Anti-GD2 4th Generation CART Cells Targeting Refractory and/or Recurrent Neuroblastoma

INCLUSION CRITERIA:

1. Patients with neuroblastoma have received standard first-line therapy and been judged to be non-resectable, metastatic, progressive/persistent or recurrent.
2. The GD2 antigen status of the neuroblastoma will be determined for eligibility. Positive expression is defined by GD2 antibody staining results based on immunohistochemistry or flow cytometry analyses.
3. Body weight greater than or equal to 10 kg.
4. Age: ≥1 year and ≤ 14 years of age at the time of enrollment.
5. Life expectancy: at least 8 weeks.
6. Prior Therapy: 1) There is no limit to the number of prior treatment regimens. Any grade 3 or 4 non-hematologic toxicity of any previous therapy must have resolved to grade 2 or less. 2) Must not have received hematopoietic growth factors for at least 1 week prior to mononuclear cells collection. 3) At least 7 days must have elapsed since the completion of therapy with a biologic agent, targeted agent, tyrosine kinase inhibitor or a metronomic nonmyelosuppressive regimen. 4) At least 4 weeks must have elapsed since prior therapy that included a monoclonal antibody. 5) At least 1 weeks since any radiation therapy at the time of study entry.
7. Karnofsky/jansky score of 60% or greater.
8. Cardiac function: Left ventricular ejection fraction greater than or equal to 40/55 percent .
9. Pulse Ox greater than or equal to 90% on room air.
10. Liver function: defined as alanine transaminase (ALT) \<3x upper limit of normal (ULN), aspartate aminotransferase (AST) \<3x ULN; serum bilirubin and alkaline phosphatase \<2x ULN.
11. Renal function: Patients must have serum creatinine less than 3 times upper limit of normal.
12. Marrow function: White blood cell count ≥1000/ul, Absolute neutrophil count ≥500/ul, Absolute lymphocyte count ≥500/ul, Platelet count ≥25,000/ul (not achieved by transfusion).
13. Patients with known bone marrow metastatic disease will be eligible for study as long as they meet hematologic function criteria, and the marrow disease not evaluable for hematologic toxicity.
14. Patients must have autologous transduced T cells at levels greater than or equal to 2x10e5 cells per kilogram body weight.
15. For all patients enrolled in this study, their parents or legal guardians must sign an informed consent and assent.

EXCLUSION CRITERIA:

1. Existing severe illness (e.g. significant cardiac, pulmonary, hepatic diseases, etc.) or major organ dysfunction, with the exception of grade 3 hematologic toxicity.
2. Untreated central nervous system (CNS) metastasis:

   Patients with previous CNS tumor involvement that has been treated and is stable for at least 6 weeks following completion of therapy are eligible.
3. Previous treatment with other genetically engineered GD2-CAR T cells.
4. Active HIV, Hepatitis B virus (HBV), Hepatitis C virus (HCV) infection or uncontrolled infection.
5. Patients who require systemic corticosteroid or other immunosuppressive therapy.
6. Patients previously experienced severe toxicity from cyclophosphamide or fludarabine.
7. Evidence of tumor potentially causing airway obstruction.
8. Inability to comply with protocol requirements.
9. Insufficient CAR T cells availability.