Neoepitope-based Personalized DNA Vaccine Approach in Pediatric Patients With Recurrent Central Nervous System Tumors

Step 1 Eligibility Criteria for Tissue Sequencing Inclusion Criteria: * Any patient between the ages of 12 and 25 years of age (inclusive) who was diagnosed with any of the following: * High-grade glioma (HGG); newly diagnosed patients * Diffuse midline glioma (DMG); newly diagnosed patients * A pediatric CNS (brain or spine) tumor of any histologic subtype, who has now developed recurrent or refractory disease. * All patients enrolled in this trial will receive treatment for pediatric CNS tumors, including systemic agents, investigational agents, or radiation therapy, prior to receiving the neoantigen DNA vaccine. Co-enrollment to another interventional clinical trial is permitted during the vaccine manufacture period. * Availability of tissue for sequencing to determine presence of targetable neoantigen. This may be fresh tissue collected as part of routine care, another research project, or banked fresh frozen samples from tissue obtained at time of progression from a previous biopsy, subtotal resection, total gross resection, or re-resection, with the following disease specific restrictions: * For HGG and DMG patients, tissue may be collected either at diagnosis or after tumor recurrence or progression. * For pediatric CNS tumor patients, tissue must be collected after tumor recurrence or progression. * Life expectancy \> 24 weeks. * Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable) or patient has a guardian who has the ability to understand and willingness to sign an IRB approved written informed consent document. * 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. Should a woman become pregnant or suspect she is pregnant while participating in this study, or should a man suspect he has fathered a child, s/he must inform her treating physician immediately. Step 1 Exclusion Criteria: * 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. * Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * 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. * Patients with HIV are eligible unless their CD4+ T-cell counts are \< 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended. * Presence of clinically significant increased intracranial pressure (e.g. impending herniation) or hemorrhage, uncontrolled seizures, or requirement for immediate palliative treatment. * Individuals in whom a measurement of the circumference of the thigh at the midpoint between the hip and knee is \< 35 cm. * Individuals in whom a skinfold measurement of the cutaneous and subcutaneous tissue for eligible injection sites (left and right vastus laterals muscles) 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 (e.g. hypertrophic skin patches, keloids, or other conditions which could interfere with the administration procedure or subsequent assessment of local reactogenicity) or permanent body art. * Has a metal implant or implantable device within the area of the electroporation injection or has any non-removable electronic stimulation device, such as cardiac demand pacemaker, automatic implantable cardiac defibrillator, nerve stimulator, or deep brain stimulator. * Acute or chronic, clinically significant hematologic, pulmonary, cardiovascular, or hepatic or renal functional abnormality as determined by the investigator based on medical history, physical examination, EKG, and/or laboratory screening test. * Participants with seizure disorder may be enrolled if seizures are well-controlled. Patients with neurologic deficits should have deficits that are stable for a minimum of 1 week prior to enrollment Step 2 Eligibility Criteria for Treatment Administration Inclusion Criteria: * Personalized neoantigen DNA vaccine manufactured for administration. * HGG or DMG patients ONLY: must have developed recurrent or refractory disease after receiving at least one line of prior treatment. * Karnofsky/Lansky performance status ≥ 50% * Life expectancy \> 12 weeks. * Prior therapy washout requirements (with exception of bevacizumab): * Myelosuppressive chemotherapy: Participants must have received their last dose of known myelosuppressive anticancer chemotherapy at least 3 weeks prior to first dose of vaccine or at least 6 weeks prior if nitrosurea. * Biologic agent: Participant must have received their last dose of the biologic agent at least 7 days prior to first dose of vaccine. * For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended to beyond the time during which adverse events are known to occur. The duration of this interval should be discussed with the study PI. * For biologic agents that have a prolonged half-life, the appropriate interval since last treatment should be discussed with the PI prior to first dose of vaccine. * Monoclonal antibody treatment: At least three half-lives must have elapsed prior to first dose of vaccine. Such participants should be discussed with the PI prior. * Bone Marrow Transplant: Participant must be: * ≥ 6 months since allogeneic bone marrow transplant prior to first dose of vaccine. * ≥ 3 months since autologous bone marrow/stem cell prior to first dose of vaccine. * Radiotherapy (in instances of lesions amenable to radiotherapy, such as bone metastases or metastases causing nerve impingement): The last fraction must have been at least 4 weeks prior to first dose of vaccine. * Investigational agents: The last dose must have been at least 4 weeks prior to first dose of vaccine. * Adequate bone marrow and organ function as defined below: * Absolute neutrophil count ≥ 1.5 K/cumm * Platelets ≥ 100 K/cumm * Hemoglobin level ≥ 8 g/dL * Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) * AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN * Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal * Any adverse event patients may have experienced during prior therapy must have resolved to ≤ grade 1 CTCAE v5. * Systemic corticosteroid therapy is permitted provided dosing is minimal based on age, defined as 0.1mg/kg/day with a max of 4mg daily (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 high dose of corticosteroids. Step 2 Exclusion Criteria: * No candidate neoantigen identified during the vaccine evaluation process. * Ongoing or active infection requiring systemic therapy (e.g. active HBV or HCV infection that requires treatment) or causing fever (temperature \> 38.1˚C) or subjects with unexplained fever (temperature \> 38.1˚C) within 7 days prior to the first vaccine dose. * Administration of live vaccine within 30 days prior to first dose of vaccine. Participants may receive the COVID-19 vaccine within this time period as it is not a live vaccine. * Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days of first dose of vaccine. * Syncopal episode within 12 months of first dose of vaccine.