Tuesday 28 April 2020

Major study of hypermutated gliomas published in Nature

Mechanisms and therapeutic implications of hypermutation in gliomas.
https://www.ncbi.nlm.nih.gov/pubmed/32322066
https://sci-hub.tw/10.1038/s41586-020-2209-9  (sci-hub link to the full PDF document)

Unfortunately this study provides negative evidence to the idea that hypermutated gliomas would be more responsive to treatment with PD-1 blockers such as nivolumab and pembrolizumab.

from the study
"MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. "

"Because our prior analyses indicated that patients with hypermutated gliomas might have reduced survival, we used a second set of historical controls to compare the outcome of hypermutated gliomas treated with PD-1 blockade versus other systemic agents. Unexpectedly, we observed a longer median OS for patients treated with other systemic agents when compared to those treated with PD-1 blockade"

However, the mismatch repair deficient, hypermutated tumor cells were sensitive to the chemotherapy agent CCNU (lomustine).

"We next treated native and engineered isogenic MMR-knockout glioma models with temozolomide or the nitrosourea lomustine (CCNU), a chloroethylating alkylating agent that generates DNA interstrand crosslinks and double-strand breaks (Fig. 2c, Extended Data Fig. 8g–i). All MMR-deficient models were resistant to temozolomide and sensitive to CCNU, consistent with the lack of hypermutation in samples from nitrosourea-treated patients"


This confirms advice I've given to patients with temozolomide-driven hypermutated recurrent gliomas: CCNU (lomustine) chemotherapy is probably the best choice in terms of conventional chemotherapy options.  However it argues against advice that PD-1/PD-L1 blockade (drugs such as pembrolizumab or nivolumab) would be the best option.

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