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

Abstract

We present the case of a patient with a left frontal glioblastoma with PNET 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 CNS immunosurveillance following checkpoint blockade therapy.

Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment

“…Second, we identified a correlation between hypermutation and increased frequency of CD8 + lymphocytes, both at primary diagnosis and at disease recurrence, albeit with different mutational signatures. This subset of patients may be responsive to checkpoint inhibition blockade, to which limited successes have been reported (Bouffet et al, 2016; Johanns et al, 2016). …”

Replicative DNA polymerase defects in human cancers: Consequences, mechanisms, and implications for therapy

“…Other hypermutated tumors such as melanomas and lung cancers are also highly immunogenic [95,96]. Consequently, hypermutated tumors, including rare relapses of POLE -mutant EC, have responded well to immunotherapy [42,93,95– 97]. While further studies are needed, this may indicate that immunotherapy alone, if necessary, could replace radiation and chemotherapy after surgery in these cases.…”

Targeting Neoantigens in Glioblastoma

“…The use of neoantigen load as a biomarker to identify patients that may benefit from checkpoint inhibitor therapy also appears to apply to patients with GBM. In 2 recent studies, both an adult patient with a hypermutated GBM secondary to a germline POLE mutation 106 as well as 2 pediatric patients with GBM due to germline biallelic mismatch repair deficiencies 107 were shown to have dramatic responses to anti-PD-1 therapy after having progressed on standard of care treatment. While the overall incidence of patients with hypermutated GBM is relatively low at time of diagnosis, 108 there is growing appreciation that a subset of recurrent GBM, approximately 20% to 25%, acquire a hypermutated phenotype at time of recurrence due to an acquired deficiency in the mismatch repair pathway.…”