Recent data indicates that glioma tumors with low TMB are more likely to respond to IT (19). Clinical trials have demonstrated that IT can work for intracranial metastatic disease (20,21).…”

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“…Survival differences were maintained after excluding IDH-mutated, MGMT methylated, and hypermutated patients and were not related to steroid dosage [68]. Notably, these associations were not showed in primary GBM patients [68]. Accordingly, in a recent observational study, 13 patients (eight GBM, four anaplastic astrocytomas, one anaplastic oligodendroglioma) with partial or complete loss of mismatch repair proteins had no apparent clinical benefit from pembrolizumab treatment (median PFS 2.2 months, median OS 5.6 months, no partial or complete response) [69].…”

“…Transcriptomic analyses also showed enriched inflammatory gene signatures in recurrent GBM tumors with a low TMB [68]. Survival differences were maintained after excluding IDH-mutated, MGMT methylated, and hypermutated patients and were not related to steroid dosage [68]. Notably, these associations were not showed in primary GBM patients [68].…”

“…Recently, in two cohorts stratified by TMB, recurrent GBM patients with ≤ median TMB had more prolonged survival after anti-PD-1/PD-L1 blockade than those with > median TMB [68]. Transcriptomic analyses also showed enriched inflammatory gene signatures in recurrent GBM tumors with a low TMB [68].…”

“…Recently, in two cohorts stratified by TMB, recurrent GBM patients with ≤ median TMB had more prolonged survival after anti-PD-1/PD-L1 blockade than those with > median TMB [68]. Transcriptomic analyses also showed enriched inflammatory gene signatures in recurrent GBM tumors with a low TMB [68]. Survival differences were maintained after excluding IDH-mutated, MGMT methylated, and hypermutated patients and were not related to steroid dosage [68].…”