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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。假设：供体T细胞的基因转移将允许在范可尼贫血的高风险移植中安全输注免疫反应细胞。本研究的目的是提高替代供体（非相关或错配相关）造血细胞移植（HCT）治疗范可尼贫血（FA）患者的疗效和安全性。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，这将允许在体内根除中度至重度移植物抗宿主病（GVHD）发生时转导的T细胞。使用这些技术，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，同时提供对潜在威胁生命的GVHD的更多控制。为了鉴定被逆转录病毒成功转导的细胞，人类截断神经生长因子受体（NGFR）基因也被包括在逆转录病毒构建物中，导致在T细胞上不表达的人类细胞表面分子的表达。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，以确保几乎所有注入的T细胞都含有HSV-tk基因。第一阶段研究的主要目的是确定转导方案的可行性、安全性和可重复性。本研究将使用GCRC收集研究样本，监测实验细胞的输注，并使用GCRC细胞治疗核心进行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.