This is an open-label, phase 1 study to assess the safety and tolerability of EGFRvIII T cells in combination with pembrolizumab (PD-1 Inhibitor) in patients with newly diagnosed, EGFRvIII+, MGMT-unmethylated glioblastoma.

Inclusion Criteria:

1. One of the following diagnoses of GBM:

   a. Newly diagnosed glioblastoma multiforme that is histologically confirmed by pathology review of surgically resected tissue; OR b. An integrated molecular/pathologic diagnosis of diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV. This diagnosis requires patients have one of the following: i. High-level amplification of EGFR; OR ii. Combined whole chromosome 7 gain and whole chromosome 10 loss (+7/-10); OR iii. TERT promoter mutation.

2. Undergone tumor resection.

3. No prior systemic therapies, radiation, tumor-treating fields, or intratumoral therapeutic agents including Gliadel wafers are allowed. Tumor resection must be the only tumor-directed treatment that the patient has received for glioboblastoma.

4. Tumor tissue is positive for EGFRvIII expression, as performed by either the University of Pennsylvania's in-house fusion transcript panel (RNA-based assay using Illumina HiSeq platform) or NeoGenomics Laboratories (quantitative RT-PCR assay).

5. Tumor tissue is negative for MGMT promoter methylation (i.e. the tumor is MGMT-unmethylated), as performed by either the University of Pennsylvania's in-house pyrosequencing protocol or NeoGenomics Laboratories.

6. Patients ≥ 18 years of age

7. ECOG performance status 0-1

8. Provides written informed consent

9. Must have adequate organ function as measured by:

   1. White blood count ≥ 2500/mm3; platelets ≥ 100,000/mm3, hemoglobin ≥ 9.0 g/dL; without transfusion or growth factor support
   2. AST, ALT, LDH, alkaline phosphatase within 2.5 x upper normal limit, and total bilirubin ≤ 2.0 mg/dL
   3. Serum creatinine < 1.5 x upper limit of normal
   4. Adequate cardiac function (LVEF ≥ 45%)

10. Subjects of reproductive potential must agree to use acceptable birth control methods.

Exclusion Criteria:

1. Pregnant or lactating women
2. Inadequate venous access for or contraindications to leukapheresis.
3. Active Hepatitis B, hepatitis C, or HIV infection, or other active, uncontrolled infection
4. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40)
5. History of severe hypersensitivity reactions to other monoclonal antibodies which in the opinion of the investigator may post an increased risk of serious infusion reactions.
6. Requirement for immunosuppressive agents including but not limited to cyclosporine, MMF, tacrolimus, rapamycin, or anti-TNF agents within 4 weeks of eligibility confirmation by the physician-investigator.
7. Subjects with a history of known or suspected, severe or uncontrolled autoimmune or connective tissue disease. Patients with vitiligo, controlled type 1 diabetes mellitus (on stable insulin dose), residual autoimmune-related hypothyroidism (due to autoimmune condition only requiring hormone replacement), or psoriasis (not requiring systemic treatment), or conditions not expected to recur in the absence of an external trigger, are permitted to enroll.
8. Known history or current interstitial lung disease or non-infectious pneumonitis
9. Prior allogenic bone marrow or solid organ transplant

11. Any uncontrolled active medical or psychiatric disorder that would preclude participation as outlined.

12. Severe, active co-morbidity in the opinion of the physician-investigator would preclude participation in this study, including but not limited to the following:

1. Unstable angina within 6 months prior to eligibility confirmation by the physician-investigator

2. Transmural myocardial infarction within the last 6 months prior to eligibility confirmation by the physician-investigator

3. New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to eligibility confirmation by the physician-investigator.

4. Serious and inadequately controlled cardiac arrhythmia

5. Serious or non-healing wound, ulcer, or history of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to eligibility confirmation by the physician-investigator, with the exception of the craniotomy for tumor resection.

   13. Patients with tumors primarily localized to the brain stem or spinal cord.