Step 1 Inclusion Criteria for Tissue Sequencing:
* Newly diagnosed histologically or molecularly consistent with WHO grade IV high grade glioma, IDH wildtype.
* Patients who had prior craniotomy with biopsy, subtotal resection, total gross resection, or re-resection will be permitted.
* Consent to genome sequencing and dbGaP-based data sharing and has provided or will provide germline (PBMC) and tumor DNA/RNA samples of adequate quality for sequencing. (Acquisition of specimens for sequencing and the sequencing itself may be done as part of routine care or another research project.)
* At least 18 years of age.
* Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
Step 2 Inclusion Criteria for Treatment Administration:
* Confirmed MGMT promoter unmethylated glioblastoma multiforme. Patients with secondary glioblastoma, in particular those who are IDH1 or IDH2 mutant, will not be excluded. High grade gliomas with molecular features of glioblastoma will be included. MGMT promoter methylation status must be determined by a standard PCR-based assay.
Note: While tissue sequencing can begin prior to confirmation of MGMT promotor status, the manufacturing process will not begin until MGMT promotor is confirmed as unmethylated.
* Personalized neoantigen DNA vaccine manufactured for administration.
* Karnofsky performance status ≥ 60%
* Normal bone marrow and organ function as defined below:
* Absolute neutrophil count ≥ 1,500/mcL
* Platelets ≥ 100,000/mcL
* Total bilirubin ≤ 1.5 x IULN
* AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN
* Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
* Systemic corticosteroid therapy is permitted provided dosing is no greater than 2 mg per day (dexamethasone or equivalent) on the day of vaccine administration. Participants using topical, ocular, intra-articular, or intranasal/inhaled steroids may participate. Brief courses of corticosteroids for prophylaxis (eg, contrast dye allergy) or study treatment-related standard premedication are permitted.
* Bevacizumab will be allowed if given for symptomatic control of vasogenic edema and to avoid corticosteroid use.
* Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation, including at least 5 months (for women of childbearing potential) and at least 7 months (for men) after last dose of study drug. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
* Patients who require additional surgery prior to vaccination (craniotomy with biopsy, subtotal resection, total gross resection, or laser interstitial thermal therapy (LITT) laser ablation) will not be considered ineligible.
Step 2 Exclusion Criteria:
* As this study aims to assess the immunogenicity of a personalized neoantigen DNA vaccine in combination with checkpoint blockade, no prior immunotherapy will be permitted.
* Inadequate tissue acquisition to allow for neoantigen screening.
* No candidate neoantigen identified during screening.
* A history of other malignancy ≤ 3 years previous with the exception of non-melanoma skin cancer, any in situ cancer that has been successfully resected and cured, treated superficial bladder cancer, or any early-stage solid tumor that was successfully resected without need for adjuvant radiation or chemotherapy.
* Known allergy, or history of serious adverse reaction to, vaccines such as anaphylaxis, hives, or respiratory difficulty.
* A history of allergic reactions attributed to compounds of similar chemical or biologic composition to any agents used in the study.
* History of immunodeficiency disorder or autoimmune condition requiring active immunosuppressive therapy. This includes inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic vasculitis, scleroderma, psoriasis, multiple sclerosis, hemolytic anemia, immune-mediated thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, or other rheumatologic disease or any other medical condition or use of medication which might make it difficult for the patient to complete the full course of treatments or to generate an immune response to vaccines.
* Presence of acute or chronic bleeding or clotting disorder that would contraindicate IM injections.
* Presence of a cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is located ipsilateral to the intended deltoid injection site (unless deemed acceptable by a Cardiologist).
* Presence of any metal implants or implantable medical device within the electroporation area.
* Any active uncontrolled neurologic disorder, including seizures and epilepsy.
* Recurrent known vasovagal-related syncopal episodes resulting in loss of consciousness.
* Individuals in whom skin pinch thickness for all eligible injection sites exceeds 50 mm.
* Individuals in whom the ability to observe possible local reactions at the eligible injection sites is, in the opinion of the investigator, unacceptably obscured due to a physical condition or permanent body art.
* History of organ transplant, including allogeneic stem cell transplantation.
* Receiving any other investigational agents within 4 weeks of beginning study treatment.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring systemic antibiotics or antifungal treatment, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Evidence of interstitial lung disease, history of interstitial lung disease, or active, non-infectious pneumonitis.
* Presence of clinically significant increased intracranial pressure (e.g. impending herniation) or hemorrhage, uncontrolled seizures, or requirement for immediate palliative treatment.
* Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days of first dose of vaccine.
* Has received a live vaccine within 28 days of the planned start of study drug. Participants may receive the COVID-19 vaccine as long as it is not a live vaccine. COVID-19 vaccination will be captured in the eCRF as a concomitant medication. Administration of study treatment may be delayed to ensure vaccination is completed.
* Active HBV or HCV infection that requires treatment. Hepatitis B virus DNA and HCV RNA must be undetectable upon testing. Participants who have cleared a prior HBV infection (defined as HBsAg negative, hepatitis B surface antibody positive, hepatitis B core antibody positive) are eligible for the study.
* Note: For participants with cleared prior HBV infection, HBV prophylaxis should be considered per the investigator's discretion. Monitor for HBV reactivation every 3 cycles by performing HBV viral load and HBsAg serology test. Additional viral serologic testing may be performed at the investigator's discretion.
* Note: Participants with no prior history of HBV infection who have been vaccinated against HBV and who have a positive test result for antibody to hepatitis B surface antigen as the only evidence of prior exposure may participate in the study.
* Note: Hepatitis C antibody-positive participants who received and completed treatment for hepatitis C that was intended to eradicate the virus may participate if HCV RNA levels are undetectable.
