Acute Lymphoblastic Leukemia
Conditions
Keywords
Immunotherapy, Gene Therapy, Paediatric, B cell Acute Lymphoblastic Leukaemia
Brief summary
The aim of this clinical 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 Haematopoietic Stem Cell Transplantation (HSCT).
Interventions
GENETICdonor-derived EBV-specific cytotoxic T-cells (EBV-CTL) transduced with the retroviral vector SFGalpha-CD19-CD3zeta
All patients will be treated at the same total dose level of 2 x 10\^8/m2
BIOLOGICALIrradiated donor-derived Lymphoblastoid Cell Line
The initial cohort of 5 patients (regardless of arm of study) will be treated as described. If transduced CTL infusion is safe in this initial cohort and real-time DNA PCR studies demonstrate that transduced CTL are undetectable in \> 50% of patients by 2 months post-infusion, the remaining 25 patients (in either arm of the study) will be treated as above but with an additional vaccination of CD19-zeta-transduced EBV-LCL infusion. Vaccination will consist of 3 doses of 5 x 10\^6 irradiated (70Gy) donor-derived EBV-lymphoblastoid cell line used to generate CTL and will be administered subcutaneously into the thigh (volume 0.3 ml) at day -2, week 4 and 8 post-transduced CTL infusion.
Sponsors
European Union
The Leukemia and Lymphoma Society
Children with Leukaemia
Department of Health, United Kingdom
JP Moulton Charitable Foundation
Deutsche Krebshilfe e.V., Bonn (Germany)
University College, London
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 18 Years
Healthy volunteers
No
Inclusion criteria
Pre-emptive arm Children (18 years or younger) with CD19+ precursor B cell ALL fulfilling one of the following criteria who are undergoing an allogeneic stem cell transplant from an EBV-seropositive donor: In first remission, if at least one of the following criteria are met: * t(9;22) and MRD positive (BCR-ABL/ABL ratio \> 0.01%) after HR3 block of EsPhALL or pre-HSCT or * Infant ALL age \< 6 months at diagnosis with MLL gene rearrangement and either presenting wcc \>300 x 10\^9/L or poor steroid early response (i.e circulating blast count \>1x10\^9/L following 7 day steroid pre-phase of Interfant 06) or * Resistant disease (\> 30% blasts at end of induction treatment day 28-33) in subsequent morphological CR or * High level bone marrow MRD (\> 1 in 1000) at week 12 ALL-BFM 2000/AIEOP BFM ALL 2009/EORTC 58951 protocols, week 12-15 of FRALLE A or at week 14 of UKALL2011 Relapsed patients if at least one of the following criteria are met: * Very early (\< 18 months from diagnosis) bone marrow or extramedullary relapse in second CR or * Early (within 6 months of finishing therapy) isolated bone marrow relapse with bone marrow MRD \> 1 in 100 at day 35 of reinduction in second CR or * Early (within 6 months of finishing therapy) bone marrow or combined relapse with high level bone marrow MRD (\> 1 in 1000) at the end of consolidation therapy (week 12-13 UKALL R3/INTREALL and COOPRALL protocols, prior to protocol M in BFM relapse protocol (ALL-REZ BFM 2002) and after Protocol II-IDA in AIEOP LLA Rec 2003)or * Any relapse of infant or Philadelphia-positive ALL in morphological complete remission * Any patient being transplanted in 3rd or greater CR These patients have a high (\> 50%) risk of relapse and will be monitored for evidence of MRD in bone marrow aspirates (monthly for months 1-6, 6 weekly months 7.5-12 post HSCT) for the first year post-transplant. Patients who become MRD +ve in the marrow at a level minimum 5 x 10-4 (or BCR-ABL/ABL ratio 0.05% in Ph+ve ALL patients with no IgH MRD marker) but are in morphological remission (\<5% blasts in BM) will be eligible to be treated pre-emptively with CD19ζ transduced CTL Prophylaxis arm Additionally, any patient (≤ 18 years) with ALL relapsing in the bone marrow (isolated or combined) after myeloablative allogeneic HSCT who achieves morphological remission after re-induction and who is a candidate for second HSCT at one of the participating centres is eligible to receive CD19ζ transduced CTL prophylactically * Stem cell donors must be EBV sero-positive and HLA-matched (8/8 HLA A,B,C and DR at medium resolution typing) or a single antigenic/allelic (7/8) mismatch with the recipient * A life expectancy of at least 12 weeks * Karnofsky score of \>60% if \>10 years old or Lansky performance score of \>60 if ≤ 10 years old * Patients must have transduced donor-derived EBV-specific CTLs with 15% or higher expression of CD19ζ determined by flow-cytometry which meet the specified release criteria * Informed written consent indicating that patients are aware this is a research study and have been told of its possible benefits and toxic side effects
Exclusion criteria
* Patients with CD19 negative precursor B cell ALL * EBV seronegative or \> single antigenic/allelic HLA-mismatched donor * Active acute GVHD overall Grade 2 or higher or significant chronic GVHD requiring systemic steroids at the time of scheduled infusion of transduced CTL will be excluded until the patient is GVHD-free and off steroids * Pre-existing severe lung disease (FEV1 or FVC \< 50% predicted) pre-HSCT or an oxygen requirement of \>28% O2 supplementation or active pulmonary infiltrates on chest X-ray at the time scheduled for transduced CTL infusion * Serum bilirubin \>3 times the upper limit of normal or an AST or ALT \> 5 times the upper limit of normal * Serum creatinine \>3 times upper limit of normal * Active severe intercurrent infection at the time of transduced CTL infusion (if present consult with Chief investigator). * Patients in whom transduced donor-derived EBV-specific CTLs don't meet release criteria * Serologically positive for Hepatitis B, C or HIV pre-HSCT * Females of childbearing age with a positive pregnancy test * Known allergy to DMSO
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity attributable to transfer of CD19-zeta transduced CTL | 1 year | 1. Incidence of grade 3-5 toxicity attributable to transfer of CD19-zeta transduced CTL within 12 weeks of infusion. 2. Incidence of significant (Grade II-IV) and severe (Grade III-IV) acute GVHD before day 100 and limited/extensive chronic GVHD between day 100-365. 3. Incidence of hypogammaglobulinaemia after CD19-zeta CTL transfer at day 100, 6 months and 1 year post-HSCT |
| Biological efficacy as assessed by effect of CD19-zeta transduced CTL on Minimal Residual Disease levels in the bone marrow in the first year post- transduced CTL infusion | 1 year | — |
Secondary
| Measure | Time frame |
|---|---|
| In vitro anti-leukaemic response of circulating PBMC post adoptive transfer of CD19-zeta transduced CTL using interferon-gamma ELISPOT assays after stimulation with CD19+ve targets | 1 year |
| Persistence and frequency of circulating CD19-zeta transduced CTL in the peripheral blood of recipients after adoptive transfer as assessed by flow cytometry and quantitative real-time PCR. | 1 year |
| Relapse rate, disease-free survival and overall survival at 1 and 2 years after adoptive immunotherapy with CD19ζ-transduced EBV-CTL | 2 years |
Countries
Germany, United Kingdom
Outcome results
None listed