Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency Journal Article


Authors: Bouffet, E.; Larouche, V.; Campbell, B. B.; Merico, D.; de Borja, R.; Aronson, M.; Durno, C.; Krueger, J.; Cabric, V.; Ramaswamy, V.; Zhukova, N.; Mason, G.; Farah, R.; Afzal, S.; Yalon, M.; Rechavi, G.; Magimairajan, V.; Walsh, M. F.; Constantini, S.; Dvir, R.; Elhasid, R.; Reddy, A.; Osborn, M.; Sullivan, M.; Hansford, J.; Dodgshun, A.; Klauber-Demore, N.; Peterson, L.; Patel, S.; Lindhorst, S.; Atkinson, J.; Cohen, Z.; Laframboise, R.; Dirks, P.; Taylor, M.; Malkin, D.; Albrecht, S.; Dudley, R. W. R.; Jabado, N.; Hawkins, C. E.; Shlien, A.; Tabori, U.
Article Title: Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency
Abstract: Purpose Recurrent glioblastoma multiforme (GBM) is incurable with current therapies. Biallelic mismatch repair deficiency (bMMRD) is a highly penetrant childhood cancer syndrome often resulting in GBM characterized by a high mutational burden. Evidence suggests that high mutation and neoantigen loads are associated with response to immune checkpoint inhibition. Patients and Methods We performed exome sequencing and neoantigen prediction on 37 bMMRD cancers and compared them with childhood and adult brain neoplasms. Neoantigen prediction bMMRD GBM was compared with responsive adult cancers from multiple tissues. Two siblings with recurrent multifocal bMMRD GBM were treated with the immune checkpoint inhibitor nivolumab. Results All malignant tumors (n = 32) were hypermutant. Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations (mean, 17,740 6 standard deviation, 7,703), all other high-grade tumors were hypermutant (mean, 1,589 6 standard deviation, 1,043), similar to other cancers that responded favorably to immune checkpoint inhibitors. bMMRD GBM had a significantly higher mutational load than sporadic pediatric and adult gliomas and all other brain tumors (P , .001). bMMRD GBM harbored mean neoantigen loads seven to 16 times higher than those in immunoresponsive melanomas, lung cancers, or microsatellite-unstable GI cancers (P , .001). On the basis of these preclinical data, we treated two bMMRD siblings with recurrent multifocal GBM with the anti-programmed death-1 inhibitor nivolumab, which resulted in clinically significant responses and a profound radiologic response. Conclusion This report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and other hypermutant cancers arising from primary (genetic predisposition) or secondary MMRD. © 2016 by American Society of Clinical Oncology.
Journal Title: Journal of Clinical Oncology
Volume: 34
Issue: 19
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2016-07-01
Start Page: 2206
End Page: 2211
Language: English
DOI: 10.1200/jco.2016.66.6552
PROVIDER: scopus
PUBMED: 27001570
DOI/URL:
Notes: Article -- Export Date: 2 August 2016 -- Source: Scopus
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  1. Michael Francis Walsh
    46 Walsh