Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency.

J Clin Oncol 2016 07 21;34(19):2206-11. Epub 2016 Mar 21.

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 Albrecht, Roy W.R. Dudley, and Nada Jabado, McGill University, Montreal, Montreal, Quebec; Samina Afzal, IWK Health Centre, Halifax, Nova Scotia; Vanan Magimairajan, Cancer Care Manitoba and University of Manitoba, Winnipeg, Manitoba, Canada; Gary Mason, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA; Roula Farah, Saint George Hospital University Medical Center, Beirut, Lebanon; Michal Yalon and Gideon Rechavi, Sheba Medical Center, Tel Hashomer; Shlomi Constantini, Rina Dvir, and Ronit Elhasid, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Michael F. Walsh, Memorial Sloan Kettering Center, New York, NY; Alyssa Reddy, University of Alabama at Birmingham, Birmingham, AL; Michael Osborn, Women's and Children's Hospital, North Adelaide, South Australia; Michael Sullivan, Jordan Hansford, and Andrew Dodgshun, Royal Children's Hospital, Melbourne, Victoria, Australia; and Nancy Klauber-Demore, Lindsay Peterson, Sunil Patel, and Scott Lindhorst, Medical University of South Carolina, Charleston, SC.

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.

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July 2016
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