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

Eric Bouffet, Valérie Larouche, Brittany B. Campbell, Daniele Merico, Richard De Borja, Melyssa Aronson, Carol Durn, Joerg Krueger, Vanja Cabric, Vijay Ramaswamy, Nataliya Zhukova, Gary Mason, Roula Farah, Samina Afzal, Michal Yalon, Gideon Rechavi, Vanan Magimairajan, Michael F. Walsh, Shlomi Constantini, Rina DvirRonit Elhasid, Alyssa Reddy, Michael Osborn, Michael Sullivan, Jordan Hansford, Andrew Dodgshun, Nancy Klauber-Demore, Lindsay Peterson, Sunil Patel, Scott Lindhorst, Jeffrey Atkinson, Zane Cohen, Rachel Laframboise, Peter Dirks, Michael Taylor, David Malkin, Steffen Albrecht, Roy W.R. Dudley, Nada Jabado, Cynthia E. Hawkins, Adam Shlien, Uri Tabori

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540 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2206-2211
Number of pages6
JournalJournal of Clinical Oncology
Issue number19
Publication statusPublished - 1 Jul 2016
Externally publishedYes

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