Phase I/II: Treatment of Adenovirus and Cytomegalovirus Infection Post Human Allogeneic Stem Cell Transplantation With Short-term Expanded Virus-specific T Cells
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 试验地点
- 2
- 主要终点
- Non pre-existing Immune System Disorders i.e. Allergic reaction, Anaphylaxis, Cytokine release syndrome or Serum sickness of Grade III-IV of seVirus-T-cell infusion within 48 hours from infusion
研究概览
简要总结
Invasive infections with CMV and Adenovirus, not responding to virostatic treatment are treated with virusspecific donor derived or autologous virusspecific T-cells.
详细描述
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only treatment option for several haematological diseases. In spite of substantial progress in this field, viral infections, mainly cytomegalovirus (CMV) and adenovirus (HAdV) in the context of delayed immunoreconstitution remain life threatening complications. Weekly screening of high-risk patients and preemptive virostatic treatment has become a current strategy. Unfortunately, treatment with virostatic drugs is associated with substantial nephro- and myelo-toxicity and of limited effectiveness. Human adenovirus (HAdV) and cytomegalvirus (CMV) disseminated infections are associated with mortality rates of up to 50%-60% despite virostatic treatment.
All HSCT patients at the St. Anna Children's Hospital undergo weekly viral quantitative PCR-screening for HAdV and CMV and weekly PB FACS (Fluorescence Activated Cell Sorter)-Analysis according to the local HSCT-diagnostic SOP (Standard Operating Procedure) from day -7 until day +100 Patients with HAdV or CMV viremia will receive preemptive treatment with either gancyclovir (in case of isolated CMV-viremia) or Cidofovir (in case of HAdV viremia or combined HAdV/CMV infection). In case of increasing viremia ≥ 1log despite antiviral treatment for two weeks or stable with 10E6 viral load and the absence of virus specific T-cells in the recipient, the treating physician will check, if the patient is eligible for seVirus-T-cell infusion (see inclusion criteria).
Study Design: Mononuclear Donor-Cells from peripheral blood (100 ml extra donation) will be cryopreserved at the time-point of HSCT. In case of progredient viremia these cells will be stimulated with interleukin-15 and peptides out of the virus molecule, virusspecific T-Cells are enriched for 2-3 logs-teps and potentially alloreactive cells diluted at the same time. This new approach reduces the risk of graft-versus-host-disease (GvHD) and enables the infusion of virus-specific T-cells also from haploidentical donors.
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
- — 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age at timepoint of HSCT ≤18 years undergoing allogeneic stem cell transplantation
- •Presence of HAdV or CMV-specific T-cells in the donor or CMV-specific T-cells in the recipient pre-transplant
- •Stable (≥ 10E6) or increasing viremia despite antiviral treatment post HSCT
- •Absence of HAdV or CMV -specific T cells post HSCT
- •Karnofsky / Lansky score >50%
- •Pregnancy excluded
- •Informed study participation consent is signed
排除标准
- •Infusion of polyclonal or monoclonal T-cell directed antibodies within 28 days before seVirus T-Cell infusion
- •Multiple organ failure at screening-timepoint seVirus T-Cell infusion
- •History of GvHD Gr III-IV or actual GvHD Gr III-IV
- •Pregnancy
- •Treatment with granulocyte transfusion within the last 72 hours
- •Karnofsky / Lansky score <50%
- •Subject is unwilling or unable to comply with the study procedures
- •High dose treatment with steroids (≥ 2mg/kg/d, methylprednisone-equivalent)
研究组 & 干预措施
ARM 1
Patients with Adenovirus or CMV infection after HSCT and no reduction of viral disease or stable disease with 10E6 viral copies within 2 weeks of antiviral treatment will receive a single infusion of virus-specific T-Cells
干预措施: virus-specific T-Cells (Biological)
结局指标
主要结局
Non pre-existing Immune System Disorders i.e. Allergic reaction, Anaphylaxis, Cytokine release syndrome or Serum sickness of Grade III-IV of seVirus-T-cell infusion within 48 hours from infusion
时间窗: 48 hours
assessment is performed according to CTCAE 4.3 Scale
De novo acute GvHD > Gr II or increase of pre-existing GvHD more than 1 grade from 2 weeks post infusion until 8 weeks post infusion
时间窗: 8 weeks
assessment is performed according to Glucksberg Scale, modified for paediatic patients from D. Jacobsohn (publication Blood 2008)
Incidence of graft rejection
时间窗: 8 weeks
次要结局
- Detection of virus-specific T-cells within 8 weeks after T-cell therapy. Measurement of the viral load following the infusion of seVirus-T-cells(6 months)
- Tracking of the infused T-cells by NGS (Next Generation Sequencing) of the TCRs (T-Cell Receptors)-beta rearrangements(3 months)
- Correlation of the presence of virus-specific T-cells with partial reduction (>1 log viral copies /ml blood) or complete clearance of viral load(8 weeks)