Inclusion Criteria:
* Histologic confirmation of glioblastoma, WHO Grade IV (GBM variants are allowed; Lower grade gliomas that have been transformed to GBM will be considered newly diagnosed GBM if the lower-grade tumor was not previously treated, and the standard treatment for GBM including radiation and temozolomide is now planned).
* MGMT methylation status if available (indeterminate methylation status will be considered unmethylated).
* Karnofsky performance status (KPS) ≥70%.
* Patients must be at least 18 years of age.
* Received maximal safe resection (biopsy only allowed) and radiotherapy concomitant with temozolomide:
1. Gliadel wafers placement at the time of surgical resection is allowed.
2. Any additional treatment directed at GBM will be considered exclusionary.
3. Minimum dose for concomitant radiotherapy is 40 Gy.
* Candidate for adjuvant high dose temozolomide and Optune therapy.
* Life expectancy of at least 3 months.
* Adequate bone marrow and organ function as defined below:
1. ANC ≥ 1,500/mcL
2. Platelets ≥ 100,000/mcL
3. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L (transfusion is allowed)
4. Serum creatinine ≤ 1.5 x IULN OR creatinine clearance by Cockcroft-Gault ≥ 60 mL/min for patients with serum creatinine \> 1.5 x IULN
5. Serum total bilirubin ≤ 1.5 x IULN OR direct bilirubin ≤ IULN for patients with total bilirubin \> 1.5 x IULN
6. AST (SGOT) and ALT (SGPT) ≤ 3 x IULN
* Participants of childbearing age must use effective contraception:
* Women of childbearing potential (WOCBP) must be using a highly effective method of contraception to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug to minimize the risk of pregnancy. Prior to study enrollment, women of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. Refer to Appendix D for guidance on highly effective contraceptive methods.
* WOCBP include any woman who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or oophorectomy) or who is not post-menopausal. Post-menopause is defined as:
* Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or
* For women with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL.
* Males with female partners of childbearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 24 weeks following the last dose of study drug.
* Ability of the patient or their legally authorized representative (LAR) to understand and willingness to sign an IRB approved written informed consent document
* Steroid dose equivalent to dexamethasone dose of ≤ 4mg daily at the time of starting adjuvant treatment
* Optune and temozolomide treatment start date will be at least 4 weeks but not more than 6 weeks from the later of last dose of concomitant temozolomide or radiotherapy. Although Optune and temozolomide should be started simultaneously, it is not required as long as both are started within this time frame
Exclusion Criteria:
* Prior treatment with anti-angiogenic agents including bevacizumab.
* History of other malignancy that, in the primary oncologist's estimation, has a higher risk of recurrence or death than the study-related cancer at the time of study participation.
* Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
* Progressive disease (according to RANO criteria). Advanced imaging is allowed to further investigate suspected pseudoprogression if deemed necessary.
* Actively participating in another clinical treatment trial intended to treat GBM.
* Multifocal gliomas defined as distinct tumors that do not have overlapping T2/FLAIR signal.
* Presence of leptomeningeal metastases.
* Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, other implanted electronic devices in the brain, or documented clinically significant arrhythmias.
* Tumor is entirely located in the infra-tentorial region.
* History of hypersensitivity reactions or allergies to hydrogels and/or compounds of similar chemical or biologic composition to Temozolomide and Pembrolizumab.
* Steroid dose equivalent to \> 4 mg dexamethasone at the time of starting adjuvant therapy.
* History of immunodeficiency or is receiving any form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment (with the exception of daily dexamethasone ≤ 4 mg).
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension, or psychiatric illness/social situations that would limit compliance with study requirements.
* History of active autoimmune disease requiring systemic treatment within the past 2 years (i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 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.
* History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
* Pregnant and/or breastfeeding. Patient must have a negative serum or urine pregnancy test within 72 hours of study entry.
* Females or males of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 24 weeks after the last dose of study drug.
* Known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA \[qualitative\] is detected) infection.
* Known history of active TB (bacillus tuberculosis).
* Known history of HIV (HIV 1/2 antibodies).
