Inclusion Criteria:

• Age ≥ 18 years.
• Histological confirmation of supratentorial glioblastoma (also known as astrocytoma Grade IV, gliosarcoma).
• Neoadjuvant patients only: Have an enhancing mass on MRI amenable to > 90% resection of contrastenhancing tumor (as determined by the neurosurgeon pre-operatively) and histological diagnosis of glioblastoma from a prior biopsy or surgery.
  • NOTE: Biopsy or subtotal resection must have been ≤ 43 days prior to registration.
• Neoadjuvant patients only: Willing to undergo craniotomy and resection of their glioblastoma at Mayo Clinic in Rochester, MN.
• Adjuvant patients only: Must have undergone craniotomy and resection of their glioblastoma ≤ 6 weeks prior to registration.
• ECOG Performance Status (PS) of 0 or 1.
• The following laboratory values obtained ≤ 28 days prior to registration:
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3;
  • Platelet count ≥ 100,000/mm^3;
  • Hemoglobin ≥ 9.0 g/dL without transfusion or EPO dependency (≤7 days prior to assessment);
  • Prothrombin Time (PT) ≤ 1.5 x ULN unless patient is receiving anticoagulant therapy and PT or PTT is within therapeutic range of intended use of coagulants;
  • Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN unless patient is receiving anticoagulant therapy and PT or PTT is within therapeutic range of intended use of coagulants;
  • Albumin ≥ 2.5 mg/dL;
  • Total bilirubin ≤ 1.5 x ULN OR Direct bilirubin ≤ULN for patients with total bilirubin levels > 1.5 x ULN;
  • Aspartate transaminase (AST) AND alanine transaminase (ALT) ≤ 2.5 x ULN;
  • Creatinine ≤ 1.0 x ULN OR measured or calculated creatinine clearance (per institutional standard) must be ≥ 60 ml/min.
• Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only (POCBP).
  • NOTE: Serum or urine pregnancy test allowed. If urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• POCBP must be willing to use adequate contraception starting with first dose through 120 days after last dose.
• Provide written informed consent.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
  • Note: During the Active Monitoring Phase of a study (i.e., active treatment and observation), participants must be willing to return to the consenting institution for follow-up. 3.19c Willing to provide tissue and blood samples for correlative research purposes.

Exclusion Criteria:

• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential who are unwilling to employ adequate contraception.
• Neoadjuvant patients only: Signs or symptoms of life-threatening raised intracranial pressure: as defined by the treating neurosurgeon, including severe headache, nausea, decreasing level of consciousness, precluding 4-7 day delay in scheduling neurosurgery.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Other active malignancy ≤ 5 years prior to registration.
  • EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.
  • NOTE: If there is a history or prior malignancy, the patient must not be receiving other specific treatment for their cancer.
• History of myocardial infarction ≤6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
  • NOTE: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
• Known history of active TB (Bacillus Tuberculosis).
• Received a live vaccine ≤ 30 days prior to registration.
• History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Hypersensitivity to pembrolizumab or any of its excipients.
• Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Received or planning to receive Optune® device.