Neoantigen-based Personalized DNA Vaccine in Patients With Newly Diagnosed, Unmethylated Glioblastoma

Inclusion Criteria:

• Newly diagnosed histologically confirmed MGMT unmethylated glioblastoma multiforme (WHO grade IV). Patients with secondary glioblastoma, in particular those who areIDH1 or IDH2 mutant, will not be excluded. High grade gliomas with molecularfeatures of glioblastoma will be included. MGMT methylation status must be confirmedby standard a PCR-based assay.

• Patients who had prior craniotomy with biopsy, subtotal resection, total grossresection, or re-resection will be permitted.

• Consent to genome sequencing and dbGaP-based data sharing and has provided or willprovide germline (PBMC) and tumor DNA/RNA samples of adequate quality forsequencing. (Acquisition of specimens for sequencing and the sequencing itself maybe done as part of routine care or another research project.)

• At least 18 years of age.

• 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) ≤ 3.0 x IULN

• Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients withcreatinine levels above institutional normal

• Systemic corticosteroid therapy is permitted provided dosing is no greater than 4 mgper day (dexamethasone or equivalent) on the day of vaccine administration.

• Bevacizumab will be allowed if given for symptomatic control of vasogenic edema andto avoid high dose of corticosteroids.

• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry andfor the duration of study participation, including at least 5 months (for women ofchildbearing potential) and at least 7 months (for men) after last dose of studydrug. Should a woman become pregnant or suspect she is pregnant while participatingin this study, she must inform her treating physician immediately.

• Ability to understand and willingness to sign an IRB approved written informedconsent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• As this study aims to assess the immunogenicity of personalized neoantigen DNAvaccine plus plasmid encoded IL-12 as an adjuvant, no prior immunotherapy will bepermitted.

• 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-melanomaskin cancer, any in situ cancer that has been successfully resected and cured,treated superficial bladder cancer, or any early-stage solid tumor that wassuccessfully resected without need for adjuvant radiation or chemotherapy.

• Receiving any other investigational agents within 4 weeks of beginning studytreatment.

• Known allergy, or history of serious adverse reaction to, vaccines such asanaphylaxis, hives, or respiratory difficulty.

• A history of allergic reactions attributed to compounds of similar chemical orbiologic composition to any agents used in the study.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements.

• History of immunodeficiency disorder or autoimmune condition requiring activeimmunosuppressive therapy. This includes inflammatory bowel disease, ulcerativecolitis, Crohn's disease, systemic vasculitis, scleroderma, psoriasis, multiplesclerosis, hemolytic anemia, immune-mediated thrombocytopenia, rheumatoid arthritis,systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, or otherrheumatologic disease or any other medical condition or use of medication whichmight make it difficult for the patient to complete the full course of treatments orto generate an immune response to vaccines.

• Presence of clinically significant increased intracranial pressure (e.g. impendingherniation) or hemorrhage, uncontrolled seizures, or requirement for immediatepalliative treatment.

• Pregnant and/or breastfeeding. Women of childbearing potential must have a negativepregnancy test within 7 days of first dose of vaccine.

• Presence of acute or chronic bleeding or clotting disorder that would contraindicateIM injections

• Fewer than 2 acceptable sites available for IM injection and CELLECTRA® 2000 EPconsidering the deltoid and anterolateral quadriceps muscles:

• Tattoos, keloids, or hypertrophic scars located within 2 cm of intendedadministration site

• Implantable-cardioverter-defibrillator (ICD) or pacemaker (to prevent alife-threatening arrhythmia) that is located ipsilateral to the deltoidinjection site (unless deemed acceptable by a cardiologist)

• Any metal implants or implantable medical device within the intended treatmentsite (i.e. electroporation area).