This is 3-arm, multicenter study that will be conducted through the Pacific Pediatric Neuro-oncology Consortium (PNOC). This study will assess the safety and immune activity of a synthetic peptide vaccine specific for the Histone 3 lysine27-to-methionine (H3.3K27M) epitope given in combination with poly-ICLC and the H3.3K27M epitope given in combination with poly-ICLC and the PD-1 inhibitor, nivolumab, in HLA-A2 (02:01)+ children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or other midline gliomas that are positive for H3.3K27M.

Participants who are eligible will receive a specific peptide vaccine, along with a helper drug called poly-ICLC, in combination with nivolumab, every 3 weeks for the first 6 months of treatment. Participants will be monitored routinely by laboratory assessments, physical evaluation, vital signs, and MRI. Participants who tolerate therapy well and have stable or improved disease after 6 months of treatment can continue to receive treatment, nivolumab continuing every 3 weeks but vaccine and poly-ICLC now every 6 weeks, for a total of 96 weeks of treatment.

Inclusion Criteria:

• Stratum A:

  • Newly diagnosed children (3-21 years old) with DIPG who are positive for the H3.3K27M mutation (positive testing in Clinical Laboratory Improvement Amendments (CLIA) laboratory) that underwent standard radiation therapy.

• Stratum B:

  • Newly diagnosed children (3-21 years old) with diagnosis of glioma other than DIPG who are positive for the H3.3K27M mutation (positive testing in CLIA laboratory) including spinal cord gliomas that underwent standard radiation therapy.

• Stratum C:

  • Newly diagnosed children 3-21 years of age with diagnosis of DIPG or midline glioma other than DIPG (excluding primary 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 or equivalent (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/m^2/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.

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

• 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 glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m2 or
• A serum creatinine based on age/gender as follows:

Age Maximum Serum Creatinine (mg/dL) Male Female 3 to < 6 years 0.8 0.8 6 to < 10 years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4 The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the Center for Disease Control (CDC).

Adequate Liver Function Defined as:

• Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age and
• serum glutamic-pyruvic transaminase (SGPT)/ alanine aminotransferase (ALT) ≤ 110 U/L and
• 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:

• Investigational Drugs

  • Patients who are currently receiving another investigational drug are not eligible.
  • Prior treatment with another investigational drug.

• Anti-cancer Agents

  • Patients who are currently receiving other anti-cancer agents are not eligible.
  • Prior treatment with other anti-cancer agents.

• Patients who have received a live / attenuated vaccine within 30 days of first treatment.

• Patients with evidence of disseminated or leptomeningeal disease.

• 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.

• 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).