Eligible patients will undergo focal radiation therapy after initial diagnosis as part of their standard of care per institutional guidelines. Patients must begin radiation therapy within 4 weeks of diagnosis by imaging, pathology, or surgery, whichever is later. For subjects undergoing surgery for more extensive resection, radiation therapy should be started within 4-6 weeks from surgery. Treatment should start 2-8 weeks after completion of radiation therapy. Children will receive subcutaneous injections of synthetic peptides of the H3.3.K27M epitope and tetanus toxoid-derived helper epitope (K27M/TT) emulsified in Montanide ISA-51 along with concurrent intramuscular injections of immunoadjuvant poly-ICLC every 3 weeks for 8 times. On the same day of vaccine treatment, patients will also receive intravenous (IV) nivolumab. If the patient demonstrates response to the combination therapy, patients will continue receiving nivolumab infusion every 3 weeks and may receive additional vaccinations every 6 weeks after the 8th dose for a total of 96 weeks (approximately 2 years).

Immunotherapy, particularly active vaccinations, has the potential to develop as an effective and safe modality for patients with pediatric malignant gliomas. Vaccines using specific peptides, in comparison to whole glioma-derived antigens, may induce glioma-specific immune responses without theoretical concerns of auto-immune encephalitis. Use of modified peptides (peptides in which amino acid residues are replaced from the wild-type sequence) may allow us to induce more efficient T-cell responses than natural antigens in whole glioma cells. Recent published laboratory data have also shown that administration of poly-ICLC along with the synthetic peptides remarkably enhances the induction of anti-peptide cytotoxic T lymphocyte (CTL) responses and trafficking of antigen-specific T-cells to the brain tumor sites.  PD-1 plays an important role in suppressing the immune system by inhibiting T cell inflammatory activity and has been shown to play a role in tumor evasion of the immune system. We hypothesize that the combination of PD-1 inhibition with the H3.3K27M specific peptide vaccine will improve activity of the peptide vaccine, by amplifying the response of peptide-primed T cells against the tumor.

Stratum A:

• To assess the safety of repeated administration of the H3.3K27M epitope specific vaccine in HLA-A2 (02:01)+ children with H3.3K27M positive DIPGs.

• To determine the overall survival at 12 months (OS12) in HLA-A2 (02:01)+ children with DIPG that are treated with repeated administration of the H3.3K27M peptide.

Stratum B:

• To assess the safety of repeated administration of the H3.3K27M epitope specific vaccine in HLA-A2 (02:01)+ children with H3.3K27M positive midline gliomas other than DIPG, including spinal cord gliomas.

Stratum C:

• To assess the safety of repeated administration of the H3.3K27M epitope specific vaccine in combination with the PD-1 inhibitor nivolumab in HLA-A2 (02:01)+ children with H3.3K27M positive midline gliomas including DIPG and midline gliomas (excluding spinal cord tumors).

Stratum A: Children (3-21 years old) with newly diagnosed diffuse intrinsic pontine glioma (DIPG) who are positive for the H3.3K27M mutation (positive testing in CLIA laboratory) and who have undergone standard radiation therapy. This stratum has fully enrolled and is closed to accrual. 

Stratum B: Children (3-21 years old) with newly diagnosed glioma other than DIPG, including spinal cord gliomas, who are positive for the H3.3K27M mutation (positive testing in CLIA laboratory) and who have undergone standard radiation therapy. This stratum has fully enrolled and is closed to accrual. 

Stratum C: Newly diagnosed children 3-21 years of age with diagnosis of DIPG or midline glioma other than DIPG (excluding spinal cord gliomas) who are positive for the H3.3K27M mutation (positive testing from a CLIA or equivalent laboratory required), that underwent standard radiation therapy.

The following eligibility criteria apply to strata A, B and C:

•The patient must test positive for HLA-A*02:01 (positive testing from a CLIA or equivalent laboratory required; only the HLA A*02:01 subtype is eligible; other subtypes are excluded)

•The patient must be either off systemic steroids or be on stable dose of dexamethasone (max 0.1 mg/kg/day; maximum 4mg/day) at time of enrollment.

•Patients must not have received any prior chemotherapy, immunotherapy or bone marrow transplant for the treatment of their tumor. Prior use of temozolomide during radiation at maximum of the standard pediatric dosing (defined as 90 mg/m2 /dose continuously during radiation therapy for 42 days) or dexamethasone is allowed.

•Patients must have undergone radiation therapy and surgery as part of their standard of care.

o Stratum A: Radiation therapy must have started within 4 weeks of diagnosis by imaging or surgery, whichever is later.

o Stratum B: For subjects undergoing surgery for more extensive resection, radiation therapy should be started within 4-6 weeks from surgery. 

o Stratum C: Radiation therapy must have started within 4 weeks of diagnosis by imaging or surgery, whichever is later. For subjects undergoing surgery for more extensive resection, radiation therapy should be started within 4-6 weeks from surgery.

•H3.3K27 mutation must have been confirmed in the tumor tissue in a CLIA or equivalent approved laboratory.

•Karnofsky ≥50 for patients ≥16 years of age, and Lansky ≥50 for patients < 16 years of age (See Appendix A). Patients 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.

The patient must have adequate organ function defined as:

Adequate Bone Marrow Function Defined as:

• Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 and

• Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)

Adequate Renal function defined as:

• Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 OR a serum creatinine within normal limits based on age and gender as follows:
  • Age 3 to <6 years: 0.8 (male); 0.8 (female)
  • Age 6 to < 10 years: 1 (male); 1 (female)
  • Age 10 to <13 years: 1.2 (male); 1.2 (female)
  • Age 13 to <16 years: 1.5 (male); 1.4 (female)
  • Age ≥ 16 years: 1.7 (male); 1.4 (female)

Adequate liver function defined as:

• Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age
• SGPT (ALT) ≤ 110 U/L.
• Serum albumin ≥ 2 g/dL

Adequate Pancreatic Function Defined as:

•Serum lipase ≤ ULN at baseline.

Adequate Pulmonary Function Defined as:

• No evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and a pulse oximetry of > 92% while breathing room air.

Adequate Neurologic Function Defined as:

• Patients with seizure disorder may be enrolled if seizure disorder is well controlled.

• The effects of the H3.3K27M vaccine and nivolumab on the developing human fetus are unknown.  For this reason, females of child-bearing potential and males must agree to use adequate contraception. Adequate methods include: hormonal or barrier method of birth control; or abstinence prior to study entry and for the duration of study participation.  Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.  Males treated or enrolled on this protocol must also agree to use adequate contraception prior to the study and for the duration of study participation.

• Ability to understand a written informed consent document, and the willingness to sign it. Assent will be obtained when appropriate based on the subjects age.

EXCLUSION CRITERIA

• Patients who are currently receiving another investigational drug or had prior treatment with another investigational drug are not eligible.
• Patients who are currently receiving other anti-cancer agents or had prior treatment with other anti-cancer agents are not eligible.
• Patients who have received a live / attenuated vaccine within 30 days of first treatment are not eligible.
• Patients with a known disorder that affects their immune system, such as HIV or Hepatitis B or C, or an auto-immune disorder requiring systemic cytotoxic or immunosuppressive therapy are not eligible. Note: Patients that are currently using inhaled, intranasal, ocular, topical or other non-oral or non-IV steroids are not necessarily excluded from the study but need to be discussed with the study chair.
• Patients with a ≥ Grade 2 hypothyroidism due to history of autoimmunity are not eligible. (Note: Hypothyroidism due to previous irradiation or thyroidectomy will not impact eligibility).
• Patients who have received prior solid organ or bone marrow transplantation are not eligible.
• Patients with uncontrolled infection are not eligible.
• Female patients of childbearing potential must not be pregnant or breast-feeding. Female patients of childbearing potential must have a negative serum or urine pregnancy test prior to the start of therapy (as clinically indicated).

Funding is provided by The V Foundation and BMS.