The primary purpose of this study is to test the safety of Pembrolizumab and Temozolomide in treating recurrent glioblastoma and to characterize the effect of this treatment on the participants tumor and immune system..

Participants will undergo screening tests to determine if they are eligible to participate. This will involve a complete history and physical examination, vital signs, blood tests including complete blood count (CBC), and serum chemistry (CMP).

Participants will receive one cycle of Temozolomide and Pembrolizumab prior to removing recurrent tumor, followed by three weekly cycles of treatment until progression.

Inclusion Criteria:

-Inclusion Criteria Patients are eligible to be included in the only if they meet all of the following criteria

1. Histopathologically proven diagnosis of glioblastoma prior to registration, by pathology report;

2. The tumor must be confined to the supratentorial compartment

3. The tumor tissue block from the primary diagnosis must be available to be sent for pathology review, after registration.

4. History/physical examination within 7 days prior to registration

5. Karnofsky performance status ≥ 60 within 7 days prior to registration.

6. Adequate Organ Function Laboratory Values

   • Absolute neutrophil count (ANC) ≥1,500/mcL
   • Platelets ≥100,000/mcL
   • Hemoglobin ≥9.0 g/gL or ≥5.6 mmol/L, without recent transfusion
   • Creatine ≤1.7 x upper limit of normal (ULN) or Measure or Calculated creatinine clearance ≥ 60.0mL/min for subject with creatinine levels > 1.5 X institutional ULN (GFR can also be used in place of creatinine or CrCl)
   • Total bilirubin ≤ 1.5 x ULN or Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 x ULN
   • AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN or ≤ 5 x ULN for subjects with liver metastases

7. The patient must have completed chemoradiation with Radiotherapy and Temozolomide of the primary tumor according to standard of care.

8. Patients must have received no more than 3 prior therapies for Recurrent High Grade Glioma.

9. Subjects must have the ability to understand and willingness to sign a written informed consent document.

10. Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

11. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication.

12. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Exclusion Criteria:

-Exclusion Criteria Patients will be excluded from the study if they meet any of the following criteria

1. Previous use of an immunotherapy such as a vaccine therapy, dendritic cell vaccine or intracavitary or convectional enhanced delivery of therapy.

2. Prior invasive malignancy (except non-melanomatous skin cancer) within the previous three years

3. Severe, active co-morbidity defined as follows:

   • Transmural myocardial infarction or unstable angina within the last 6 months prior to registration
   • History of stroke, cerebral vascular accident (CVA) or transient ischemic attack within 6 months prior to registration
   • Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) or clinically significant peripheral vascular disease
   • Known history of Tuberculosis or acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
   • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
   • Patients with active autoimmune disease or history of autoimmune disease that might recur, will be considered on an individual basis
   • Any other major medical illnesses or psychiatric impairments that in the investigator's opinion will prevent administration or completion of protocol therapy.
   • Is pregnant or breastfeeding
   • Has received prior therapy with an anti-Programmed Death 1 (PD-1), anti- Programmed Death-ligand 1 (PD-L1), or anti- Programmed Death-ligand 1 (PD-L2) agent.

4. Patient must have < 1.5 cm midline shift pre-operative

5. History of severe hypersensitivity reaction to any monoclonal antibody including pembrolizumab.

6. Patients who cannot safely undergo MRI due to non-MRI compatible pacemaker, or other reason.