PHOX2B Peptide-Centric Chimeric Antigen Receptor Autologous T cells for the Treatment of Relapsed or Refractory Neuroblastoma

Inclusion Criteria

• Patients must meet the age-related criteria listed below during dose escalation: *Dose level -1: All patients will be ≥ 12 years of age * Dose level 1: The first patient will be ≥ 12 years of age, all other patients will be ≥ 1 years of age * Dose level 2: The first patient will be ≥ 12 years of age, all other patients will be ≥ 1 years of age * Dose level 3: The first patient will be ≥ 12 years of age, all other patients will be ≥ 1 years of age *Dose expansion: All patients will be ≥ 1 year of age
• Patients must demonstrate expression of at least one of the human leukocyte antigen (HLA) alleles by HLA genotyping (conducted at Children's Hospital of Philadelphia [CHOP]) to be eligible. Allele and Population frequency (%): *HLA-A*24:02 18.18 *HLA-A*24:03 0.47 *HLA-A*24:04 0.43 *HLA-A*24:07 0.44 *HLA-A*24:124 0.64 *HLA-A*24:143 4 *HLA-A*24:17 0.12 *HLA-A*24:242 3.11 *HLA-A*24:305 0.12 *HLA-A*24:314 0.58 *HLA-A*24:33 1.37 *HLA-A*24:353 0.75 *HLA-A*24:41 6.47 *HLA-A*24:51 1.52 *HLA-A*24:63 0.14 *HLA-A*24:87 1.2 *HLA-A*24:92 0.64 *HLA-A*23:01 5.4 *HLA-A*23:17 0.25 *HLA-A*23:25 0.64 *HLA-A*23:39 0.22
• 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. ** Note: 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
• In addition, the patient must have experienced at least one of the following: * New disease site documented on at least one of the following: ** 123I-meta-iodobenzylguanidine (MIBG) or 18F-mFBG (meta-fluorobenzylguanidine) scan; OR ** computed tomography (CT)/magnetic resonance imaging (MRI); OR ** Fludeoxyglucose (FDG) or Ga-68 Dotatate positron emission tomography (PET) (in patients known to have MIBG non-avid tumor) and MRI findings consistent with tumor (i.e., bone lesions), OR ** Biopsy confirmed 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 * 12 months to < 2 years: Maximum serum creatinine 0.6 mg/dL (male), 0.6 mg/dL (female) * 2 to < 6 years: Maximum serum creatinine 0.8 mg/dL (male), 0.8 mg/dL (female) * 6 to < 10 years: Maximum serum creatinine 1 mg/dL (male), 1 mg/dL (female) * 10 to < 13 years: Maximum serum creatinine 1.2 mg/dL (male), 1.2 mg/dL (female) * 13 to < 16 years: Maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female) * >= 16 years: Maximum serum creatinine 1.7 mg/dL (male),1.4 mg/dL (female)
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (exception: total bilirubin ≤ 3 ULN for patients with Gilbert’s Disease or liver metastases).
• Alanine aminotransferase (ALT) ≤ 3.0 ULN (exception: ALT ≤ 5 x ULN for patients with liver metastases)
• Aspartate aminotransferase (AST) ≤ 3.0 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
• Patients of child-bearing potential ( patients who have reached menarche and have not experienced treatment-related premature ovarian failure) must have a negative serum pregnancy test performed at the time of screening It is recommended that all patients of reproductive potential use at least one medically acceptable form of contraception for at least 1 year after their last infusion of PHOX2B PC-CAR T cells. Investigators shall counsel patients on the importance of pregnancy prevention and the implications of an unexpected pregnancy

Exclusion Criteria

• Patients with active hepatitis B or active hepatitis C
• Patients with active HIV infection (patients undergoing anti-retroviral therapy with undetectable HIV viral load are eligible)
• 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 system (CNS) metastases, including parenchymal or leptomeningeal involvement. (Note: CNS imaging at screening is only required if there is a clinical indication of suspected CNS metastasis)
• 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 who have received any live vaccines within 30 days prior to enrollment
• Pregnant or nursing (lactating) patients