Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy.
We present the case of a patient with a left frontal glioblastoma with primitive neuroectodermal tumor features and hypermutated genotype in the setting of a POLE germline alteration. During standard-of-care chemoradiation, the patient developed a cervical spine metastasis and was subsequently treated with pembrolizumab. Shortly thereafter, the patient developed an additional metastatic spinal lesion. Using whole-exome DNA sequencing and clonal analysis, we report changes in the subclonal architecture throughout treatment. Furthermore, a persistently high neoantigen load was observed within all tumors. Interestingly, following initiation of pembrolizumab, brisk lymphocyte infiltration was observed in the subsequently resected metastatic spinal lesion and an objective radiographic response was noted in a progressive intracranial lesion, suggestive of active central nervous system (CNS) immunosurveillance following checkpoint blockade therapy.



It is unclear whether hypermutated glioblastomas are susceptible to checkpoint blockade in adults. Herein, we provide proof of principle that glioblastomas with DNA-repair defects treated with checkpoint blockade may result in CNS immune activation, leading to clinically and immunologically significant responses. These patients may represent a genomically stratified group for whom immunotherapy could be considered. Cancer Discov; 6(11); 1230-6. ©2016 AACR.See related commentary by Snyder and Wolchok, p. 1210This article is highlighted in the In This Issue feature, p. 1197.
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.|Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri.
Tanner M
TM
Johanns
McDonnell Genome Institute, Washington University, St. Louis, Missouri.|Division of Genomics and Bioinformatics, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
Christopher A
CA
Miller
Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri.
Ian G
IG
Dorward
Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri.
Christina
C
Tsien
Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
Edward
E
Chang
Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.|Department of Pathology, University of California, San Francisco, San Francisco, California.
Arie
A
Perry
Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri.
Ravindra
R
Uppaluri
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
Cole
C
Ferguson
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
Robert E
RE
Schmidt
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
Sonika
S
Dahiya
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.|Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri.|The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri.
George
G
Ansstas
McDonnell Genome Institute, Washington University, St. Louis, Missouri. gpdunn@wustl.edu Elaine.Mardis@nationwidechildrens.org.|Division of Genomics and Bioinformatics, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.|The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri.
Elaine R
ER
Mardis
Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri. gpdunn@wustl.edu Elaine.Mardis@nationwidechildrens.org.|Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri.|The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri.
Gavin P
GP
Dunn
D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000276:immunology; D004257:DNA Polymerase II / Q000235:genetics*; D018095:Germ-Line Mutation; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D007167:Immunotherapy; D008297:Male; D000075223:Poly-ADP-Ribose Binding Proteins
D061067:Antibodies, Monoclonal, Humanized; D000075223:Poly-ADP-Ribose Binding Proteins; C582435:pembrolizumab; D004257:DNA Polymerase II; C119525:POLE protein, human
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