Immunotherapy With CD19ζ Gene-modified EBV-specific CTLs After Stem Cell Transplant in Children With High-risk Acute Lymphoblastic Leukaemia
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 29
- 试验地点
- 7
- 主要终点
- Toxicity attributable to transfer of CD19-zeta transduced CTL
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Prophylaxis arm
Patients who have relapsed in the bone marrow after previous myeloablative HSCT and achieve remission after chemotherapy will be treated prophylactically with CD19-specific gene-engineered T cells after a second HSCT with reduced intensity conditioning.
干预措施: donor-derived EBV-specific cytotoxic T-cells (EBV-CTL) transduced with the retroviral vector SFGalpha-CD19-CD3zeta (Genetic)
Prophylaxis arm
Patients who have relapsed in the bone marrow after previous myeloablative HSCT and achieve remission after chemotherapy will be treated prophylactically with CD19-specific gene-engineered T cells after a second HSCT with reduced intensity conditioning.
干预措施: Irradiated donor-derived Lymphoblastoid Cell Line (Biological)
Pre-emptive arm
In this arm, patients identified at high (> 50%) risk of relapse will be eligible for generation of donor-derived EBV CTL immediately prior to HSCT. These patients will be monitored for evidence of MRD in regular bone marrow aspirates for the first year post-HSCT. MRD positivity post-HSCT is highly predictive of subsequent relapse. In those patients who become MRD+ in the marrow at a level of minimum 5 x 10-4, cryopreserved CTL that have been transduced with a retroviral vector carrying the CD19-zeta transgene will be thawed and administered to the patient pre-emptively.
干预措施: donor-derived EBV-specific cytotoxic T-cells (EBV-CTL) transduced with the retroviral vector SFGalpha-CD19-CD3zeta (Genetic)
Pre-emptive arm
In this arm, patients identified at high (> 50%) risk of relapse will be eligible for generation of donor-derived EBV CTL immediately prior to HSCT. These patients will be monitored for evidence of MRD in regular bone marrow aspirates for the first year post-HSCT. MRD positivity post-HSCT is highly predictive of subsequent relapse. In those patients who become MRD+ in the marrow at a level of minimum 5 x 10-4, cryopreserved CTL that have been transduced with a retroviral vector carrying the CD19-zeta transgene will be thawed and administered to the patient pre-emptively.
干预措施: Irradiated donor-derived Lymphoblastoid Cell Line (Biological)
结局指标
主要结局
Toxicity attributable to transfer of CD19-zeta transduced CTL
时间窗: 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
时间窗: 1 year
次要结局
- 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)
- 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)