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.

过继转移的治疗性细胞毒性 T 细胞 (CTL) 的功效已在同种异体骨髓移植后治疗白血病和病毒感染中得到证实，但这种方法难以在体外重复产生足够量的限制性特异性 T 细胞。最近的基因治疗方法包括通过基因工程改变 T 细胞的抗原特异性，从而实现病毒或肿瘤特异性。事实上，越来越多的研究采用 TCR 基因修饰的 T 细胞用于实验模型和首次临床试验。最常见的是，逆转录病毒载体用于对 T 细胞以及造血干细胞 (HSC) 的基因进行基因修饰。在一项治疗试验中，编码常见细胞因子受体γ链（¿c）的基因被转移到HSC中，逆转录病毒整合诱导了不受控制的指数克隆增殖并导致淋巴瘤样疾病。目前尚不清楚是什么原因导致了恶性肿瘤，据认为是未分化状态以及由肿瘤细胞赋予的生长优势。 c 可能有助于淋巴瘤发生，因为 TCR 也具有生长优势，至少只要存在病毒或肿瘤来源的同源配体（MHC-肽复合物），评估 TCR 基因转移的风险是必不可少的。 (i) 转基因水平：提供短暂生长优势的基因（如 TCR）能否维持具有恶性潜能的克隆的扩增？ (ii) 细胞水平：终末分化的 T 细胞是否也容易发育？这些问题将在人类和小鼠模型中得到解决。