TRANSPLANTATION OF URB T CELLS CONTAINING THE HSV-TK SUICIDE GENE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。假设：供者T细胞的基因转移将使免疫反应细胞在Fanconi贫血的高危移植中得到安全的输注。本研究的目的是提高Fanconi贫血(FA)患者替代供者(非血缘或不匹配血缘)造血细胞移植(HCT)的有效性和安全性。供体T细胞将被基因修饰以表达单纯疱疹病毒胸苷激酶(HSV-tk)基因，这将导致工程细胞对药物更昔洛韦(GCV)的敏感性增加，如果出现中到重度移植物抗宿主病(GVHD)，这将使转导的T细胞在体内被根除。利用这些技术，预计T细胞在HCT中的积极作用(即增强植入和免疫恢复)将保持不变，同时加强对潜在威胁生命的移植物抗宿主病的控制。为了鉴定成功转导逆转录病毒的细胞，人类截短神经生长因子受体(NGFR)基因也被包括在逆转录病毒构建中，导致人类细胞表面分子的表达，否则T细胞上不会表达。T细胞表面NGFR的存在将用于从非转导细胞中纯化转导细胞，以确保几乎所有输注的T细胞都含有HSV-tk基因。这项第一阶段研究的主要目标是确定转导方案的可行性、安全性和重复性。在这项研究中，GCRC将用于收集研究样本，监测实验细胞的输注，以及GCRC细胞治疗核心，用于免疫监测和细胞产品的生产。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypothesis: Gene transfer of donor T cells will allow safe infusion of immune reactive cells in high risk transplanation for Fanconi anemia. The goal of this study is to increase the efficacy and safety of alternate donor (unrelated or mismatched related) hematopoietic cell transplantation (HCT) in patients with Fanconi anemia (FA). Donor T cells will be genetically modified to express the herpes simplex virus thymidine kinase (HSV-tk) gene, which results in increased sensitivity of engineered cells to the drug ganciclovir (GCV), which will allow eradication of transduced T cells in vivo should moderate to severe graft-versus-host disease (GVHD) develop. Using these techniques it is anticipated that the positive effects of T cells in HCT (i.e. enhanced engraftment and immune recovery) will be maintained while providing increased control over potentially life-threatening GVHD. To identify cells that have been successfully transduced with the retrovirus, the human truncated nerve growth factor receptor (NGFR) gene is also included in the retroviral construct, resulting in expression of a human cell surface molecule not otherwise expressed on T cells. The presence of NGFR on the surface of T cells will be used to purify transduced cells from non-transduced cells to ensure that nearly all T cells infused will contain the HSV-tk gene. The primary objective of this phase I study is to determine the feasibility, safety and reproducibility of the transduction protocol. The use of the GCRC in this study will be for collection of study samples, monitoring of infusion of experimental cells and the GCRC Cell Therapy Core for immune monitoring and production of the cellular product.