Overview

This is a single institution, open-label, multi-arm, phase I study assessing the safety and immunogenicity of a personalized neoantigen-based personalized DNA vaccine combined with PD-1 blockade therapy in subjects with newly diagnosed, MGMT promoter unmethylated glioblastoma (GBM).

Immune checkpoint blockade, specifically those targeting the PD-1/PD-L1 pathways, has shown efficacy in multiple solid and hematologic malignancies. Furthermore, as has been demonstrated in metastatic melanoma, combining PD-1/PD-L1 blockade with other immune checkpoint inhibitors has shown improved objective response rates, though there is a significant increase in serious immune-related adverse events. As such, current trials are exploring different doses, administration schedules, and immune checkpoint agents. One alternative approach, however, is to introduce a tumor-directed therapy such as a personalized neoantigen vaccine combined with these immune modulating agents (i.e. immune checkpoint blocking antibodies) to maximize the tumor-specific response but minimize the toxicity associated with increasing non-specific systemic immune activation by generating a potent and focused neoantigen specific immune response.

This study will test the hypothesis that a personalized neoantigen DNA vaccine in combination with concurrent administration of immune checkpoint blockade therapy will enhance the magnitude and breadth of neoantigen-specific T cell responses while maintaining an acceptable safety profile. The overall goal of this study is to identify the optimal vaccine plus adjuvant platform that can be tested in a subsequent phase II study to determine the efficacy of a personalized neoantigen vaccine approach in patients with GBM.

Eligibility

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.