Please note, this study has closed to accrual and is no longer accepting patients. || 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).

Funding is provided by The V Foundation and BMS.