Study of Relatlimab and Nivolumab (Opdualag) in Replication Repair Deficient HGG and DIPG

Inclusion Criteria:

* Patients must be ≥12 years and ≤39 years of age at the time of enrollment on TarGeT-SCR.
* Within the United States, patients must weight ≥ 40 kg at the time of enrollment. For all other countries, patients must weight ≥ 30 kg at the time of enrollment.

Diagnosis:

* Patients with newly-diagnosed HGG, including DIPG, are eligible. All patients mut have histologic confirmation from diagnostic biopsy or resection. The diagnosis of HGG, including DIPG must have been confirmed through TarGeT-SCR.
* All HGGs must be WHO Grade 3 or 4. Note: WHO Grade 2 gliomas with pontine epicenter and diffuse involvement of at least 2/3 of the pons are eligible.

Disease Status:

* Patients must be newly diagnosed.
* Measurable disease is not required.
* Patients with primary spinal tumors are eligible.
* Patients should have no evidence of herniation or impending herniation, and no mass effect leading to severe midline shift.
* Patients with prior malignancy are eligible.
* Metastatic disease is excluded.
* Disseminated or multifocal disease: discussion with Study Chairs is required. Patients with multifocal disease who received upfront CSI are not eligible.

Demonstration of DNA replication repair deficiency (RRD) by fulfilling at least 2 of the following criteria:

* Tumor mutational burden greater than or equal to 5 mutations/megabase (Intermediate and high TMB)
* Genetic diagnosis of germline Constitutional Mismatch Repair Deficiency (CMMRD), Lynch Syndrome, or Polymerase-Proofreading Deficiency (PPD)
* Validated functional genomic assay (e.g. LOGIC) confirming mismatch repair (MMR) deficiency
* Immunohistochemistry (IHC) demonstrating loss of protein expression of any of the 4 MMR genes

Performance Level: Karnofsky ≥ 50 for patients \> 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age

Prior Therapy for HGG:

* Surgery, RT, and/or dexamethasone are permissible. Temozolomide administration is highly discouraged with concurrent RT, but permissible. Anti-VEGF treatment used for vasogenic edema or steroid weaning is permitted. No other prior anticancer therapy for HGG will be allowed. Anti-VEGF use is well-established to not impact outcomes in HGG and is not considered as oncologic treatment but rather as a supportive measure to minimize steroid use in this setting. Discussion with Study Chairs is highly recommended.
* RT requirements: Patients must have received photon or proton focal RT and administered at a standard dose, including:
* 54 Gy in 30 fractions for DIPG
* 54-59.4 Gy in 30-33 fractions for other HGG
* 45-54 Gy for primary spinal cord HGG Note: Variances in RT dose within 10% of standard doses listed above are acceptable.
* Timing between diagnosis and start of RT: Patients must have started RT \< 42 calendar days from initial diagnosis.
* Timing post-RT: The earliest patent can begin protocl treatment is 28 days post-completion of RT. It is recommended treatment should begin within 25 days, however patients must start treatment on TarGeT-F no later than 8 weeks post-completion of RT.

Organ Function Requirements:

* ANC ≥ 1000/mm3
* Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).
* Hemoglobin \> 8g/dL (may be transfused)
* Creatinine clearance or radioisotope GFR≥ 70 mL/min/1.73 m2 OR serum creatinine based on age/gender as follows:

  10 to \< 13 years: 1.2 mg/dL for males and females 13 to \< 16 years: 1.5 mg/dL for males and 1.4 mg/dL for females
  * 16 years: 1.7 mg/dL for males and 1.4 mg/dL for females
* AST/ALT \< 3 times the ULN. For the purpose of this study, the ULN for ALT and AST is 45 U/L.
* Ejection fraction greater than or equal to 50% as measured by echocardiogram or multiple-gated acquisition
* QTc ≤ 480 msec (by Bazett formula)
* Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.
* TSH within institutional guidelines for normal range.

Exclusion Criteria:

* Pregnant or breastfeeding patients are excluded.
* Patients with uncontrolled infection.
* Patients with bone marrow failure syndrome.
* Participants who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
* Inflammatory bowel disease
* Moderate to severe pulmonary conditions defined by need for medical intervention and/or limiting activities of daily living or shortness of breath with limited exertion.
* Personal history of pneumonitis.
* Cardiac conditions.
* Patients with a history of severe or life-threatening adverse dermatologic reactions such as SJS or toxic epidermal necrolysis, or other severe reactions that have been associated with prior immune checkpoint inhibitor therapy.
* Active tuberculosis
* Active autoimmune disease requiring systemic treatment in the past 2 years
* Chronic HBV infections with active disease
* Personal known history of HPC who have not completed curative antiviral treatment
* Personal known history of HIV
* Receipt of any organ transplantation
* Treated with other malignancy within 1 year prior to enrollment with the exception of the following: curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, and in situ cervical cancer.
* Receipt of a live or live-attenuated vaccine within 4 weeks prior to enrollment
* Previous treatment with relatlimab
* Patients with ongoing or clinically significant illness, medical or psychiatric conditions that, in the investigator's opinion, could affect the safety of the participant, or could impair assessment of the study's results are not eligible.