Therapeutisches Potenzial und Risikoanalyse von T-Zellrezeptor genmodifizierten Knochenmark-Stammzellen für die adoptive T-Zelltherapie

T细胞受体基因修饰骨髓干细胞用于过继性T细胞治疗的治疗潜力和风险分析

• 批准号: 22749242
• 负责人: Professor Dr. Wolfgang Uckert
• 金额: --
• 依托单位: Max-Delbrück-Centrum für Molekulare Medizin (MDC) in der Helmholtz-Gemeinschaft
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/22749242?language=en
• 关键词: Therapeutisches; Potenzial; und; Risikoanalyse; von

The therapeutic efficacy of adoptively transferred cytotoxic T cells (CTLs) has been demonstrated in the treatment of leukemias and viral infections after allogeneic bone marrow transplantation. However, this approach is restricted by the difficulty to reproducibly generate sufficient amounts of specific T cells in vitro. Recent gene therapy approaches include the genetic engineering of T cells to change their antigen specificity. One example is the T cell receptor (TCR) gene transfer to achieve virus or tumor specificity. Such redirected T cells can recognize and destroy virus infected and tumor cells. Indeed, there is a growing number of studies employing TCR genemodified T cells that are used in experimental models and in first clinical trials. Most commonly, retroviral vectors are employed to genetically modify T cells, but also hematopoietic stem cells (HSCs). In a gene therapy trial, where the gene encoding the common cytokine receptor gamma chain (¿c) was transferred into HSCs, the retroviral integration induced an uncontrolled exponential clonal proliferation and led to lymphoma-like disease. Even though it is not yet clear what caused the malignancy, it is thought that the undifferentiated state as well as the growth advantage conferred by the ¿c may have contributed to lymphomatogenesis. Since the TCR confers a growth advantage as well, at least as long as its cognate ligand (MHC-peptide complex) of viral or tumor origin is present, it is indispensable to evaluate the risk of TCR gene transfer on (i) transgene level: Can genes providing a transient growth advantage (such as TCR) sustain the amplification of clones with malignant potential? (ii) Cellular level: Are terminally differentiated T cells also prone to develop malignancy? These issues will be addressed in human and mouse models.

在同种异体骨髓移植后，已证明了适当转移的细胞毒性T细胞（CTL）的理论有效性在白血病和病毒感染中得到了证明。但是，这种方法受到难以在体外产生足够数量的特定T细胞的限制。最近的基因治疗方法包括T细胞的基因工程以改变其抗原特异性。一个例子是T细胞受体（TCR）基因转移以实现病毒或肿瘤特异性。这种重定向的T细胞可以识别并破坏感染病毒和肿瘤细胞。实际上，在实验模型和首次临床试验中使用的TCR基因定型T细胞的研究越来越多。最常见的是，逆转录病毒载体用于遗传修饰T细胞，但也用于造血干细胞（HSC）。在一项基因疗法试验中，编码共同细胞因子受体伽马链（C）的基因被转移到HSC中，逆转录病毒整合引起了不受控制的指数克隆增殖并导致淋巴瘤样疾病。即使尚不清楚是什么原因引起了恶性肿瘤，但人们认为未分化的状态以及C赋予的生长优势可能导致淋巴瘤发生。由于TCR也具有增长优势，至少只要存在病毒或肿瘤起源的同源配体（MHC肽复合物），就可以评估（I）转基因水平的TCR基因转移的风险是必不可少的：可以提供瞬时增长优势的基因（例如TCR）可维持具有不症状潜在势力的稳定性的基因吗？ （ii）细胞水平：末端分化的T细胞也容易出现恶性​​肿瘤吗？这些问题将在人类和鼠标模型中解决。