Immunotherapy Before and After Surgery for Treatment of Recurrent or Progressive High Grade Glioma in Children and Young Adults

Inclusion Criteria:

1. Participants with recurrent or progressive high-grade gliomas (HGG) (World HealthOrganization (WHO) grade III or grade IV) who are candidates for surgical tumordebulking will be enrolled in this trial

2. All assessments are to occur within 14 days of registration except where otherwisenoted. The participant and their legal parent/guardian must be thoroughly informedabout all aspects of the study, including the study visit schedule and requiredevaluations and all regulatory requirements for informed consent. The writteninformed consent must be obtained from the participant and legal parent/guardianprior to enrollment

3. Have a history of previously treated histologically confirmed World HealthOrganization grade III or IV HGG. Previous first line therapy with radiation and/orchemotherapy

4. Have evidence of recurrence or progression of disease by MRI scan

5. Participants must be adequate medical candidates for surgical resection. The intentof surgical resection is to allow both cytoreduction and tumor debulking as part ofstandard of care, and also collect a minimum of 100 mg of tumor tissue for the studytissue endpoints

6. A primary goal of surgery must be cytoreduction, and not solely on diagnostic biopsy

7. Age: Participants must be > 6 months and < 25 years of age at time of enrollment

8. Karnofsky >= 50 for participants > 16 years of age and Lansky >= 50 for participants =< 16 years of age. Participants who are unable to walk because of paralysis, butwho are up in a wheelchair, will be considered ambulatory for the purpose ofassessing the performance score

9. Patients with neurological deficits should have deficits that are stable for aminimum of 1 week prior to enrollment (on stable or tapering dosing of steroids). Abaseline detailed neurological exam should clearly document the neurologic status ofthe patient at the time of enrollment on the study.

10. Prior Therapy: Participants must have fully recovered from the acute toxic effectsof all prior anti-cancer therapy and must meet the following minimum duration fromprior anti-cancer directed therapy prior to enrollment. If after the requiredtimeframe, the defined eligibility criteria are met, e.g. blood count criteria, thepatient is considered to have recovered adequately

• Cytotoxic chemotherapy or other anti-cancer agents known to bemyelosuppressive. At least 21 days after the last dose of cytotoxic ormyelosuppressive chemotherapy (42 days if prior nitrosourea)

• An interval of at least 12 weeks from the completion of radiation therapy toregistration unless there is unequivocal histologic confirmation of tumorprogression

• Hematopoietic growth factors: At least 14 days after the last dose of along-acting growth factor (e.g. pegfilgrastim) or 7 days for short actinggrowth factor. For agents that have known adverse events occurring beyond 7days after administration, this period must be extended beyond the time duringwhich adverse events (AEs) are known to occur. The duration of this intervalmust be discussed with the study chair.

• Had their last dose of biologic (anti-neoplastic agent) ≥7 days prior tostudy registration, or beyond the time during which AEs are known tooccur.

• Anti-cancer agents not known to be myelosuppressive (e.g. not associated withreduced platelet or absolute neutrophil count [ANC] counts): At least 7 daysafter the last dose of agent

• Interleukins, interferons and cytokines (other than hematopoietic growthfactors): >= 21 days after the completion of interleukins, interferon orcytokines (other than hematopoietic growth factors)

• Antibodies: >= 21 days must have elapsed from infusion of last dose ofantibody, and toxicity related to prior antibody therapy must be recovered tograde =< 1

• An interval of at least 12 weeks from prior exposure to PD-1 or PD-L1inhibitors.

• Stem cell infusion (with or without total-body irradiation (TBI)):

• Autologous stem cell infusion including boost infusion: >= 42 days

11. Participants must be willing to forego cytotoxic anti-tumor therapies exceptstudy-defined therapy while being treated on study

12. Organ Function Requirements:

• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3

• Platelet count >= 100,000/mm^3

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows:

• Age: Maximum Serum Creatinine (mg/dL)

• 6 months to < 3 years: 0.6 (male and female)

• 3 to < 6 years: 0.8 (male and female)

• 6 to < 10 years: 1 (male and female)

• 10 to < 13 years: 1.2 (male and female)

• 13 to < 16 years: 1.5 (male), 1.4 (female)

• >= 16 years: 1.7 (male), 1.4 (female)

• Bilirubin (sum of conjugated and unconjugated) =< 1.5 x upper limit of normal (ULN) for age (except participants with Gilbert syndrome who must have a totalbilirubin level of < 3.0

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x ULN

• Serum albumin >= 2

13. Pregnancy: The effects of nivolumab on the developing human fetus are unknown. Forthis reason women of child-bearing potential must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) prior tostudy entry, for the duration of study participation and 5 months after completionof therapy. Should a woman become pregnant or suspect she is pregnant while she orher partner is participating in this study, she should inform her treating physicianimmediately.

14. MRI within 28 days prior to registration.

Exclusion Criteria:

1. Current or planned participation in a study of an investigational agent or using aninvestigational device.

2. Has a diagnosis of immunodeficiency.

3. Has tumor primarily localized to the brainstem or spinal cord.

4. Has presence of diffuse leptomeningeal disease or or disseminated/multi-focaldisease, or extracranial disease.

5. Has received systemic immunosuppressive treatments (such as methotrexate,chloroquine, azathioprine, etc.), aside from anti-neoplastic chemotherapy orsystemic corticosteroids within six months of registration.

6. Participants with a concurrent condition requiring systemic treatment with eithercorticosteroids (> 0.25 mg/kg daily prednisone equivalent) or otherimmunosuppressive medications within 14 days of start of study treatment. Inhaled ortopical steroids, and adrenal replacement steroid doses > 0.25 mg/kg dailyprednisone equivalent, are permitted in the absence of active autoimmune disease.

7. Unable to taper steroids due to ongoing mass effect; a maximum dexamethasone dose of 0.1 mg/kg/day is allowed (4mg maximum), but preferably have been discontinued (inhaled or topical use of steroids is allowed).

8. Has a known history of active TB (Bacillus tuberculosis).

9. Has a known additional malignancy that is progressing or requires active treatmentwithin 3 years of registration. Exceptions include basal cell carcinoma of the skin,squamous cell carcinoma of the skin, or in situ cervical cancer that has undergonepotentially curative therapy.

10. Has active autoimmune disease that has required systemic treatment in the past 2years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment.

11. Has known history of, or any evidence of active non-infectious pneumonitis.

12. Has an active infection requiring systemic therapy.

13. Has a known hypersensitivity to any of the study therapy products.

14. Has a known history of positive test for human immunodeficiency virus (HIV) or knownacquired immunodeficiency syndrome (AIDS).

• NOTE: Testing for HIV must be performed at sites where mandated locally

15. Any prior positive test result for hepatitis B virus or hepatitis C virus indicatingpresence of virus, e.g., hepatitis B surface antigen (HBsAg, Australia antigen)positive, or hepatitis C antibody (anti-HCV) positive (except if HCV-ribonucleicacid (RNA) negative).

16. Participants who have had prior allogenic hematopoietic stem cell transplant (HSCT).

17. Any serious or uncontrolled medical disorder that, in the opinion of theinvestigator may increase the risk associated with study participation or study drugadministration, impair the ability of the participant to receive protocol therapy orinterfere with interpretation of study results.