Who can participate?

Inclusion Criteria:
Tumor

• Patients must have a histologically confirmed diagnosis of recurrent, progressive or refractory non-brainstem high-grade glioma; or
• A diffuse intrinsic pontine glioma (DIPG) that is recurrent, progressive, or refractory; histologic diagnosis is not required for patients with typical imaging findings of DIPG (defined as patients with a diffuse expansile mass centered in and involving at least 2/3 of the pons); patients with brainstem tumors who have undergone biopsy with a diagnosis of high-grade glioma or diffuse infiltrating glioma are also eligible
• Patients with non-brainstem high grade glioma must have adequate pre-trial formalin-fixed, paraffin-embedded (FFPE) tumor material available for use in the biology studies; while tissue is required for PD-1 and PD-L1 patients will be deemed eligible with a minimum of 5 unstained slides for the PD-1/PD-L1 immunohistochemical analysis
• All subjects must have measurable disease in 2-dimensions on MRI scan of the brain and/or spine 
• Patients must have received prior radiation therapy and/or chemotherapy and recovered from the acute treatment related toxicities (defined as =< grade 1 if not defined in eligibility criteria) of all prior chemotherapy, immunotherapy or radiotherapy prior to entering this study; there is no upper limit to the number of prior therapies that is allowed
• Patients must have received their last dose of known myelosuppressive anticancer therapy at least three (3) weeks prior to study enrollment or at least six (6) weeks if prior nitrosourea 
• Investigational/biologic agent:
• Biologic or investigational agent (anti-neoplastic): patient must have received their last dose of the investigational or biologic agent >= 7 days prior to study enrollment
  • For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration must be discussed with and approved by the study chair
• Monoclonal antibody treatment and/or agents with prolonged half-lives: at least three half-lives must have elapsed prior to enrollment
• Patient must have completed immunotherapy (e.g. tumor vaccines, oncolytic viruses, etc.) at least 42 days prior to registration
• Patients must have had their last fraction of:
• Craniospinal irradiation >= 3 months prior to enrollment
• Other substantial bone marrow irradiation >= 6 weeks prior to enrollment
• Local palliative radiation therapy (XRT) (small port) >= 2 weeks
• Patient must be >= 12 weeks since autologous bone marrow/stem cell transplant prior to enrollment
• All races and ethnic groups are eligible for this study 
• Patients with neurological deficits should have deficits that are completely stable for a minimum of 1 week prior to enrollment
• Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score (LPS for =< 16 years of age) assessed within two weeks of enrollment must be >= 50; patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score 
• Absolute neutrophil count >= 1,000/mm^3
• Platelets >= 100,000/mm^3 (unsupported, defined as no platelet transfusion within 7 days) 
• Hemoglobin >= 8 g/dl (may receive transfusions)
• Total bilirubin =< 1.5 times institutional upper limit of normal (ULN) 
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal
• Albumin >= 2 g/dl 
• Serum creatinine based on age/gender as noted below; patients that do not meet the criteria below but have a 24 hour creatinine clearance or glomerular filtration rate (GFR) (radioisotope or iothalamate) >= 70 ml/min/1.73 m^2 are eligible
•  ◦1 to < 2 years: 0.6 mg/dl
• ◦2 to < 6 years: 0.8 mg/dl
• ◦6 to < 10 years: 1 mg/dl
• ◦10 to < 13 years: 1.2 mg/dl
• ◦13 to < 16 years: 1.5 mg/dl (male), 1.4 mg/dl (female)
• ◦>= 16 years: 1.7 mg/dl (male), 1.4 mg/dl (female)
• Pulse oximetry > 93% on room air and no evidence of dyspnea at rest
• Patients must be off all colony-forming growth factor(s) for at least 1 week prior to registration (i.e. filgrastim, sargramostim, erythropoietin); 2 weeks must have elapsed for long-acting formulations 
• Female subjects of childbearing potential must not be pregnant or breast-feeding; female patients of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required; pregnant women are excluded from this study; breastfeeding should be discontinued
• Patients of childbearing or child fathering potential must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity while being treated on this study and for 4 months after the last dose of study medication 
• The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document, inclusive of assent where appropriate, according to institutional guidelines

Exclusion Criteria:

Concurrent illness

• Patients with active autoimmune disease or documented history of autoimmune disease/syndrome that requires ongoing systemic steroids or systemic immunosuppressive agents, except
  • Patients with vitiligo or resolved asthma/atopy
  • Patients with hypothyroidism stable on hormone replacement or Sjogren's syndrome
• History of or ongoing pneumonitis or significant interstitial lung disease
• Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results
• Patients with other malignancies
• Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible
• Patients who have a known active hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV] RNA-qualitative is detected) are ineligible; patient must have documented evidence of negative tests for the presence of hepatitis B surface antigen and hepatitis C RNA-qualitative; human immunodeficiency virus (HIV)-positive patients are eligible if the following criteria are met:
  • Stable on their antiretroviral agents
  • Have cluster of differentiation (CD)4 counts above 400
  • Undetectable viral loads, and
  • No need for prophylactic medications for an opportunistic infections
• Patients who have received the last vaccination of a live vaccine =< 30 days prior to enrollment are ineligible; examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine; seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and must meet timeline for live vaccine
• Patients with a history severe (>= grade 3) hypersensitivity reaction to a monoclonal antibody are ineligible
• Patients who have received previous therapy with an anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4), anti-CD137, anti-PD-L1 or anti-PD-1 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
• Patients with uncontrolled seizures defined as seizures that require regular use of rescue medications or in the opinion of the investigator require increasing doses of anti-epileptic medications or would compromise the ability to tolerate study therapy or interfere with protocol therapy or procedures; patients with seizures that are well controlled are eligible and may be on antiepileptic medications if on a stable dose
• Patients may not be on chronic (> 1 week) immunosuppressive therapy, including corticosteroids (with the exception of physiologic replacement) at time of registration; however, patients who require intermittent use of bronchodilators or local steroid injections will not be excluded from the study