Κυριακή, 10 Απριλίου 2016

IMMUNOTHERAPY FOR MSI-H GLIOBLASTOMA

Glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency was characterized by hypermutation and elevated neoantigen load—characteristics associated with response to immune checkpoint inhibitors in other settings—according to a study reported in the Journal of Clinical Oncology by Bouffet et al. Two children with recurrent biallelic mismatch repair deficiency glioblastoma multiforme were successfully treated with nivolumab (Opdivo).
High Mutation and Neoantigen Loads
The study involved exome sequencing and neoantigen prediction for a cohort of biallelic mismatch repair deficiency cancers, including 21 glioblastoma multiforme cases, and comparison with mutation and neoantigen load in other childhood and adult brain neoplasms and other cancers. All malignant tumors (n = 32) were hypermutant, with the highest mutation load exhibited by biallelic mismatch repair deficiency brain tumors (mean = 17,740 per exome, reflecting a high number of secondary polymerase mutations); all other high-grade tumors were also hypermutant (mean = 1,589 per exome), similar to the mutation load exhibited by other cancers responsive to immune checkpoint inhibitors.
The mutation load in biallelic mismatch repair deficiency glioblastoma multiforme was significantly higher than that in sporadic pediatric and adult gliomas and other brain tumors (P < .001). Mean neoantigen load in biallelic mismatch repair deficiency glioblastoma multiforme was 7 to 16 times higher than that in immunoresponsive melanomas, lung cancers, and microsatellite-unstable gastrointestinal cancers.
Nivolumab Treatment
On the basis of these findings, two biallelic mismatch repair deficiency siblings with recurrent multifocal glioblastoma multiforme were treated with the programmed cell death protein 1 (PD-1) inhibitor nivolumab as single-agent therapy, with both exhibiting remarkable and durable clinical and radiologic responses.
The investigators concluded: “This report of initial and durable responses of recurrent glioblastoma multiforme to immune checkpoint inhibition may have implications for glioblastoma multiforme in general and other hypermutant cancers arising from primary (genetic predisposition) or secondary mismatch repair deficiency.”
The study was supported by a Canadian Institute of Health Research joint Canada-Israel health research grant and grants from the Garron Family Cancer Center, BRAINchild Canada, and the McLaughlin Center.
Uri Tabori, MD, of The Hospital for Sick Children, Toronto, is the corresponding author of the Journal of Clinical Oncology article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

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