Abstract：
Oncolytic virotherapy is a promising therapeutic approach for glioblastoma (GBM) treatment, although the outcomes are partially satisfactory. Hence, more effective strategies are needed urgently to modify therapeutic viruses to enhance their efficiency and safety in killing tumor cells and improve the survival rate of GBM patients. This study generated a new-generation oncolytic adenovirus Ad5 KT-E1A-IL-15 (TS-2021) and evaluated its antitumor efficacy. Ex vivo analyses revealed Ki67 and TGF-β2 co-localized in GBM cells. In addition, TS-2021 selectively replicated in GBM cells, which was dependent on the expression of Ki67 and TGF-β2. The immunocompetent mice model of GBM demonstrated the in vivo efficacy of TS-2021 by inhibiting tumor growth and improving survival proficiently. Notably, TS-2021 effectively reduced MMP3 expression by inactivating the MKK4/JNK pathway, thereby reducing tumor invasiveness. Altogether, the findings of the present study highlight that TS-2021 can effectively target GBM cells expressing high levels of Ki67 and TGF-β2, exerting potent antitumor effects. Additionally, it can improve efficacy and suppress tumor invasiveness by inhibiting the MKK4/JNK/MMP3 pathway. Thus our study demonstrates the efficiency of the novel TS-2021 in the mouse model and provides a potential therapeutic option for patients with GBM.
摘要：
溶瘤病毒疗法是胶质母细胞瘤（GBM）治疗的一种有前途的治疗方法，尽管结果部分令人满意。因此，迫切需要更有效的策略来修饰治疗性病毒，以提高其杀伤肿瘤细胞的效率和安全性，并提高GBM患者的生存率。这项研究产生了新一代溶瘤腺病毒Ad5KT-E1A-IL-15（TS-2021），并评估了其抗肿瘤功效。离体分析显示Ki67和TGF-β2共定位在GBM细胞中。此外,TS-2021在GBM细胞中选择性复制，依赖于Ki67和TGF-β2的表达。GBM的免疫活性小鼠模型证明了TS-2021通过抑制肿瘤生长和熟练地提高存活率的体内功效。值得注意的是,TS-2021通过灭活MKK4/JNK途径有效降低MMP3表达，从而降低肿瘤侵袭性。总之,本研究的发现强调TS-2021可以有效靶向表达高水平Ki67和TGF-β2的GBM细胞，发挥有效的抗肿瘤作用。此外,它可以通过抑制MKK4/JNK/MMP3通路来提高疗效和抑制肿瘤的侵袭性。因此，我们的研究证明了新型TS-2021在小鼠模型中的效率，并为GBM患者提供了潜在的治疗选择。
