Immunotherapy With Tacrolimus Resistant EBV CTL for Lymphoproliferative Disease After Solid Organ Transplant
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 4
- 试验地点
- 2
- 主要终点
- Toxicity at 6 weeks post infusion
研究概览
简要总结
This is an open label, non-randomised, multicentre Phase I to determine the safety of tacrolimus-resistant autologous EBV-specific cytotoxic T-cells (EBV CTL) and compare their expansion/persistence with control EBV CTL in solid organ transplant patients with post-transplant lymphoproliferative disease (PTLD). Each patient will receive an infusion of two ATIMPs - autologous EBV CTL retrovirally transduced with (a) a calcineurin mutant (CNA12) that confers resistance to tacrolimus and (b) a control calcineurin mutant (CNA8).
详细描述
This is a multi-centre, non-randomised, open label Phase 1 clinical trial of Advanced Therapy Investigational Medicinal Products (ATIMPs) in adult and paediatric (age 1-70 years) solid organ transplant recipients with histologically proven B-lineage EBV+ post-transplant lymphoproliferative disease (PTLD).
The ATIMPs for this study are autologous EBV CTL transduced with the (a) the retroviral vector SFG-CNA12 encoding a calcineurin A mutant (CNA12) that confers resistance to tacrolimus and (b) the retroviral vector SFG-CNA8 encoding a control calcineurin A mutant (CNA8).
Following informed consent and registration to the trial, patients will undergo an unstimulated leucapheresis for generation of both ATIMPs. Patients will receive an equal dose of each ATIMP (10x7 CNA8+ or CNA12+ CTL/m2) which will be administered intravenously.
Other immunosuppressants (e.g. MMF) will be reduced, but tacrolimus will be maintained at therapeutic levels.The trial will evaluate the safety of the ATIMPs in organ transplant recipients developing EBV+ PTLD and compare the persistence and frequency of circulating CNA12 and CNA8 CTL in the peripheral blood.
Our hypothesis is that in the presence of ongoing immunosuppression with tacrolimus, CNA12 CTL will show preferential expansion and prolonged persistence compared with CNA8 CTL. If successful this will result in durable clearance of PTLD without the need to reduce tacrolimus, thus reducing the risk of graft rejection.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 70 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult and paediatric (age 1-70 years) solid organ transplant recipients with histologically proven B-lineage EBV+ post-transplant lymphoproliferative disease (PTLD) either de novo or resistant to Rituximab
- •EBV viraemia at enrolment
- •On immunosuppression with tacrolimus
- •Agreement to have a pregnancy test and use of contraception for duration of trial (if applicable)
- •Written informed consent
排除标准
- •Fulminant disease
- •Requirement for supplemental oxygen
- •Burkitt's lymphoma/Mature B-acute lymphoblastic leukaemia with IgH-Myc rearrangement
- •T-lineage PTLD
- •Bilirubin > 3 x upper limit of normal
- •Creatinine > 3 x upper limit of normal
- •Active hepatitis B, C or HIV infection
- •Women who are pregnant or breast-feeding
- •ECOG performance score ≥ 4
- •Inability to tolerate leucapheresis
研究组 & 干预措施
Autologous EBV-CTL transduced with SFG-CNA12/SFG-CNA8
All patients will receive the autologous EBV CTL retrovirally transduced with with (a) a calcineurin mutant (CNA12) that confers resistance to tacrolimus and (b) a control calcineurin mutant (CNA8). For each patient two ATIMPs will be generated:
- Autologous EBV-specific cytotoxic T-cells (CTL) transduced with the retroviral vector SFG-CNA12
- Autologous EBV-specific cytotoxic T-cells (CTL) transduced with the control retroviral vector SFG-CNA8
An equal dose (10x7/m2) of CNA12+ EBV CTL and CNA8+ EBV CTL will be administered intravenously on day 0.
While awaiting ATIMP generation, patients may receive a single dose of Rituximab and other immunosuppressants (e.g. MMF) will be reduced, but tacrolimus will be maintained at therapeutic levels.
干预措施: Autologous EBV-CTL transduced with vector SFG-CNA12 (Biological)
Autologous EBV-CTL transduced with SFG-CNA12/SFG-CNA8
All patients will receive the autologous EBV CTL retrovirally transduced with with (a) a calcineurin mutant (CNA12) that confers resistance to tacrolimus and (b) a control calcineurin mutant (CNA8). For each patient two ATIMPs will be generated:
- Autologous EBV-specific cytotoxic T-cells (CTL) transduced with the retroviral vector SFG-CNA12
- Autologous EBV-specific cytotoxic T-cells (CTL) transduced with the control retroviral vector SFG-CNA8
An equal dose (10x7/m2) of CNA12+ EBV CTL and CNA8+ EBV CTL will be administered intravenously on day 0.
While awaiting ATIMP generation, patients may receive a single dose of Rituximab and other immunosuppressants (e.g. MMF) will be reduced, but tacrolimus will be maintained at therapeutic levels.
干预措施: Autologous EBV-CTL transduced with control vector SFG-CNA8 (Biological)
Autologous EBV-CTL transduced with SFG-CNA12/SFG-CNA8
All patients will receive the autologous EBV CTL retrovirally transduced with with (a) a calcineurin mutant (CNA12) that confers resistance to tacrolimus and (b) a control calcineurin mutant (CNA8). For each patient two ATIMPs will be generated:
- Autologous EBV-specific cytotoxic T-cells (CTL) transduced with the retroviral vector SFG-CNA12
- Autologous EBV-specific cytotoxic T-cells (CTL) transduced with the control retroviral vector SFG-CNA8
An equal dose (10x7/m2) of CNA12+ EBV CTL and CNA8+ EBV CTL will be administered intravenously on day 0.
While awaiting ATIMP generation, patients may receive a single dose of Rituximab and other immunosuppressants (e.g. MMF) will be reduced, but tacrolimus will be maintained at therapeutic levels.
干预措施: Leucapheresis (Procedure)
结局指标
主要结局
Toxicity at 6 weeks post infusion
时间窗: 6 weeks
Toxicity as assessed by NCI Common toxicity criteria within 6 weeks of infusion
Persistence and frequency of circulating EBV CTL
时间窗: 12 months
Persistence and frequency of circulating EBV CTL transduced with CNA12 compared with control vector CNA8 in the peripheral blood
次要结局
- Disease free survival(2 years)
- Organ graft Rejection(2 years)
- Disease response(6 weeks)
- Relapse rate(2 years)