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

过继转移的细胞毒性T细胞（CTL）的治疗效果已被证明在治疗白血病和病毒感染后异基因骨髓移植。然而，这种方法受到难以在体外可重复地产生足够量的特异性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细胞可以识别和破坏病毒感染和肿瘤细胞。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遗传修饰T细胞，但也用于造血干细胞（HSC）。在基因治疗试验中，将编码共同细胞因子受体γ链（c）的基因转移到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。尽管目前还不清楚是什么导致了恶性肿瘤，但人们认为，未分化状态以及由c赋予的生长优势可能有助于淋巴瘤发生。由于TCR也赋予生长优势，至少只要存在其病毒或肿瘤来源的同源配体（MHC-肽复合物），就必须在（i）转基因水平上评估TCR基因转移的风险：提供瞬时生长优势的基因（例如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细胞也容易发生恶性肿瘤吗？这些问题将在人类和小鼠模型中得到解决。

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.