Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency
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Published:2016-07-01
Issue:19
Volume:34
Page:2206-2211
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ISSN:0732-183X
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Container-title:Journal of Clinical Oncology
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language:en
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Short-container-title:JCO
Author:
Bouffet Eric1, Larouche Valérie1, Campbell Brittany B.1, Merico Daniele1, de Borja Richard1, Aronson Melyssa1, Durno Carol1, Krueger Joerg1, Cabric Vanja1, Ramaswamy Vijay1, Zhukova Nataliya1, Mason Gary1, Farah Roula1, Afzal Samina1, Yalon Michal1, Rechavi Gideon1, Magimairajan Vanan1, Walsh Michael F.1, Constantini Shlomi1, Dvir Rina1, Elhasid Ronit1, Reddy Alyssa1, Osborn Michael1, Sullivan Michael1, Hansford Jordan1, Dodgshun Andrew1, Klauber-Demore Nancy1, Peterson Lindsay1, Patel Sunil1, Lindhorst Scott1, Atkinson Jeffrey1, Cohen Zane1, Laframboise Rachel1, Dirks Peter1, Taylor Michael1, Malkin David1, Albrecht Steffen1, Dudley Roy W.R.1, Jabado Nada1, Hawkins Cynthia E.1, Shlien Adam1, Tabori Uri1
Affiliation:
1. Eric Bouffet, Brittany B. Campbell, Daniele Merico, Richard de Borja, Carol Durno, Joerg Krueger, Vanja Cabric, Vijay Ramaswamy, Nataliya Zhukova, Peter Dirks, Michael Taylor, David Malkin, Cynthia E. Hawkins, Adam Shlien, and Uri Tabori, The Hospital for Sick Children, Toronto; Melyssa Aronson, and Zane Cohen, Zane Cohen Centre for Digestive Diseases, Mount Sinai, Ontario; Valérie Larouche and Rachel Laframboise, Université Laval, Quebec City; Jeffrey Atkinson, Montreal Children’s Hospital; Steffen...
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 ± standard deviation, 7,703), all other high-grade tumors were hypermutant (mean, 1,589 ± 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.
Publisher
American Society of Clinical Oncology (ASCO)
Subject
Cancer Research,Oncology
Cited by
663 articles.
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