B7-H3-Specific CAR T Cell Therapy (Loc3CAR T Cells) for the Treatment of Pediatric Patients with Primary Central Nervous System Tumors

Inclusion Criteria

• SCREENING: Age =< 21 years of age
• SCREENING: Primary CNS tumor
• SCREENING: Participant’s tumor must meet the following criteria for Cohort A: * Evidence of relapsed or refractory non-brainstem CNS tumor (note: may include participants with leptomeningeal spread). ** Relapsed refers to cancer that has completely responded (i.e. no evidence of disease using standard imaging modalities) to first-line therapy but has recurred for the first or subsequent time ** Refractory refers to cancer that does not respond to treatment; the cancer may be resistant at the beginning or may become resistant during standard first-line therapy based on radiographic imaging
• SCREENING: Participant must meet one of the following criteria for Cohort B: * Has adequate tumor tissue from primary tumor resection or biopsy for central pathology review (i.e., B7-H3 expression evaluation by immunohistochemistry [IHC] or H3K27M mutation if pontine lesion) * Has a diagnosis of diffuse midline glioma that harbors a mutation associated with this entity (e.g. H3K27M) * Has presumptive/suspected brainstem high-grade neoplasm with available imaging for central imaging review
• SCREENING: Participant has a life expectancy of > 12 weeks
• SCREENING: Adult patient, parent or legal guardian can understand and is willing to sign a written informed consent document according to institutional guidelines
• PROCUREMENT AND T-CELL PRODUCTION: Age =< 21 years of age
• PROCUREMENT AND T-CELL PRODUCTION: Primary CNS tumor with measurable or evaluable disease. Participant’s tumor must meet criteria for either Cohort A or B: * Relapsed/refractory non-brainstem CNS primary tumor AND tumor is B7-H3 positive (H-score >= 100) * Diffuse midline glioma AND tumor is: ** B7-H3 positive (H-score >=100) if non pontine ** OR H3K27-altered diffuse midline pontine glioma ** OR Radiographically-confirmed classic/typical diffuse intrinsic pontine glioma (DIPG) *** Note that participants for Cohort B can undergo apheresis during standard radiation therapy but must have completed any radiation therapy regimen prior to commencement of Loc3CAR treatment *** DIPG defined as a tumor with a pontine epicenter and diffuse involvement of more than 2/3 of the pons
• PROCUREMENT AND T-CELL PRODUCTION: Estimated life expectancy of > 12 weeks
• PROCUREMENT AND T-CELL PRODUCTION: Karnofsky or Lansky (age-dependent) performance score >= 50. Note that participants who are unable to walk because of paralysis, but are up in a wheelchair, will be considered ambulatory for the purpose of assessing performance score
• PROCUREMENT AND T-CELL PRODUCTION: Participant of childbearing/child-fathering potential agrees to use contraception
• PROCUREMENT AND T-CELL PRODUCTION: For females of childbearing age: * Not pregnant with negative serum pregnancy test * Not lactating with intent to breastfeed
• PROCUREMENT AND T-CELL PRODUCTION: Cytotoxic chemotherapy/biologic therapy: All chemotherapy/biologic therapy must be discontinued >= 7 days prior to enrollment
• PROCUREMENT AND T-CELL PRODUCTION: Antibody Therapy: The last dose of antibody therapy (including checkpoint inhibitor) must be at least 3 half-lives or 30 days, whichever is shorter, from the time of enrollment (bevacizumab will be considered biologic therapy)
• PROCUREMENT AND T-CELL PRODUCTION: Cellular Therapy: must be at least 30 days from most recent cell infusion prior to enrollment
• PROCUREMENT AND T-CELL PRODUCTION: Steroid use: All systemically administered (i.e. subcutaneous, intramuscular, intravenous [IV] or per os [PO]) corticosteroid therapy (unless physiologic replacement dosing) must be stable or decreasing for >= 1 week prior to enrollment, with a maximum dexamethasone dose of 2.8 mg/m^2/day (0.5 mg/kg/day methylprednisolone) ongoing at enrollment. Corticosteroid physiologic replacement therapy for management of pituitary/adrenal axis insufficiency and/or topical administration (e.g. inhaled or dermatologic) is allowed
• PROCUREMENT AND T-CELL PRODUCTION: Meets eligibility criteria to undergo autologous apheresis, or have previously undergone autologous apheresis at a Foundation of the Accreditation of Cellular Therapy (FACT)-accredited hematopoietic cell transplant and/or cell therapy program
• PROCUREMENT AND T-CELL PRODUCTION: Adult patient, parent or legal guardian can understand and is willing to sign a written informed consent document according to institutional guidelines
• TREATMENT: Age =< 21 years old at the time of CAR T cell production
• TREATMENT: Primary CNS tumor with measurable or evaluable disease
• TREATMENT: Available autologous transduced T-cell product that has met Good Manufacturing Practice (GMP) release criteria
• TREATMENT: Participant has a CNS reservoir catheter (e.g., Ommaya) or programable shunt
• TREATMENT: First CAR T cell infusion is planned/scheduled >= 5 days from CNS surgery, including catheter placement
• TREATMENT: The following treatments must be discontinued for the specified duration (wash-out period) prior to treatment enrollment: * Radiation therapy: must be >= 6 weeks from most recent radiation therapy * Bevacizumab: must be >= 28 days weeks from most recent bevacizumab infusion * Cytotoxic chemotherapy: must be >= 21 days from most recent cytotoxic chemotherapy * Biologic agents: Must be >= 7 days from most recent biologic agent therapy * Antibody therapy: must be >= 3 half-lives or 30 days (whichever is shorter) from most recent antitumor antibody therapy * Cellular therapy: must be >= 30 days from most recent cell therapy treatment * Investigational agent: must be >= 3 half-lives or 30 days (whichever is shorter) from treatment with an investigational agent * Steroid use: All systemically administered (i.e. subcutaneous, intramuscular, IV or PO) corticosteroid therapy (unless physiologic replacement dosing) must be stable or decreasing for >= 1 week prior to enrollment, with a maximum dexamethasone dose of 2.8 mg/m^2/day (0.5 mg/kg/day methylprednisolone) ongoing at enrollment. Corticosteroid physiologic replacement therapy for management of pituitary/adrenal axis insufficiency and/or topical administration (e.g. inhaled or dermatologic) is allowed
• TREATMENT: Estimated life expectancy of > 8 weeks
• TREATMENT: Karnofsky or Lansky (age-dependent) performance score >= 50 * Note that participants who are unable to walk because of paralysis, but are up in a wheelchair, will be considered ambulatory for the purpose of assessing performance score
• TREATMENT: Echocardiogram with a left ventricular ejection fraction >= 50%
• TREATMENT: Calculated creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 50 mL/min/1.73m^2 * Note that for participants < 2 years of age, GFR >= 50 mL/min/1.73m^2 by Cockcroft-Gault formulation is acceptable
• TREATMENT: Forced vital capacity (FVC) >= 50% of predicted value or pulse oximetry >= 90% on room air
• TREATMENT: Total bilirubin =< 3 times the upper limit of normal for age * Note that this criterion does not apply for participants diagnosed with Gilbert’s syndrome
• TREATMENT: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 5 times the upper limit of normal for age
• TREATMENT: Hemoglobin > 8.0 g/dL (can be transfused)
• TREATMENT: Platelet count > 50,000/mm^3 (can be transfused)
• TREATMENT: Absolute neutrophil count (ANC) >= 1000/uL
• TREATMENT: Participant is taking an anti-seizure medication, or agrees to initiate anti-seizure medication prior to starting study therapy
• TREATMENT: Has recovered from all National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade III-IV, non-hematologic acute toxicities from prior therapy
• TREATMENT: Male participants of child-fathering potential agree to use contraception
• TREATMENT: Females participants of childbearing potential: * Negative serum pregnancy test within 7 days prior to infusion * Not lactating with intent to breastfeed * If sexually active, agrees to use birth control until 3 months after T-cell infusion. Male partners should use a condom
• TREATMENT: Adult patient, parent or legal guardian can understand and is willing to sign a written informed consent document according to institutional guidelines
• TREATMENT (COHORT A): Relapsed/refractory non-brainstem CNS primary tumor
• TREATMENT (COHORT A): Tumor must be considered B7-H3 positive (H-score >= 100)
• TREATMENT (COHORT B): Diffuse midline glioma
• TREATMENT (COHORT B): Must meet one of the following criteria: * Tumor B7-H3 positive (H-score >= 100) * H3K27-altered diffuse midline pontine glioma * Radiographically-confirmed classic/typical DIPG
• TREATMENT (COHORT B): Must complete standard radiation therapy regimen prior to Loc3CAR treatment start and be a minimum of 6 weeks post-completion of radiation therapy

Exclusion Criteria

• SCREENING: Participant has other clinically significant medical disorders (e.g. serious infections or significant cardiac, pulmonary, hepatic, psychiatric, or other organ dysfunction) that could compromise their ability to tolerate protocol therapy or would interfere with study procedure, in the opinion of the study principal investigators (PIs)
• PROCUREMENT AND T-CELL PRODUCTION: Known primary immunodeficiency or acquired immunodeficiency
• PROCUREMENT AND T-CELL PRODUCTION: Known human immunodeficiency virus (HIV) positivity
• PROCUREMENT AND T-CELL PRODUCTION: Severe intercurrent bacterial, viral or fungal infection (e.g. active hepatitis B or C infection or adenovirus infection)
• PROCUREMENT AND T-CELL PRODUCTION: Rapidly progressive disease (in the opinion of the study PIs)
• PROCUREMENT AND T-CELL PRODUCTION: Known underlying medical condition for which, in the investigator’s opinion, participation in this trial would not be in the best interest of the participant (e.g., compromises the health of the subject) or that could prevent, limit or confound protocol assessments. Adult patient, parent, or legal guardian is unwilling or unable to provide consent for participation in a 15 year long-term follow up study.
• TREATMENT: Participant has a non-programmable ventricular shunt that could compromise study therapy (in the opinion of the study PIs)
• TREATMENT: Participant has a reservoir catheter or shunt in a location that could compromise study therapy or patient safety (in the opinion of the study PIs).
• TREATMENT: Known primary immunodeficiency or acquired immunodeficiency
• TREATMENT: Known HIV positivity
• TREATMENT: Severe intercurrent bacterial, viral or fungal infection
• TREATMENT: Myocardial infarction, unstable angina, New York Heart Association class III and IV congestive heart failure, myocarditis, or ventricular arrhythmias requiring medication within 6 months prior to study entry
• TREATMENT: Receiving therapy as outlined during the ‘wash-out’ period.
• TREATMENT: Rapidly progressing disease (in the opinion of the study PIs)
• TREATMENT: Received any live vaccines within 30 days prior to enrollment
• TREATMENT: Known underlying medical condition for which, in the investigator’s opinion, participation in this trial would not be in the best interest of the participant (e.g., compromises the health of the subject) or that could prevent, limit or confound protocol assessments
• TREATMENT: Adult patient, parent, or legal guardian is unwilling or unable to provide consent for participation in a 15 year long-term follow up study
• TREATMENT: Evidence of uncontrolled hypertension. Anti-hypertensive medications are permitted if on a stable dose
• TREATMENT: Uncontrolled seizures