CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Age ≥ 12 months and \< 30 years at the time of consent. The first patient on each dose level will need to be age ≥ 6 years old
2. Disease Status:

   1. Patients must have histologic verification of neuroblastoma at diagnosis or at relapse
   2. Patients must have high-risk neuroblastoma according to Children's Oncology Group (COG) risk classification at time of study enrollment
   3. Patients must have persistent/refractory or relapsed disease for which standard curative measures are no longer effective, as defined in the protocol
   4. Patients must have evaluable or measurable disease per the revised International Neuroblastoma Response Criteria (INRC)
3. Adequate washout from prior treatment regimens
4. Adequate organ function
5. Adequate performance status defined as Lansky or Karnofsky performance score ≥50%
6. Subjects of reproductive potential must agree to use acceptable birth control methods
7. Signed informed consent

Exclusion Criteria:

1. Pregnant or nursing (lactating) women
2. Patients with uncontrolled active infection
3. Patients who are concurrently receiving other investigational agents
4. Patients who have received prior CART-cell or other gene-modified immune-effector cell therapy, are not eligible unless they are \>8 weeks from time of infusion, have fully recovered from any associated toxicities and have documented lack of persistence of the product
5. Patients with a known additional malignancy other than non-melanomatous skin cancer or carcinoma in situ, unless not requiring active treatment and stable or disease-free for at least 3 years
6. Uncontrolled CNS metastasis
7. CNS disorder such as cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or autoimmune disease with CNS involvement which may impair the ability to evaluate neurotoxicity
8. History of severe hypersensitivity reaction to compounds used in the study
9. HIV/HBV/HCV infection
10. Patients receiving systemic steroid therapy (physiologic replacement, inhaled steroids and premedication for blood products are allowed)
11. Primary immunodeficiency or history of systemic autoimmune disease requiring systemic immunosuppression/disease modifying agents within the last 2 years
12. Uncontrolled intercurrent illness
13. Inability to comply with the study requirements

主要终点：Phase 1: Determine the Maximum Tolerated Dose (MTD) of hALK.CAR T cells · The Maximum Tolerated Dose (MTD) of hALK.CAR T cells will be determined by measuring the incidence of dose limiting toxicities (DLT) following administration of the hALK.CAR T cell product using a 3+3 dose escalation design. · 5 years；Phase 1: Evaluate Manufacturing Feasibility of hALK.CAR T cells · Manufacturing feasibility will be evaluated as the proportion of patients undergoing leukapheresis who achieve manufacturing of a hALK.CAR T cell product that meets release criteria. · 5 years；Phase 2: Estimate Response Rates · The complete response (CR) and partial response (PR) rates per revised International Neuroblastoma Response Criteria (INRC) of subjects with relapsed or refractory high-risk neuroblastoma who are treated with hALK.CAR T cells will be estimated. · Up to 5 years
次要终点：Phase 1: Estimate Response Rates；Estimate Progression Free Survival and Overall Survival；Evaluate Patient-Reported Symptoms；Persistence of hALK.CAR T cells；Cytokine levels in the peripheral blood

• Phase 1 Dose Escalation · EXPERIMENTAL · The dose escalation arm will determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of hALK.CAR T cells using a standard 3+3 dose escalation design.

This Phase 1/2 trial aims to determine the safety and feasibility of administration of autologous chimeric antigen receptor (CAR) T cells targeting the human Anaplastic Lymphoma Kinase (ALK) receptor in pediatric subjects with relapsed or refractory neuroblastoma (NB). The trial will be conducted in two phases: Phase 1 will determine the maximum tolerated dose (MTD) of autologous hALK.CAR T cells using a 3+3 dose escalation design. Phase 2 will be an expansion phase to determine rates of response to hALK.CAR T cells.