A Study of RNA-lipid Particle (RNA-LP) Vaccines for Newly Diagnosed Pediatric High-Grade Gliomas (pHGG) and Adult Glioblastoma (GBM)

Stratum 1 (Adult GBM) * Age ≥ 21 years. * Histopathologically proven newly-diagnosed de novo GBM (WHO Grade IV glioma, secondary GBM not eligible) that is MGMT low level or unmethylated. * The tumor must have a supratentorial component. * Patient must have been enrolled on a screening consent and have had sterile collection of tumor material in a manner suitable for RNA extraction, amplification, and loading of lipid particles (LPs). * Residual post-surgical disease burden ≤ 3 cm as defined by longest perpendicular diameter of tumor on post-operative MRI. * Patients must have recovered from the effects of surgery, postoperative infection, and other complications. * A diagnostic contrast-enhanced MRI of the brain must be performed preoperatively and postoperatively. Pre-op MRI must be performed within 28 days prior to study enrollment. Post-op MRI must be completed within 7 days after surgery. Preoperative and postoperative scans must be the same type. * Performance Score: (KPS) ≥ 60. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. * Bone Marrow: * ANC (Absolute neutrophil count) ≥ 1,000µl (unsupported) * Platelets ≥ 150/µl (unsupported for at least 7 days) * Hemoglobin \> 8 g/dL * Renal: * BUN ≤ 25 mg/dl * Creatinine ≤ 1.7 mg/dl * Hepatic * Bilirubin ≤ 2.0 mg/dl * ALT ≤ 5 times institutional upper limits of normal for age * AST ≤ 5 times institutional upper limits of normal for age * Willing to take an antiepileptic medication such as levetiracetam for the duration of RNA-LP vaccinations * Signed informed consent. If the patient's mental status precludes his/her giving informed consent, written informed consent may be given by the legally authorized representative. * For women of childbearing potential (WOCBP), negative serum/urine pregnancy test at enrollment (test will be repeated within 72 hours prior to starting TMZ in Stratum 1 patients). * WOCBP must be willing to use acceptable contraceptive methods to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug. Refer to Appendix F for definition of WOCBP and guidance on acceptable contraceptive methods. * 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. * Participants with post-surgical neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment. Stratum 2 (Newly-diagnosed Pediatric HGG) * Age \> 3 and ≤ 25 years. * Histologically confirmed WHO Grade III or IV malignant glioma * Patient must have been enrolled on a screening consent and have had sterile collection of tumor material in a manner suitable for RNA extraction, amplification, and loading of lipid particles (LPs). * Residual post-surgical disease burden ≤ 3 cm as defined by longest diameter of tumor on post-operative MRI. * Patients must have recovered from the effects of surgery, postoperative infection, and other complications. * A diagnostic contrast-enhanced MRI of the brain must be performed preoperatively and postoperatively. Pre-op MRI must be performed within 28 days prior to study enrollment. Post-op MRI must be completed within 7 days after surgery. Preoperative and postoperative scans must be the same type. * Performance Score: Karnofsky ≥ 60 for participants \> 16 years of age and Lansky ≥ 60 for participants \< 16 years of age assessed within 2 weeks prior to enrollment. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. * Bone Marrow: 1. ANC (Absolute neutrophil count) ≥ 1,000/µl (unsupported) 2. Platelets ≥ 100/µl (unsupported for at least 7 days) 3. Hemoglobin \> 8 g/dL (may be supported) * Renal: Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73 m2 or acceptable serum creatinine based on age/gender * Hepatic: 1. Bilirubin ≤ 3 times upper limit of institutional normal for age. 2. SGPT (ALT) ≤ 5 times upper limit of institutional normal for age. 3. SGOT (AST) ≤ 5 times upper limit of institutional normal for age. * Participants who are receiving systemically-administered steroids must be on a stable or decreasing dose for \>1 week prior to enrollment. The patient steroid dose should be no more than a dexamethasone-equivalent of 2.8 mg/m2/day. Corticosteroid physiologic replacement therapy for management of pituitary/adrenal axis insufficiency and/or topical administration (e.g. inhaled or dermatologic) is allowed. * Willing to take an antiepileptic medication such as levetiracetam for the duration of RNA-LP vaccinations. * A legal parent/guardian or patient must be able to understand and be willing to sign a written informed consent and assent document, as appropriate. * For women of childbearing potential (WOCBP), negative serum/urine pregnancy test at enrollment * WOCBP must be willing to use acceptable contraceptive methods to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug. Refer to Appendix F for definition of WOCBP and guidance on acceptable contraceptive methods. * Males of child-fathering 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. * Participants with post-surgical neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment. * Patients must be enrolled on PNOC COMP prior to enrollment on PNOC020 if PNOC COMP is open to accrual at the enrolling institution. Exclusion Criteria: Stratum 1 (Adult GBM) * Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease free for ≥ 3 years. (For example, carcinoma in situ of the breast, oral cavity, and cervix are all permissible.) * MGMT Methylated tumors * Gliomatosis Cerebri * Metastases detected below the tentorium or beyond the cranial vault and leptomeningeal involvement. * Recurrent or multifocal malignant gliomas. * Metastatic or leptomeningeal disease * Residual post-surgical disease burden \> 3 cm as defined by longest perpendicular diameter on MRI. * Known HIV, Hepatitis B, or Hepatitis C seropositive. * Known active infection or immunosuppressive disease. * Participants who require corticosteroids above physiologic doses or not weaned to physiologic dosing within 1 week of scheduled vaccination. * Prior chemotherapy or radiosensitizers (including Gliadel wafers) for cancers of the head and neck region, other than TMZ prescribed during radiation for GBM (prior chemotherapy for a different cancer is allowable). * Prior radiotherapy to the head or neck, resulting in overlap of radiation fields. Radiosurgery is not permitted. * Severe, active co-morbidity, defined as follows: * Unstable angina and/or congestive heart failure requiring hospitalization. * Unstable cardiac arrhythmias, abnormalities, or transmural myocardial infarction within the last 6 months. * Acute bacterial or fungal infection requiring intravenous antibiotics at initiation of XRT/TMZ. * Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at initiation of XRT/TMZ. * Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects. * Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. * Patients with autoimmune disease requiring medical management with immunosuppressants. * Major medical illnesses or psychiatric impairments that, in the investigator's opinion, will prevent administration or completion of protocol therapy. * Active connective tissue disorders such as lupus or scleroderma that, in the investigator's opinion, place the patient at high risk for radiation toxicity. * Pregnancy or women of childbearing potential and men who are sexually active and who are unwilling or unable to use an acceptable method of contraception for the entire study period; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic. * Women of childbearing potential must not be pregnant or breast-feeding. * Prior history of brachial neuritis or Guillain-Barré syndrome. * Participants who are receiving any other investigational agents or who have been treated on any other therapeutic clinical protocols within 30 days prior to study entry. * Participants who are unwilling or unable to receive treatment and undergo follow-up evaluations Stratum 2 (Pediatric HGG) * Diffuse intrinsic pontine glioma, brainstem diffuse midline glioma, or BRAFV600E+ * Bulky disease, defined as: * Tumor with evidence of clinically significant uncal herniation, midline shift, tonsillar herniation, or brainstem infiltration, or that shows significant mass effect in either brain or spine * Tumor with extensive and diffuse multilobular involvement (\>3 lobes) * Tumor with extracranial disease * Known HIV, Hepatitis B, or Hepatitis C seropositive. * Uncontrolled seizure disorder * History of myocarditis * Receipt of any live vaccine within 30 days prior to enrollment * Known active infection or immunosuppressive disease. * Participants with significant renal, cardiac (congestive cardiac failure, myocardial infarction, myocarditis), pulmonary, hepatic or other organ dysfunction. * Severe or unstable concurrent medical conditions. * Women must not be pregnant or breast-feeding. * Participants who are receiving any other investigational agents or who have been treated on any other therapeutic clinical protocols within 30 days prior to study entry. * Participants who are unwilling or unable to receive treatment and undergo follow-up evaluations.