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.