A Vaccine (Rhsc-Dipgvax) in Combination with Immunotherapy (Balstilimab and Zalifrelimab) for Treatment of Diffuse Intrinsic Pontine Glioma and Diffuse Midline Glioma in Pediatric Patients

Inclusion Criteria

• Subjects with newly diagnosed typical or non-typical, biopsy-proven DIPG or DMG are eligible for study enrollment. Biopsy is not required for subjects with radiographically typical DIPG meeting imaging criteria. Radiology report from local radiologist must be submitted showing confirmation of typical DIPG imaging criteria being met. * For DMGs, and non-radiographically typical DIPGs (requiring biopsy as part of standard of care [SOC]), H3K27M-mutation status must be confirmed by pathology report. Verification of H3K27M-mutation status is not required for radiographically typical DIPG meeting imaging criteria. Pathology will not be centrally reviewed but Clinical Laboratory Improvement Act (CLIA)-certified pathology report with confirmation of H3K27M-mutation status must be submitted prior to enrollment. H3K27M-mutation status may be confirmed by either immunohistochemistry or genetic sequencing. Note: Radiographically typical DIPG defined as a tumor with a pontine epicenter and diffuse involvement of more than 2/3 of the pons, are eligible without histologic confirmation
• Subjects must be >= 12 months and =< 18 years of age at the time of study enrollment
• Body surface area: Subjects must have a body surface area >= 0.35 m^2 at the time of study enrollment
• Performance Level: Karnofsky: Karnofsky >= 50% for subjects > 16 years of age and Lansky >= 50 for subjects =< 16 years of age * Note: Subjects 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
• Prior Therapy: All subjects must receive focal radiation therapy prior to starting on-study treatment. Patients must start radiation therapy within 42 days (6 weeks) from the date of diagnostic imaging and have completed radiation therapy prior to cycle 1 day 1 (C1D1) to be eligible. C1D1 must be within day +42 (6 weeks) post radiation to day +70 post radiation (10 weeks). Day +1 from radiation is the considered the day AFTER the last dose of radiation was received. Prior dexamethasone and minor surgical procedures (i.e. biopsy and ventriculoperitoneal shunt placement) are allowed
• Corticosteroids: After completion of radiation, or during radiation, if clinically tolerable, subjects should be weaned to the lowest tolerable dose of steroids or have steroids discontinued prior to initiation of study drugs. Maximum tolerated steroid dose within 7 days of initiation of treatment is dexamethasone 2 mg/day. If the steroid dose is above this dosing, the subject will not be eligible for study. Steroids can dampen the efficacy of the study drugs so the least possible dose is desired. However, steroids can be necessary in the management of DIPG so the protocol will allow some steroid use
• Subjects must have measurable disease evaluable disease
• Subjects must have a life expectancy greater than 3 months
• Peripheral absolute neutrophil count (ANC) of >= 1000/mm^3
• Hemoglobin (Hgb) >= 9 g/dL (transfusions allowed within one week of testing)
• Platelet count of >= 100,000/mm^3 (transfusion independent, defined as not receiving a platelet transfusion for at least 7 days prior to enrollment)
• Total bilirubin (serum conjugated and unconjugated sum) =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) alanine aminotransferas [ALT] =< 3 x ULN = 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L
• Serum glutamic-oxaloacetic transaminase (SGOT) aspartate aminotransferase (AST) =< 3 x ULN = 144 U/L. For the purpose of this study, the ULN for SGOT is 48 U/L
• Serum albumin >= 2 g/dL
• Creatinine based on age/gender as follows: * 3 to < 6 years (age): 0.8 mg/dL (male), 0.8 mg/dL (female) * 6 to < 10 years (age): 0.8 mg/dL (male), 0.8 mg/dL (female) * 10 to < 13 years (age): 1.2 mg/dL (male), 1.2 mg/dL (female) * 13 to < 16 years (age): 1.5 mg/dL (male), 1.4 mg/dL (female) * >= 16 years (age): 1.7 mg/dL (male), 1.4 mg/dL (female) Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2. * Threshold creatinine values based on Schwartz formula for estimating GFR utilizing child length and status data published by the Centers for Disease Control and Prevention (CDC) * eGFR is estimated GFR calculated by the abbreviated Modification of Diet in Renal Disease (MDRD) equation
• Thyroid-stimulating hormone (TSH) and free thyroxine (T4) levels within the normal limits of the institutional lab parameters
• Creatine kinase (CPK) and troponin levels within the normal limits of the institutional lab parameters
• Amylase and lipase levels within the normal limits of the institutional lab parameters
• For subjects with a known history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• The effects of rHSC-DIPGVax, balstilimab, and zalifrelimab on the developing human fetus are unknown. For this reason, females of child-bearing potential (FOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from time of informed consent, for the duration of study participation, and for 30 days following completion of therapy. Should a female subject become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception from time of informed consent, for the duration of study participation, and 4 months after completion of administration * NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: ** Has not undergone a hysterectomy or bilateral oophorectomy ** Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months)
• FOCBP must have a negative pregnancy test prior to registration on study
• Subjects or their parents/legally authorized representatives (LARs) must have the ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Subjects with disseminated disease
• Prior Therapy: Subjects who received any prior anti-cancer therapy such as chemotherapy, immunotherapy, or bone marrow transplant, or investigational drugs for the treatment of DIPG and DMG (except for radiotherapy). Subjects receiving craniospinal radiation are ineligible given risk of bone marrow suppression
• Subjects who have not completed radiation therapy will be excluded from this study
• Subjects who have not recovered from adverse events due to radiation therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
• Autoimmune or Immune Disorders: Subjects with the following are excluded: * Known autoimmune disorders * Immune disorders * Immunodeficiencies ** Note: Autoimmune disorders include but are not limited to rheumatoid or juvenile idiopathic arthritis, systemic lupus erythematosus, juvenile dermatomyositis, Addison’s disease, autoimmune hepatitis, Crohn’s disease, multiple sclerosis, Hashimoto’s thyroiditis, and scleroderma. Patients with autoimmune disease with external/environmental triggers are also excluded
• Inflammatory Bowel Disease: Subjects with Crohn’s disease or ulcerative colitis or other inflammatory bowel disease will not be included in this study
• Pancreatitis: Subjects with active pancreatitis or history of pancreatitis within the last 3 months will not be included in this study
• Active Respiratory Disorder/Infection: The following subjects are excluded: * Require oxygen * Require continuous positive airway pressure (CPAP)/biphasic positive airway pressure (BiPAP) * Require mechanical ventilation * Have active respiratory infections * Have been treated for a respiratory infection in which they required oxygen support within the last 7 days * Have chronic lung disease (not including asthma) * Subjects with baseline oxygen (O2) saturation < 92% on room air
• Infections: The following subjects are excluded: * Any known active infections (within the last 7 days prior to enrollment) * Previous fungal infection within the last month * Active serious viral infections including influenza, cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, herpes zoster, hepatitis A/B/C, herpes simplex virus 1/2 ** Note: Subjects at high risk for tuberculosis (TB) should have a purified protein derivative (PPD) placed or quantiferon gold serum testing done prior to enrollment. Subjects who are positive for TB are excluded
• Subjects with active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis requiring treatment with systemic steroids
• Subjects with a known history of hepatitis C and human immunodeficiency virus (HIV)
• Major Surgical Procedures: Subjects who have received a major surgical procedure =< 28 days of beginning study treatment, or minor surgical procedures (including ventriculoperitoneal [VP] shunt placement or stereotactic biopsy of the tumor) =< 7 days are not eligible * Note: There is no waiting period for port-a-cath or other central venous access placement. There is no waiting period for gastrostomy tube (G-tube) placement
• Herbal Preparations: Herbal preparations are not allowed throughout the study. These medications include but are not limited to St. John’s wort, kava, ephedra (ma hung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng. Cannabis products of any type are not allowed throughout the study. Subjects should stop using these herbal medications or cannabis products 7 days prior to enrollment
• Subjects who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to rHSC-DIPGVax, balstilimab, and zalifrelimab
• Subjects who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible: * Hypertension that is not controlled on medication * Ongoing or active infection requiring systemic treatment * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Myocarditis * Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the subject’s safety or study endpoints
• Compliance: Subjects who in the opinion of the investigator may not be able to comply with safety monitoring requirements of the study are not eligible
• Female subjects who are pregnant or nursing. Pregnant women are excluded from this study because rHSC-DIPGVax, balstilimab, and zalifrelimab are immunotherapies with potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with rHSC-DIPGVax, balstilimab, and zalifrelimab, breastfeeding should be discontinued if the mother is treated with these study drugs