Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy

Cancer Discov. 2016 Nov;6(11):1230-1236. doi: 10.1158/2159-8290.CD-16-0575. Epub 2016 Sep 28.

Abstract

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.

Significance: 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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies, Monoclonal, Humanized / administration & dosage*
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Checkpoints / immunology
  • DNA Polymerase II / genetics*
  • Germ-Line Mutation
  • Glioblastoma / drug therapy*
  • Glioblastoma / genetics
  • Glioblastoma / pathology
  • Humans
  • Immunotherapy*
  • Male
  • Poly-ADP-Ribose Binding Proteins

Substances

  • Antibodies, Monoclonal, Humanized
  • Poly-ADP-Ribose Binding Proteins
  • pembrolizumab
  • DNA Polymerase II
  • POLE protein, human