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

Authors :
Bouffet E
Larouche V
Campbell BB
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 MF
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 RW
Jabado N
Hawkins CE
Shlien A
Tabori U
Source :
Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2016 Jul 01; Vol. 34 (19), pp. 2206-11. Date of Electronic Publication: 2016 Mar 21.
Publication Year :
2016

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.<br />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.<br />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.<br />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.<br /> (© 2016 by American Society of Clinical Oncology.)

Details

Language :
English
ISSN :
1527-7755
Volume :
34
Issue :
19
Database :
MEDLINE
Journal :
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Publication Type :
Academic Journal
Accession number :
27001570
Full Text :
https://doi.org/10.1200/JCO.2016.66.6552