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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。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性细胞。本研究的目的是提高范可尼贫血（FA）患者替代供者（无关或不匹配的相关）造血细胞移植（HCT）的疗效和安全性。供体T细胞将被遗传修饰以表达单纯疱疹病毒胸苷激酶（HSV-tk）基因，这导致工程化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转导的T细胞，如果中度至重度移植物抗宿主病（GVHD）发展。使用这些技术，预期将维持HCT中T细胞的积极作用（即增强的植入和免疫恢复），同时提供对潜在危及生命的GVHD的增加的控制。为了鉴定已成功用逆转录病毒转导的细胞，人截短的神经生长因子受体（NGFR）基因也包括在逆转录病毒构建体中，导致表达在T细胞上不表达的人细胞表面分子。T细胞表面上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。本I期研究的主要目的是确定转导方案的可行性、安全性和重现性。在本研究中，GCRC将用于采集研究样本，监测实验细胞输注，GCRC细胞治疗核心用于免疫监测和细胞产品生产。

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.