Fratricide-resistant autologous chimeric antigen receptor T cells targeting CCR9 for the treatment of T cell acute lymphoblastic leukaemia/ lymphoma
Relapsed or refractory T-cell malignancies (T-ALL or T-LBL)
Both cohorts (adult (≥18 years old) and paediatric: 1. Leukapheresis: following registration, patients will undergo an unstimulated leukapheresis which will be used for the manufacture of the CARCCR9 T cells 2. Lymphodepletion: patients will receive fludarabine 30 mg/m2 (on days -6 to -3) and cyclophosphamide 500 mg/m2 (on days -6 to -5) 3. CARCCR9 T cells: Intravenous infusion on Day 0 at a dose assigned according to the Continuous Reassessment Method design. The following dose levels will be tested: Dose level 1: 0.5 x 10^6 CARCCR9 T cells/kg Dose level 2: 1.0 x 10^6 CARCCR9 T cells/kg Dose level 3: 2.0 x 10^6 CARCCR9 T cells/kg 4. Follow-up – patients remain in hospital for at least 2 weeks post-infusion and then are actively followed up for 2 years. Following this, patients are followed up annually until 15 years post-infusion.
1. Relapsed or refractory T-ALL/T-LBL following at least: 1.1. Patients ≥18 years old: one standard prior line of combination cytotoxic therapy 1.2. Patients <18 years old: two standard prior lines of combination cytotoxic therapy 2. All disease types: CCR9-positive disease as assessed by flow cytometry 3. T-LBL patients only: Patients must have measurable disease which is CCR9-positive by standard flow cytometry tests (on tissue biopsy, blood, bone marrow, or malignant effusion) 4. Agreement to have a pregnancy test, use adequate contraception (if applicable) 5. Written informed consent
1. ECOG performance score >2 (patients aged ≥10 years old) OR Lanksy score ≤50% (patients aged <10 years old) (see Appendix 2) 2. Stem Cell Transplant patients only: active significant acute GvHD (overall Grade ≥ II, modified Glucksberg criteria) or moderate/severe chronic GvHD (NIH consensus criteria) requiring immunosuppressive therapy and/or systemic steroids (see Appendix 5) 3. Active CNS involvement of disease 4. Active hepatitis B, C or HIV infection 5. Oxygen saturation ≤90% on air 6. Bilirubin >3 x upper limit of normal 7. GFR <30 ml/min 8. Cardiac dysfunction as defined by: 8.1. Patients ≥18 years old: cardiac dysrhythmias (excluding well-controlled atrial fibrillation or other supraventricular tachycardia) or significant cardiac disease and left ventricular ejection fraction <40% 8.2. Patients <18 years old: Left ventricle shortening fraction <28% on echocardiogram 9. Patients receiving corticosteroids at a supraphysiological dose that cannot be discontinued 10. Known allergy to albumin, DMSO, PBS/EDTA (or any component of the ATIMP) 11. Any contraindications to lymphodepletion or to the use of cyclophosphamide or fludarabine as per local SmPC 12. Women who are pregnant or breastfeeding 13. Life expectancy <3 months 14. Fulminant or rapidly progressive disease