Medizinische Klinik und Poliklinik IV-Campus Grosshadern, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany.
Center for Translational Cancer Research (TranslaTUM), Klinikum rechts der Isar der Technischen Universität München, Radiation Immuno-Oncology group, Munich, Germany.
Clin Cancer Res. 2019 Oct 1;25(19):5997-6008. doi: 10.1158/1078-0432.CCR-18-4092. Epub 2019 Jun 13.
The innate tumor homing potential of mesenchymal stem cells (MSCs) has been used for a targeted delivery of the theranostic sodium iodide symporter () transgene into solid tumors. We have previously shown that external beam radiotherapy (EBRT) results in the enhanced recruitment of expressing MSCs into human hepatocellular carcinoma (HuH7). In parallel, the tumor-associated cytokine TGFB1 becomes strongly upregulated in HuH7 tumors in response to EBRT.
We therefore evaluated the effects of combining focused EBRT (5 Gy) with MSC-mediated systemic delivery of the theranostic transgene under control of a synthetic TGFB1-inducible SMAD-responsive promoter (SMAD-NIS-MSCs) using I-scintigraphy followed by I therapy in CD1 nu/nu mice harboring subcutaneous human hepatocellular carcinoma (HuH7).
Following tumor irradiation and SMAD-NIS-MSC application, tumoral iodide uptake monitored by I-scintigraphy was enhanced as compared with nonirradiated tumors. Combination of EBRT and SMAD-NIS-MSC-mediated I therapy resulted in a significantly improved delay in tumor growth and prolonged survival in therapy mice as compared with the combined therapy using CMV-NIS-MSCs or to control groups receiving EBRT or saline only, or EBRT together with SMAD-NIS-MSCs and saline applications.
MSC-based NIS-mediated I therapy after EBRT treatment dramatically enhanced therapeutic efficacy when a TGFB1-inducible SMAD-responsive promoter was used to drive expression in adoptively applied MSCs. The remarkable therapeutic effect seen is thought to be linked in large part to the enhanced TGFB1 produced in this context, which leads to a highly selective and focused amplification of MSC-based expression within the tumor milieu.
间充质干细胞（MSCs）的固有肿瘤归巢潜力已被用于将治疗性钠碘同向转运体（）转基因靶向递送至实体瘤。我们之前已经表明，外照射放疗（EBRT）导致表达的 MSCs 更有效地募集到人类肝癌（HuH7）中。平行地，肿瘤相关细胞因子 TGFB1 在 HuH7 肿瘤中对 EBRT 反应强烈上调。
因此，我们在 CD1nu/nu 小鼠中评估了在皮下人肝癌（HuH7）中联合使用聚焦 EBRT（5 Gy）和 MSC 介导的系统递送达治疗性转基因的效果，该转基因受合成 TGFB1 诱导型 SMAD 反应性启动子（SMAD-NIS-MSCs）控制，然后通过 I 治疗进行 I 扫描。
与未照射的肿瘤相比，通过 I 扫描监测到肿瘤碘摄取在肿瘤照射和 SMAD-NIS-MSC 应用后增强。与使用 CMV-NIS-MSCs 进行的联合治疗或仅接受 EBRT 或生理盐水或 EBRT 联合 SMAD-NIS-MSCs 和生理盐水应用的对照组相比，EBRT 和 SMAD-NIS-MSC 介导的 I 治疗的联合使用显著延迟了肿瘤生长并延长了治疗小鼠的存活。
当使用 TGFB1 诱导型 SMAD 反应性启动子驱动过继应用的 MSC 中表达时，基于 MSC 的 NIS 介导的 I 治疗在 EBRT 治疗后大大增强了治疗效果。在这种情况下，观察到的显著治疗效果在很大程度上与产生的高度上调的 TGFB1 相关，这导致了在肿瘤环境中基于 MSC 的表达的高度选择性和集中扩增。
