Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
Exp Mol Med. 2017 Jul 28;49(7):e360. doi: 10.1038/emm.2017.104.
Donor lymphocyte infusion (DLI) followed by hematopoietic stem cell transplantation has served as an effective prevention/treatment modality against the relapse of some hematologic tumors, such as chronic myeloid leukemia (CML). However, the therapeutic efficacies of DLI for other types of leukemia, including acute lymphocytic leukemia (ALL), have been limited thus far. Therefore, we examined whether increasing the reactivity of donor T cells by gene modification could enhance the therapeutic efficacy of DLI in a murine model of ALL. When a CTLA4-CD28 chimera gene (CTC28) in which the intracellular signaling domain of CTLA4 was replaced with the CD28 signaling domain was introduced into CD4 and CD8 T cells in DLI, the graft-versus-tumor (GVT) effect was significantly increased. This effect was correlated with an increased expansion of donor CD8 T cells in vivo, and the depletion of CD8 T cells abolished this effect. The CD8 T cell expansion and the enhanced GVT effect were dependent on the transduction of both CD4 and CD8 T cells with CTC28, which emphasizes the role of dual modification in this therapeutic effect. The CTC28-transduced T cells that expanded in vivo also exhibited enhanced functionality. Although the potentiation of the GVT effect mediated by the CTC28 gene modification of T cells was accompanied by an increase of graft-versus-host disease (GVHD), the GVHD was not lethal and was mitigated by treatment with IL-10 gene-modified third-party mesenchymal stem cells. Thus, the combined genetic modification of CD4 and CD8 donor T cells with CTC28 could be a promising strategy for enhancing the therapeutic efficacy of DLI.
供者淋巴细胞输注（DLI）联合造血干细胞移植已被用于预防和治疗某些血液系统肿瘤，如慢性髓系白血病（CML）的复发。然而，迄今为止，DLI 对其他类型白血病（包括急性淋巴细胞白血病[ALL]）的治疗效果有限。因此，我们研究了通过基因修饰来增强供者 T 细胞的反应性是否可以提高 DLI 在 ALL 小鼠模型中的治疗效果。当将 CTLA4-CD28 嵌合体基因（CTC28）引入 DLI 中的 CD4 和 CD8 T 细胞时，该基因将 CTLA4 的细胞内信号域替换为 CD28 信号域，从而显著增强了移植物抗白血病（GVL）效应。这种效果与供者 CD8 T 细胞在体内的扩增有关，而 CD8 T 细胞的耗竭则消除了这种效果。CD8 T 细胞的扩增和增强的 GVL 效应依赖于 CTC28 转导的 CD4 和 CD8 T 细胞，这强调了双重修饰在这种治疗效果中的作用。在体内扩增的 CTC28 转导 T 细胞也表现出增强的功能。尽管 CTC28 基因修饰 T 细胞增强 GVL 效应伴随着移植物抗宿主病（GVHD）的增加，但 GVHD 并不致命，并可以通过 IL-10 基因修饰的第三方间充质干细胞治疗来减轻。因此，用 CTC28 对供者 CD4 和 CD8 T 细胞进行联合基因修饰可能是增强 DLI 治疗效果的一种有前途的策略。
