由白细胞介素-6控制的间充质干细胞基于钠/碘共转运体基因治疗改善了携带胶质母细胞瘤的小鼠的生存率。
Interleukin-6-controlled, mesenchymal stem cell-based sodium/iodide symporter gene therapy improves survival of glioblastoma-bearing mice.
发表日期：2023 Sep 21
作者：
Carolin Kitzberger, Khuram Shehzad, Volker Morath, Rebekka Spellerberg, Julius Ranke, Katja Steiger, Roland E Kälin, Gabriele Multhoff, Matthias Eiber, Franz Schilling, Rainer Glass, Wolfgang A Weber, Ernst Wagner, Peter J Nelson, Christine Spitzweg
来源：
Stem Cell Research & Therapy
摘要：
对于胶质母细胞瘤（GBM）这种耐受标准治疗的肿瘤，需要紧急开发新的治疗策略，因其高复发风险和极差预后。基于其固有的肿瘤趋附性，应用人工转移的间充质干细胞（MSCs）可以用来将治疗性的钠/碘共转运体（NIS）输送到肿瘤微环境深处。白细胞介素-6（IL-6）是GBM微环境中包括招募的MSCs在内的多功能、高表达的细胞因子。通过工程化MSCs使其在IL-6启动子被激活后驱动NIS表达，提供了一种针对GBM的新型靶向基因疗法的可能性。因此，在携带原位GBM的小鼠中，利用稳定转染含有受人类IL-6启动子控制的NIS表达质粒（IL-6-NIS-MSCs），并进行全身应用。与接受野生型MSCs的小鼠相比，通过18F-四氟硼酸酯-正电子发射计算机断层扫描/磁共振成像（PET/MRI）检测到IL-6-NIS-MSC应用后肿瘤的显著放射示踪物摄取增加。对肿瘤和非靶器官的体外分析显示了肿瘤特异性的NIS蛋白表达。在IL-6-NIS-MSC应用后进行后续的131I治疗结果显示，通过MRI评估明显延迟了肿瘤生长，并使GBM携带小鼠的中位生存率提高了60%以上，相比之下，这些小鼠是对照组。总之，应用以MSC介导的NIS基因疗法为重点的IL-6生物学诱导NIS转基因表达是治疗GBM的一种有前景的方法。© 2023 The Authors.
New treatment strategies are urgently needed for glioblastoma (GBM)-a tumor resistant to standard-of-care treatment with a high risk of recurrence and extremely poor prognosis. Based on their intrinsic tumor tropism, adoptively applied mesenchymal stem cells (MSCs) can be harnessed to deliver the theranostic sodium/iodide symporter (NIS) deep into the tumor microenvironment. Interleukin-6 (IL-6) is a multifunctional, highly expressed cytokine in the GBM microenvironment including recruited MSCs. MSCs engineered to drive NIS expression in response to IL-6 promoter activation offer the possibility of a new tumor-targeted gene therapy approach of GBM. Therefore, MSCs were stably transfected with an NIS-expressing plasmid controlled by the human IL-6 promoter (IL-6-NIS-MSCs) and systemically applied in mice carrying orthotopic GBM. Enhanced radiotracer uptake by 18F-Tetrafluoroborate-PET/magnetic resonance imaging (MRI) was detected in tumors after IL-6-NIS-MSC application as compared with mice that received wild-type MSCs. Ex vivo analysis of tumors and non-target organs showed tumor-specific NIS protein expression. Subsequent 131I therapy after IL-6-NIS-MSC application resulted in significantly delayed tumor growth assessed by MRI and improved median survival up to 60% of GBM-bearing mice as compared with controls. In conclusion, the application of MSC-mediated NIS gene therapy focusing on IL-6 biology-induced NIS transgene expression represents a promising approach for GBM treatment.© 2023 The Authors.