DLI using genetically modified T cells: Phase 1 trial

使用转基因 T 细胞的 DLI：1 期试验

• 批准号: 6918590
• 负责人: John F. Dipersio
• 金额: $ 31.37万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-08 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6918590
• 关键词: NOD mouse; SCID mouse; T lymphocyte; biotechnology; bone marrow transplantation; cell death; clinical research; clinical trial phase I; combination therapy; ganciclovir; gene therapy; genetic transduction; graft versus host disease; herpes simplex virus 1; homologous transplantation; human subject; human therapy evaluation; immunopathology therapy; injection /infusion; neoplasm /cancer relapse /recurrence; neoplasm /cancer therapy; nonhuman therapy evaluation; patient oriented research; thymidine kinase; transfection /expression vector

DESCRIPTION (provided by applicant): The purpose of the proposed study is to perform genetically manipulated allogeneic donor lymphocyte infusions in patients who have relapsed hematologic malignancies after allogeneic stem cell transplantation (SCT). Donor lymphocyte infusions (DL1) have resulted in the cure of some patients with relapsed leukemia or lymphoproliferative disorders after allogeneic BMT, but have been complicated by the development of graft versus host disease (GvHD). The central hypotheses of this study are the following: Retroviral mediated transfer of a chimeric CD34-Thymidine Kinase (CD34-TK75) suicide gene into human T cells to control GvHD can be performed safely, and will result in functional T cells that express a selectable marker and a suicide gene. Transduced T cells can be selected with very high efficiency using a clinical CD34+ cell selection device. After exerting anti-leukemic effects in the recipient, donor T cells can be eliminated in response to in vivo administration of ganciclovir, before damage from GvHD occurs. Initial studies from our group have shown highly efficacious killing of CD34-TK75 fusion gene-transduced murine T cells in a murine model of GvHD. These studies strongly suggest the potential for using T cell suicide gene therapy during donor lymphocyte infusions in clinical trials. The use of the CD34-TK75 fusion gene provides significant advantages over several previous studies that used bicistronic vectors, because the epitope marker gene (CD34) and the suicide gene (TK) are expressed as one protein, so there is no discordant expression resulting in inefficient selection or infusion of unmarked T cells. The expression of the chimeric CD34-TK75 suicide gene in activated T cells allows for an enhanced level of safety in the proposed clinical gene therapy trial, since cells potentially activated by retroviral insertional mutagenesis could be killed by in vivo administration of ganciclovir. The initial goal of the current application is to scale up the human T cell transduction at the Good Manufacturing Process (GMP) level, in preparation for a clinical trial (Aim 1), in the new GMP facility at Washington University. The Recombinant Advisory Committee (RAC) has approved this trial (RAC approval # 03011-566) and an IND will soon be filed with the FDA. The pre-IND meeting has been completed. The second goal is to begin enrolling patients to this trial as soon as FDA approval is granted (Aim 2). We expect that the first patient would be enrolled early in the first year of potential funding. This novel T cell suicide gene therapy/donor lymphocyte infusion study has the potential to eliminate residual leukemic cells while preventing post-infusion morbidity and mortality from GvHD. This approach could extend the life expectancy of patients with relapsed leukemia after allogeneic transplant, a population that currently has only a 50% chance of 100 day survival and only a 15-20% chance of one year survival.

描述（由申请方提供）：拟定研究的目的是在异基因干细胞移植（SCT）后复发性恶性血液病患者中进行基因操作的异基因供体淋巴细胞输注。供体淋巴细胞输注（DL 1）已导致一些患者在同种异体BMT后复发性白血病或淋巴组织增生性疾病的治愈，但移植物抗宿主病（GvHD）的发展已经变得复杂。本研究的中心假设如下：逆转录病毒介导的嵌合CD 34-胸苷激酶（CD 34-TK 75）自杀基因转移到人T细胞中以控制GvHD可以安全地进行，并将产生表达选择标记和自杀基因的功能性T细胞。可以使用临床CD 34+细胞选择装置以非常高的效率选择转导的T细胞。在受体中发挥抗白血病作用后，供体T细胞可以在GvHD损伤发生之前响应于更昔洛韦的体内施用而被消除。 我们小组的初步研究表明，在GvHD小鼠模型中，CD 34-TK 75融合基因转导的小鼠T细胞具有高度有效的杀伤作用。这些研究有力地表明了在临床试验中供体淋巴细胞输注期间使用T细胞自杀基因治疗的潜力。使用CD 34-TK 75融合基因提供了优于使用双顺反子载体的几个先前研究的显著优点，因为表位标记基因（CD 34）和自杀基因（TK）作为一种蛋白质表达，因此不存在导致无效选择或输注未标记的T细胞的不一致表达。嵌合的CD 34-TK 75自杀基因在活化的T细胞中的表达允许在所提出的临床基因治疗试验中提高安全性水平，因为通过逆转录病毒插入诱变潜在活化的细胞可以通过更昔洛韦的体内施用而被杀死。 本申请的初始目标是在华盛顿大学的新GMP设施中，在良好生产工艺（GMP）水平上扩大人T细胞转导，以准备临床试验（Aim 1）。重组咨询委员会（RAC）已经批准了这项试验（RAC批准# 03011-566），IND将很快提交给FDA。IND前会议已完成。第二个目标是一旦获得FDA批准，就开始招募患者参加本试验（目标2）。我们预计，第一名患者将在潜在资金的第一年早期入组。这项新的T细胞自杀基因治疗/供体淋巴细胞输注研究有可能消除残留的白血病细胞，同时预防输注后GvHD的发病率和死亡率。这种方法可以延长异基因移植后复发性白血病患者的预期寿命，目前这一人群只有50%的机会存活100天，只有15-20%的机会存活一年。