This is a Phase I study to demonstrate the manufacturing feasibility and safety, and to determine the maximum tolerated dose (MTD) of RNA-LP vaccines in adult patients with recurrent glioblastoma.

This is a first in human Phase I study of RNA-LP vaccines for recurrent adult glioblastoma. Participants will receive two study drug products. The first, pp65 RNA-LP, is a messenger RNA (mRNA) pp65 vaccine given for the first 3 vaccines to try to change how the tumor behaves. The second study drug RNA-LP, given as monthly vaccines 4-15, includes pp65 mRNA and tumor RNA from each patient's tumor tissue.

Patients will may receive up to three pp65 RNA-LP vaccines (DP1) before receiving full dose monthly RNA-LPs (RNA loaded lipid particles, RNA-LPs, DP2). All participants will receive the same number of vaccines, up to 15.

The immunotherapy with RNA lipid particle (RNA-LP) vaccines is the treatment portion of this study. During this study, we will make, test and give the RNA-LP vaccine therapy. As part of this study, participants will undergo up to 4 additional MRIs.

Inclusion Criteria:

• Age >/= 18years

• Histopathologically proven GBM using the 2021 WHO Classification of Tumors of the CNS (WHO CNS5).

• Unequivocal evidence of tumor progression as documented by brain MRI scan per RANO criteria.

• Tumor must have a primary supratentorial component at the time of disease progression.

• Patients must have received surgery and completed Fractionated Radiation therapy as frontline treatment for primary disease, either alone or with concurrent therapy (including temozolomide or another systemic chemotherapy agent). Patients must be at least 12 weeks post chemoradiation completion.

• Patient must be at least 90 days from completion of prior radiation

• Any adverse events patient has experienced from prior therapy must have resolved to ≤ Gr. 1 according to CTCAE (NCI Common Terminology Criteria for Adverse Events) v5.0 prior to enrollment

• Patient must be either weaned off steroids or weaned onto physiologic dosing at the time of enrollment.

• Patient must be a candidate for surgery/biopsy as acceptable standard of care for sterile collection of tumor material in a manner suitable for RNA extraction, amplification, and loading of lipid particles (LPs).

• 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.

• 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) ≥ 1,500µl (unsupported)
  • Platelets ≥ 100/µl (unsupported for at least 3 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

• Patient must be able to give consent.

• 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.

• 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.

Exclusion Criteria:

• Patients who received prior treatment with bevacizumab.

• Known active infection (requiring treatment by antiviral or antibiotics) or immunosuppressive disease.

• Patients with multifocal recurrent disease characterized by more than one enhancing lesion separated by noncontiguous T2/FLAIR signal abnormality. Patients with recurrence outside of the original tumor site are eligible if there is stability at the original site of disease.

• Patients with uncontrolled seizure disorders

• Any patients that have received any live vaccines within 30 days prior to enrollment

• Tumors with primary localization to the brainstem or spinal cord

• 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 treatment at study treatment.
  • Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at study treatment
  • 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.
  • 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.

• Participants who are receiving any other investigational agents or who have been treated on any other therapeutic clinical protocols within 30 days prior to projected first dose of study treatment.

• Participants who are unwilling or unable to receive treatment and undergo follow-up evaluations