GD2 Specific CAR and Interleukin-15 Expressing Autologous NKT Cells to Treat Children With Neuroblastoma

Procurement Inclusion Criteria:

1. Relapsed or refractory high risk neuroblastoma
2. Life expectancy of at least 12 weeks
3. Age greater than 1 year and less than 21 years old
4. Karnofsky/Lansky score of 60% or greater
5. Absence of HAMA prior to enrollment (only in patients that have been previously treated with murine antibodies)
6. Ability to tolerate leukocyte apheresis
7. Informed consent and assent (as applicable) obtained from parent/guardian and child.
8. Patients must have an ANC greater than or equal to 500/µl, platelet count greater than or equal to 20,000/µl. Patients may be transfused to obtain a platelet count greater than or equal to 20,000/µl.
9. Pulse Ox greater than or equal to 90% on room air
10. Serum AST less than 3 times the upper limit of normal
11. Total Bilirubin less than 1.5 times the upper limit of normal
12. Creatinine \< 1.5 times the upper limit of normal
13. Recovered from the acute toxic effects of all prior chemotherapy based on the enrolling physician's assessment (if some effects of chemotherapy are expected to last long term, patient is eligible if meeting other eligibility criteria).
14. Weight greater than 12kg
15. Negative QuantiFERON-TB or T-SPOT testing within 3 months prior to procurement

Procurement Exclusion Criteria:

1. Rapidly progressive disease
2. History or hypersensitivity to murine protein-containing products
3. Tumor causing airway obstruction
4. Currently receiving immunosuppressive drugs such as corticosteroids, tacrolimus or cyclosporine
5. Severe previous toxicity from cyclophosphamide or fludarabine based on the enrolling physician's assessment
6. HIV infection
7. History of hypersensitivity, anaphylaxis, and/or adverse event with Etanercept

Treatment Inclusion Criteria:

1. Relapsed or refractory high risk neuroblastoma
2. Life expectancy of at least 12 weeks
3. Age greater than 1 year and less than 21 years old
4. Karnofsky/Lansky score of 60% or greater
5. Patients must have an ANC greater than or equal to 500/µl, platelet count greater than or equal to 20,000/µl. Patients may be transfused to obtain a platelet count greater than or equal to 20,000/µl.
6. Pulse Ox greater than or equal to 90% on room air
7. Serum AST less than 3 times the upper limit of normal
8. Total Bilirubin less than 1.5 times the upper limit of normal
9. Creatinine \< 1.5 times the upper limit of normal
10. Recovered from the acute toxic effects of all prior chemotherapy based on the enrolling physician's assessment (if some effects of chemotherapy are expected to last long term, patient is eligible if meeting other eligibility criteria and expected to tolerate lymphodepletion).
11. Absence of human anti-mouse antibodies (HAMA) prior to enrollment for patients who have received prior therapy with murine antibodies
12. Patients must have autologous transduced NKTs with greater than or equal to 20% expression of GD2-specific CAR.
13. Informed consent and assent (as applicable) obtained from parent/guardian and child.
14. Weight greater than 12kg
15. Negative QuantiFERON-TB or T-SPOT testing within 3 months prior to the start of LD

Treatment Exclusion Criteria:

1. Rapidly progressive disease
2. Currently receiving any investigational drugs
3. History or hypersensitivity to murine protein-containing products
4. Cardiomegaly or bilateral pulmonary infiltrates on chest radiograph or CT. However, patients with cardiomegaly on imaging may be enrolled if they have an assessment of cardiac function (i.e., ECHO or MUGA) within 3 weeks of starting protocol therapy that is within normal limits. Additionally, patients with bilateral pulmonary infiltrates on imaging may be enrolled if the lesions are not consistent with active neuroblastoma (i.e., negative on functional imaging with PET or MIBG, or by pathologic assessment).
5. Tumor potentially causing airway obstruction
6. Pregnancy or lactation or not willing to use birth control
7. Currently receiving immunosuppressive drugs such as corticosteroids, tacrolimus or cyclosporine
8. Severe previous toxicity form cyclophosphamide or fludarabine based on the enrolling physician's assessment
9. HIV infection
10. History of hypersensitivity, anaphylaxis, and/or adverse event with Etanercept