Genetically engineered T-cells expressing a ganciclovir-sensitive HSV-tk suicide gene for the prevention of GvHD.
Genetically engineered T-cells expressing a ganciclovir-sensitive HSV-tk suicide gene for the prevention of GvHD.
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基因工程 T 细胞表达更昔洛韦敏感的 HSV-tk 自杀基因，用于预防 GvHD。
DOI：
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发表时间：
2010
影响因子：
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通讯作者：
É. Robinet
中科院分区：
文献类型：
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作者：
L. Mailly;C. Leboeuf;P. Tiberghien;T. Baumert;É. Robinet
体外和体内临床前研究和 I/II 期临床试验表明，在输注前，在 T 细胞耗尽的造血干细胞移植 (HSCT) 时或在复发后作为供体淋巴细胞输注时，输注前（即 2 周的离体过程，包括激活、逆转录病毒转导和转导细胞的选择），将自杀基因 HSV-胸苷激酶通过逆转录病毒介导转移到供体 T 细胞中，可以有效控制供体 T 细胞T 细胞同种异体反应性。这些供体自杀基因修饰的 T 细胞 (SGMTC) 可以为同种异体 HSCT 的受者提供有益的抗白血病、抗病毒和免疫重建促进作用。然而，如果输注的 SGMTC 导致 GvHD（HSCT 的严重并发症），则可以通过施用前药更昔洛韦 (GCV) 在体内特异性地消除这些细胞，而无需任何相关的免疫抑制。这种方法的局限性包括基因转移引起的同种异体反应性和抗病毒反应性的降低、SGMTC 的免疫原性以及 GCV 抗性 SGMTC 的发展。然而，可以防止这些限制的重大改进，例如引入 CD3/CD28 共刺激和免疫磁性选择，已应用于该方法，但仍需要进一步改进。自杀基因治疗作为安全控制系统的功效允许开发这种基因治疗或免疫治疗方法的策略。
In vitro and in vivo preclinical studies and phase I/II clinical trials have demonstrated that the retroviral-mediated transfer of the suicide gene HSV-thymidine kinase into donor T-cells prior to infusion (ie, a 2-week ex vivo process including activation, retroviral transduction and selection of transduced cells), at the time of T-cell-depleted hematopoietic stem cell transplantation (HSCT) or as donor lymphocyte infusion after relapse, allows for the efficient control of donor T-cell alloreactivity. These donor suicide gene-modified T-cells (SGMTCs) can provide beneficial anti-leukemic, antiviral and immune reconstitution-facilitating effects to the recipient of an allogeneic HSCT. However, if the infused SGMTCs lead to GvHD, a severe complication of HSCT, these cells can be specifically depleted in vivo by the administration of the prodrug ganciclovir (GCV), without any associated immunosuppression. Limitations to this approach include a gene transfer-induced decrease in alloreactivity and antiviral reactivity, the immunogenicity of SGMTCs, and the development of GCV-resistant SGMTCs. However, major improvements that can prevent these limitations, such as introducing CD3/CD28 costimulation and immunomagnetic selection, have been applied to this approach, but further improvements are still required. The efficacy of suicide gene therapy as a safety control system allows the development of this strategy for gene therapy or immunotherapy approaches.