Multi-modular Chimeric Antigen Receptor Targeting GD2 in Neuroblastoma

Inclusion Criteria:

1. Age ≥ 1 and ≤ 16 years.

2. Tissue diagnosis of neuroblastoma. If sufficient biopsy material is available, GD2expression on the tumour will be confirmed. As GD2 is consistently expressed inneuroblastoma demonstration of GD2 is not mandated.

3. Disease which has relapsed after or is refractory to at least one line of salvagecombination 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 marrowaspirate or trephine) are NOT eligible for the study.

5. At least 3 weeks or 5 half-lives, whichever is shorter, after treatment with agentson 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 situpright unassisted in a wheelchair, will be considered ambulatory for the purpose ofassessing performance score.

7. Creatinine ≤1.5 ULN for age, if higher, an estimated (calculated) creatinineclearance 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 adequatecontraception (if applicable).

10. Written informed consent.

Exclusion Criteria:

1. Patients with only bone marrow detectable disease in the absence of measurabledisease 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., significantcardiac, pulmonary, hepatic or other organ dysfunction), that in the judgement ofthe investigator is likely to interfere with assessment of safety or efficacy of theinvestigational regimen and its requirements.

6. Any contraindication to lymphodepletion or to the use of Cyclophosphamide orFludarabine 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, rheumatoidarthritis, systemic lupus) requiring systemic immunosuppression /systemic diseasemodifying agents within the last 2 years.

10. Prior treatment with investigational or approved gene therapy or cell therapyproducts.

11. Life expectancy <3 months.

12. Use of rituximab (or rituximab biosimilar) within the last 3 months prior to of GD2CAR T cells infusion.

13. Systemic corticosteroid therapy ≥ 0.05 mg/kg dexamethasone daily (or equivalent) attime 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 diagnosedinfection for which the patient continues to receive antimicrobial therapy ispermitted if responding to treatment and clinically stable at the time of scheduledGD2 CAR T cells infusion.

2. Systemic corticosteroid therapy ≥ 0.05 mg/kg dexamethasone daily (or equivalent) attime of GD2 CAR T cells infusion.

3. Use of rituximab (or rituximab biosimilar) within the last 3 months prior to GD2 CART cell infusion