Donor Regulatory T Cells (Treg) Infusion (DTI) in Patients With Steroid-refractory Chronic Graft-versus-host Disease (GVHD)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 19
- 试验地点
- 2
- 主要终点
- To assess the safety of a combination of rapa administration, donor Treg infusion and low-dose IL-2 in patients with steroid-refractory chronic GVHD.
研究概览
简要总结
The immune system has offensive and defensive capacities. In bone marrow transplantation, offensive cells in the donor grafts may attack host's organs, leading to a complication known as Graft versus Host Disease (GVDH). At present, patients receive steroid treatment to combat this tricky situation. Nevertheless, some patients do not respond to this therapy. Recently, it has been shown that immune system cells having defensive capacities can help in preventing the occurrence of a GVDH.
This study aims to evaluate if these protective cells together with a non-standard immunosuppressor can improve the clinical condition and suppress the activity of the offensive cells in the graft.
详细描述
TREATMENT PLAN
1 Immunosuppressive drugs (DTI and control arms)
- Rapa will be started within 2 weeks after inclusion. Rapa will be given at 2-6 mg loading dose for one day, followed by approximately 1mg daily to achieve a target trough level of 5 to 10 ng/mL. The frequency of trough level measurements will be done according to the investigator choice;
- Rapa may be discontinued in case of resolution of chronic GVHD ≥ 3 months or in case of un-manageable side effects or progression of chronic GVHD.
- Calcineurin inhibitor discontinuation within 2 weeks after rapa initiation. No other modification of immunosuppressive drugs and in particular no decrease in the dose of steroids (unless necessary for side effects).
- Evaluation of chronic GVHD 60 days after rapa initiation. DTI will not be given in patients who had progression of their GVHD on day 60 nor in those who are in CR of their GVHD.
- Collection of donor lymphocytes (DTI arm)
- Apheresis of the donor will be performed 60-90 days after first day of rapa administration to the patient.There will be no particular preparation of the donor prior to leukapheresis. After written informed consent, the donor will undergo leukaphereses on 1 day. Leukapheresis will be performed using a continuous flow blood cell separator and following a mononuclear cell collection protocol. The volume of blood processed will be 20 liters. Anticoagulation will be performed with the ACD-A / heparin solution.
- Tregselection and infusion (DTI arm)
- Treg will be isolated at the LTCG of the CHU of Liège from apheresis product with the CliniMACS separation system (MiltenyiBiotec) following a two-step procedure (CD8 and CD19 depletion followed by CD25 positive selection)according to the manufacturer's recommendation. Aliquots (≈ 3 mL) of the Treg product will be saved for analyses.
- Treg will be infused i.v.60-90 days after first day of rapa administration and after calcineurin inhibitor discontinuation. No DTI will be performed in the control arm.
- Low-dose Il-2 (1x106 IU/day) will be started the day of DTI and will be continued for a period of 2months in order to expand infused donor Tregs.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Donor Treg infusion arm
Condition:Patients treated with steroids for a chronic GVHD occurring after allogeneic cell transplantation. Patients who have refractory chronic GVHD will be eligible. Patients in this arm will be first treated with Rapamycin while CNI (if any) will be discontinued and infused whith Treg cells 60-90 days after.
干预措施: T regulatory cells (Other)
Control
Condition:Patients treated with steroids for a chronic GVHD occurring after allogeneic cell transplantation. Patients who have refractory chronic GVHD will be eligible. Patients in this arm will be treated with Rapamycin which is an alternative immunosupression strategy allowing to fight againt GVHD and CNI (if any) will be discontinued.
干预措施: Rapamycin (Drug)
结局指标
主要结局
To assess the safety of a combination of rapa administration, donor Treg infusion and low-dose IL-2 in patients with steroid-refractory chronic GVHD.
时间窗: 12 months after inclusion
To assess the immunological changes (including Treg number/phenotype) occurring after donor Treg infusion and rapamycin administration. Treg will be defined as CD4+CD25+FoxP3+ T cells. Treg phenotype will include CD127, CD45RA, CCR4, CCR7 and KI67. Treg will also be assessed by an analysis of the methylation status of CpG dinucleotides located in a conserved region of FoxP3 intron 1.
次要结局
- To compare overall relapse incidence in patients given Treg infusion + low-dose IL-2 + rapa (DTI arm) versus in those given rapa without Treg infusion (control arm; vide infra).(1 year after rapamycin onset)
- To assess the impact of 8 weeks rapamycin administration on percentage and absolute counts of Treg and conventional T cells.(8 weeks after rapamycin onset)
- To compare immunological changes in patients given Treg infusion + low-dose IL-2 + rapa (DTI arm) versus in those given rapa without Treg infusion (control arm; vide infra).(Before DTI (day 21-28 after rapamycin onset). Week 1 and 3 after DTI (4-5 anf 6-7 weeks after rapamycin onset); month 3, 6 and 12 after rapamycin onset.)
- To assess the efficiency of Treg selection with the Clinimacs procedure.(1 month after Treg selection)
- To assess the response rate of chronic GVHD (defined using the NIH criteria as defined by Lee et al.41) to donor Treg infusion + low-dose IL-2 + rapa at 1, 2, 3, 6 and 12 months after rapa onset.(at 1, 2, 3, 6 and 12 months after rapamycin onset)
- To compare response rate of chronic GVHD in patients given Treg infusion + low-dose IL-2 + rapa (DTI arm) versus in those given rapa without Treg infusion (control arm; vide infra).(at 1, 2, 3, 6 and 12 months after rapamycin onset)
- To compare overall survival incidence in patients given Treg infusion + low-dose IL-2 + rapa (DTI arm) versus in those given rapa without Treg infusion (control arm; vide infra).(1 year after rapamycin onset)
- To compare the incidence of viral, bacterial, fungal and parasital infection in patients given Treg infusion + low-dose IL-2 + rapa (DTI arm) versus in those given rapa without Treg infusion (control arm; vide infra).(over the 12 months of the trial)
- To compare overall progression-free survival incidence in patients given Treg infusion + low-dose IL-2 + rapa (DTI arm) versus in those given rapa without Treg infusion (control arm; vide infra).(1 year after rapamycin onset)
研究者
Frédéric Baron
MD, PhD
University of Liege