Immunotherapy with CD19? gene modified EBV-specific CTLs after stem cell transplant in children with high-risk acute lymphoblastic leukaemia
Description
Design:
a multi-site, non-randomised, phase I/II, paediatric trial with 2 arms. The Advanced Therapy Medicinal product (ATMP) tested in the study is donor-derived EBV-specific cytotoxic T-cells (EBV-CTL) transduced with retroviral vector carrying CD19 chimaeric antigen receptor. 15 patients will be treated prophylactically with the EBV-CTL and a further cohort of 15 patients will be treated pre-emptively based on minimal residual disease post HSCT. If the EBV-CTL cannot be detected after 5 patients have been treated, subsequent patients will receive vaccination with irradiated donor-derived LCL (2nd ATMP) to test whether EBV-CTL persistence will be improved.
Treatment:
Patients will receive lymphodepletion with Fludarabine. Patients will receive the EBV-CTL infusion as 2 intravenous injections over consecutive days. If the CD19-CTL infusion is safe but the ATIMP is not detectable in > 50% of the 1st five patients, subsequent patients in either arm of the trial will be treated as above but with additional LCL vaccination (2nd ATIMP) postCD19-CTL infusion.
Key inclusion/exclusion criteria:
Pre-emptive arm –patients in first remission or with relapsed CD19+ B cell precursor ALL who are undergoing allogeneic stem cell transplant (ASCT). Prophylaxis arm - any patient with ALL relapsing in bone marrow after allogeneic HSCT achieving remission after re-induction, who is a candidate for second HSCT. Stem cell donors must be EBV sero-positive and HLA-matched or a single antigenic/allelic (7/8) mismatch with recipient. Patients must not have active acute or significant chronic GVHD requiring steroids, pre-existing lung disease or active intercurrent infection. Patients cannot be serologically positive for Hepatitis B, C or HIV pre-HSCT.
Duration of recruitment:
2-3 years
Aim
The primary aim of the trial is to evaluate the feasibility, safety and biological effect of adoptive transfer of CD19ζ chimaeric receptor transduced donor-derived EBV-specific cytotoxic T-lymphocytes (EBV-CTL) in patients with high-risk or relapsed B cell precursor ALL after allogeneic HSCT. Primary endpoints are toxicity within 12 weeks of infusion attributable to transfer of CD19- ζ transduced CTL and biological efficacy, assessed by effect of CD19- ζ transduced CTL on Minimal Residual Disease levels in the bone marrow in the first year post infusion.