CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Age ≥ 1 and ≤ 16 years.
2. Tissue diagnosis of neuroblastoma. If sufficient biopsy material is available, GD2 expression on the tumour will be confirmed. As GD2 is consistently expressed in neuroblastoma demonstration of GD2 is not mandated.
3. Disease which has relapsed after or is refractory to at least one line of salvage combination chemotherapy.
4. Measurable disease by cross sectional imaging or evaluable disease by uptake on 123I-MIBG scan. Patients with only bone marrow detectable disease (bone marrow aspirate or trephine) are NOT eligible for the study.
5. At least 3 weeks or 5 half-lives, whichever is shorter, after treatment with agents on other early phase clinical trial.
6. Performance status: Karnofsky (age ≥ 10 years) or Lansky (age \< 10) score ≥ 50%. Patients who are unable to walk because of paralysis, but who are able to sit upright unassisted in a wheelchair, will be considered ambulatory for the purpose of assessing performance score.
7. Creatinine ≤1.5 ULN for age, if higher, an estimated (calculated) creatinine clearance must be ≥ 60 ml/min/1.73 m2.
8. Absolute lymphocyte count ≥ 0.25 x 10\^9/L.
9. For post-pubertal subjects agreement to have a pregnancy test, use adequate contraception (if applicable).
10. Written informed consent.

Exclusion Criteria:

1. Patients with only bone marrow detectable disease in the absence of measurable disease by cross sectional imaging or evaluable disease by uptake on 123I-MIBG scan.
2. Patients with active, inoperative CNS disease including leptomeningeal disease.
3. Active hepatitis B, C or HIV infection.
4. Inability to tolerate leukapheresis.
5. Clinically significant systemic illness or medical condition (e.g., significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgement of the investigator is likely to interfere with assessment of safety or efficacy of the investigational regimen and its requirements.
6. Any contraindication to lymphodepletion or to the use of Cyclophosphamide or Fludarabine as per the local SmPC.
7. Any contraindication to the use of Anticoagulant Citrate Dextrose Solution.
8. Known allergy to albumin, EDTA or DMSO.
9. Primary immunodeficiency or history of autoimmune disease (e.g., Crohn's, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression /systemic disease modifying agents within the last 2 years.
10. Prior treatment with investigational or approved gene therapy or cell therapy products.
11. Life expectancy \<3 months.
12. Use of rituximab (or rituximab biosimilar) within the last 3 months prior to of GD2 CAR T cells infusion.
13. Systemic corticosteroid therapy ≥ 0.05 mg/kg dexamethasone daily (or equivalent) at time of GD2 CAR T cells infusion.
14. Post-pubertal subjects who are pregnant or breastfeeding.

Exclusion criteria for the ATIMP infusion:

1. Uncontrolled fungal, bacterial, viral, or other infection. Previously diagnosed infection for which the patient continues to receive antimicrobial therapy is permitted if responding to treatment and clinically stable at the time of scheduled GD2 CAR T cells infusion.
2. Systemic corticosteroid therapy ≥ 0.05 mg/kg dexamethasone daily (or equivalent) at time of GD2 CAR T cells infusion.
3. Use of rituximab (or rituximab biosimilar) within the last 3 months prior to GD2 CAR T cell infusion

主要终点：Safety of administering the ATIMP · Incidence of grade 3-5 toxicity causally related to the ATIMP, particularly severe cytokine release syndrome and severe neurotoxicity. · 28 days；Number of therapeutic products generated and the number of ATIMPs infused after successful manufacture · Feasibility of generation of the ATIMP as evaluated by the number of therapeutic products generated and the number of ATIMPs infused after successful manufacture. · 28 days
次要终点：Objective response rate；Progression Free Survival (PFS)；Time to Progression (TTP)；Overall survival

• GD2 CAR T cells · EXPERIMENTAL · Treatment with GD2 CAR T cells

MAGNETO is a single-centre, non-randomised, open label Phase I clinical trial of an Advanced Therapy Investigational Medicinal Product (ATIMP) in children and teenagers aged 1-16 years with relapsed or refractory neuroblastoma. The study will assess the feasibility of generating the ATIMP (GD2 CAR T cells) and the safety of administering the ATIMP in patients with relapsed or refractory neuroblastoma.