CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Prior diagnosis of NB or ganglioneuroblastoma either by histologic verification and/or demonstration of tumor cells in the bone marrow with increased catecholamine levels.
* Male or female subjects ≤ 26 years of age
* Diagnosis of high risk NB at initial diagnosis or if non-high risk at time of initial diagnosis must have had evidence of metastatic progression when \> 18 months of age.
* Measurable or evaluable disease
* Lansky or Karnofsky performance status score of ≥ 50
* Life expectancy of ≥ 8 weeks.
* Recovered from significant acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment onto this study.
* ≥ 7 days since last chemotherapy or biologic therapy administration
* No systemic corticosteroids (unless physiologic replacement dosing) within 7 days of enrollment. Topical Administration (e.g. inhaled or dermatologic) is allowed.
* ≥ 3 half-lives or 30 days from time of last dose of anti-tumor directed antibody therapy, whichever is shorter from time of enrollment
* ≥ 6 weeks from myeloablative therapy and autologous stem cell transplant (timed from stem cell infusion). Patients who received stem cell infusion following non-myelo-ablative therapy are eligible once they meet all other eligibility requirements. Patient must NOT have received a prior allogeneic hematopoietic stem cell transplant.
* No prior genetically modified cell therapy that is still detectable.
* Must not be receiving external beam radiation therapy at the time of study enrollment. ≥ 12 weeks from prior I131 MIBG therapy.
* Adequate organ function
* Adequate laboratory values
* Negative HIV antigen and antibody, Hepatitis B surface antigen and Hepatitis C antibody within 3 months prior to enrollment. For patients with positive Hepatitis C Ab, negative PCR testing must be documented in order to be eligible.

Exclusion Criteria:

* History of relevant CNS pathology or current relevant CNS pathology (non-febrile seizure disorder requiring ongoing anti-epileptic medications, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder). Patients may have CNS intracranial tumor.
* Pregnant or breast-feeding
* Unable to tolerate apheresis procedure including placement of temporary apheresis catheter if necessary
* Presence of active malignancy other than NB
* Presence of known intracranial metastatic neuroblastoma. Skull based disease with soft tissue extension is allowed.
* Presence of active severe infection
* Presence of any concurrent medical condition that, in the opinion of the protocol PI or designee, would prevent the patient from undergoing protocol-based therapy.
* Presence of a primary immunodeficiency/bone marrow failure syndrome
* Receiving any other anti-cancer agents or radiotherapy at the time of study entry
* Unwilling or unable to provide consent/assent for participation in the study and 15-year follow-up

主要终点：Dose Limiting Toxicity · Patients will be evaluated through day 28 for occurrence of dose limiting toxicity · 28 days
次要终点：Response (Tumor response will be evaluated by the revised International Neuroblastoma Response Criteria)

• A: 2nd Generation CE7R CAR T Cells · EXPERIMENTAL · Autologous CD4 and CD8 cells are lentivirally transduced to generate patient-derived CD171 specific CAR T cells also expressing an EGFRt. Patients will receive lymphodepletion chemotherapy prior to T cell infusion. CD171 specific CAR T cells will be administered approximately 2-3 days after lymphodepletion chemotherapy. Cells will be administered approximately 1:1 CD4 and CD8 cells with planned dose level evaluations of total T cell dose of 1x10\^6 cells/kg, 5x10\^6 cells/kg, 1x10\^7 cells/kg, 5x10\^7 cells/kg, and 1x10\^8 cells/kg will be evaluated.
• B: 3rd Generation CE7R CAR T Cells · EXPERIMENTAL · Autologous CD4 and CD8 cells are lentivirally transduced to generate patient-derived CD171 specific CAR T cells also expressing an EGFRt. Patients will receive lymphodepletion chemotherapy prior to T cell infusion. CD171 specific CAR T cells will be administered approximately 2-3 days after lymphodepletion chemotherapy. Cells will be administered approximately 1:1 CD4 and CD8 cells with planned dose level evaluations of total T cell dose of 1x10\^6 cells/kg, 5x10\^6 cells/kg, 1x10\^7 cells/kg, 5x10\^7 cells/kg, and 1x10\^8 cells/kg will be evaluated.
• C: Long Spacer 2nd Generation CE7R CAR T Cells · EXPERIMENTAL · Autologous CD4 and CD8 cells are lentivirally transduced to generate patient-derived CD171 specific CAR T cells also expressing an EGFRt. Patients will receive lymphodepletion chemotherapy prior to T cell infusion. CD171 specific CAR T cells will be administered approximately 2-3 days after lymphodepletion chemotherapy. Cells will be administered approximately 1:1 CD4 and CD8 cells with planned dose level evaluations of total T cell dose of 1x10\^6 cells/kg, 5x10\^6 cells/kg, 1x10\^7 cells/kg, 5x10\^7 cells/kg, and 1x10\^8 cells/kg will be evaluated.

Patients with recurrent or refractory neuroblastoma are resistance to conventional chemotherapy. For this reason, the investigators are attempting to use T cells obtained directly from the patient, which can be genetically modified to express a chimeric antigen receptor (CAR). The CAR enables the T cell to recognize and kill the neuroblastoma cell through the recognition of CD171, a protein expressed of the surface of the neuroblastoma cell in patients with neuroblastoma. This is a phase 1 study designed to determine the maximum tolerated dose of the CAR+ T cells.