GPC2-Directed Chimeric Antigen Receptor T Cells for the Treatment of Patients with Relapsed or Refractory Neuroblastoma

Inclusion Criteria

• DOSE ESCALATION LEVEL -1 AND 1: All patients will be >= 12 years of age
• DOSE ESCALATION LEVEL 2 AND 3: First patient will be >=12 years of age. All other patients will be >= 3 years of age
• DOSE EXPANSION: Patients >= 1 year of age will be permitted to enroll
• Patients must have high-risk neuroblastoma according to Children's Oncology Group (COG) risk classification at the time of study enrollment. Patients who were initially considered low- or intermediate-risk, but then reclassified as high-risk are also eligible
• Patients must have a previously histologically confirmed diagnosis of neuroblastoma: * That is recurrent/relapsed or refractory/persistent according to International Neuroblastoma Response Criteria (INRC) and * For which standard curative measures do not exist or are no longer effective * Patients at first relapse are eligible as no known curative therapies exist for relapsed high-risk neuroblastoma
• Patients must have evaluable or measurable disease at enrollment, defined as at least one of the following: * New disease site documented on at least one of the following: ** 123 I-metaIodobenzylguanidine scan (MIBG); or ** CT/MRI; or ** FDG-PET (in patients known to have MIBG non-avid tumor) and MRI findings consistent with tumor (i.e., bone lesions), or ** Biopsy confirmation neuroblastoma for any new or progressing lesion * Greater than 20% increase in a least one dimension of soft tissue mass documented by CT/MRI and a minimum absolute increase of 5 mm in longest dimension in existing lesion(s). Previously irradiated lesions may be included * Bone marrow biopsy shows progressive disease according to the revised INRC * Stable persistent disease, such that response at the completion of upfront therapy or salvage therapy is less than partial response AND has a biopsy of at least one site showing viable neuroblastoma * Responding persistent disease, defined as at least a partial response to frontline therapy (i.e., at least a partial response to frontline therapy but still has residual disease by MIBG scan, CT/MRI, or bone marrow aspirations/biopsies). Patients in this category are required to have histologic confirmation of viable neuroblastoma from at least one residual site (tumor seen on routine bone marrow morphology is sufficient)
• Patients must have a Lansky ( =< 16 years) or Karnofsky (> 16 years) score of >= 60
• Patients must have adequate renal function defined as age-adjusted serum creatinine =< 1.5 upper limit of normal (ULN) for age: Maximum serum creatinine (mg/dL) 0 to < 2 years: 0.6 (male); 0.6 (female) 2 to < 6 years: 0.8 (males); 0.8 (female) 6 to < 10 years: 1.0 (male); 1.0 (female) 10 to < 13 years: 1.2 (male); 1.2 (female) 13 to < 16 years: 1.5 (male); 1.4 (female) >= 16 years: 1.7 (male); 1.4 (female)
• Total bilirubin =< 1.5 x ULN (exception: total bilirubin =< 3 ULN for patients with Gilbert’s Disease)
• Aspartate aminotransferase (AST) =< 2.5 ULN (exception: AST =< 5 x ULN for patients with liver metastases)
• Alanine aminotransferase (ALT) =< 2.5 ULN (exception: ALT =< 5 x ULN for patients with liver metastases)
• Patients need to have a baseline pulse oximetry of at least 92% on room air and diffusion capacity of the lung for carbon monoxide (DLCO) >= 60% (corrected for anemia) if pulmonary function tests (PFTs) are clinically appropriate as determined by the treating investigator
• Left ventricular shortening fraction (LVSF) >= 28% or ejection fraction (LVEF) >= 50% confirmed by echocardiography (echo), or adequate ventricular function documented by a scan or a cardiologist
• Female patients of reproductive potential (women who have reached menarche and have not experienced treatment-related premature ovarian failure) must have negative serum pregnancy test performed at the time of screening and a negative urine pregnancy test prior to starting lymphodepleting chemotherapy and GPC2 CAR T cell infusion
• Due to the unknown risks of the CAR T cells with respect to pregnancy, as well as risks associated with lymphodepleting chemotherapy, it is recommended that all patients (male and female) of reproductive potential use at least one medically acceptable form of contraception for at least 1 year after their last infusion of GPC2 CAR T cells. Investigators shall counsel patients on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Medically acceptable forms of birth control include: * Condoms (male or female) with or without a spermicidal agent * Diaphragm or cervical cap with spermicide * Intrauterine device (IUD) * Hormonal-based contraception
• Patients who are not of reproductive potential (females who are premenarchal or have experienced treatment-related premature ovarian failure or males who have documented azoospermia) do not require the use of contraception. Acceptable documentation of sterilization, azoospermia, and premature ovarian failure Written documentation by clinician or clinician’s staff through one of the following: * Tanner I or age < 11 * Physician report/letter * Operative report or other source documentation in the patient record (a laboratory report of azoospermia is required to document successful vasectomy) * Discharge summary of the sterilization procedure or hysterectomy, salpingectomy, and/or oophorectomy * Laboratory report of azoospermia * Follicle stimulating hormone measurement elevated into the menopausal range
• ELIGIBILITY CRITERIA FOR SUBSEQUENT CELL INFUSIONS:
• Response to previous infusion: Patients who had a partial response (PR) or stable disease (SD) with clinical benefit may elect to receive another infusion of cells. Patients that initially had a complete response (CR) may only receive a second dose if evaluable disease recurs. Clinical benefit is indicated by an improvement in the patient’s health status
• Subjects should not experience a significant change in performance or clinical status compared to their previous study visit that would, in the opinion of the treating physician, increase the risk of experimental cell infusion. Fever may delay or preclude infusion
• Subjects with a history of grade 4 CRS or immune effector cell associated neurotoxicity syndrome (ICANS) will only be reinfused in the setting of low disease burden at infusion
• All toxicities from the prior GPC2 CAR T cell treatment should resolve to grade 1 or baseline prior to reinfusion
• Subjects experiencing new laboratory abnormalities that in the opinion of the investigator or principal investigator (PI) feels may impact subject safety or the subjects’ ability to receive GPC2 CAR T cells may have their infusion delayed until both the investigator and PI determine it is clinically appropriate to proceed with the infusion
• Subjects should not be experiencing signs/symptoms of cytokine release syndrome (CRS) or other severe CAR T cell related toxicities

Exclusion Criteria

• Patients with active hepatitis B or active hepatitis C
• Patients with human immunodeficiency virus (HIV) infection
• Patients with uncontrolled active infection
• Patients with primary or acquired immunodeficiency disorder
• Concurrent use of systemic steroids or immunosuppression at the time of cell infusion or cell collection, or a condition, in the treating physician's opinion, that is likely to require steroid therapy or immunosuppression during collection or after infusion. Steroids for disease treatment at times other than cell collection or at the time of infusion are permitted. Use of physiologic replacement hydrocortisone or inhaled steroids is permitted as well
• Patients with actively progressing central nervous sytem (CNS) metastases, including parenchymal or leptomeningeal involvement
• Active medical disorder that, in the opinion of the investigator, would substantially increase the risk of uncontrollable cytokine release syndrome (CRS) and/or neurotoxicity
• Patients with congestive heart failure (as defined by New York Heart Association functional classification III or IV), unstable angina, serious uncontrolled cardiac arrhythmia, a myocardial infarction within 6 months prior to study entry or a history of myocarditis
• Patients who have received any live vaccines within 30 days prior to enrollment
• Pregnant or nursing (lactating) women