Background/Objectives: The geneF3, encoding Tissue Factor (TF), is expressed in many cancers and contributes to their malignancy. Among adult-type diffuse gliomas, IDH1/2 wild-type (IDHwt) glioblastomas (GBM) express more TF than IDH1/2 mutant (IDHmut) gliomas. Tisotumab vedotin (TisVed), an anti-TF antibody conjugated to monomethyl auristatin E, is a therapeutic designed to target cells expressing TF. We therefore sought to determine the therapeutic potential of TisVed in IDHwtvs. IDHmutgliomas. Methods: We treated IDHwtand IDHmutpatient-derived glioma cells with control IgG, unconjugated tisotumab (Tis), or TisVed in vitro, followed by cell viability assays and the assessment of TF signaling. We tested Tis and TisVed in mice intracranially engrafted with patient-derived IDHwtand IDHmutgliomas and mice flank engrafted with IDHwtGBM. Results: TisVed was more active against cultured IDHwtGBM cells than IDHmutglioma cells. This activity was increased by the daily washout of soluble TF secreted by IDHwtGBM cells. Unconjugated Tis had less effect than TisVed, and TF signaling was minimally inhibited. TisVed extended the survival of mice intracranially engrafted with IDHwtGBM (p= 0.006), but not mice with IDHmutglioma (p= 0.88). TisVed also reduced the growth of IDHwtGBM flank xenografts. Tis alone had no antitumor effect in either setting. Notably, both TisVed and Tis were associated with hemorrhage in flank tumors. Conclusions: TisVed targets high-TF-expressing IDHwtGBM, but not low-TF-expressing IDHmutglioma. This is predominately through the vedotin conjugate rather than inhibition of TF signaling. Though the effect size is modest, TisVed shows anticancer effects against IDHwtGBM. However, there could be complications related to hemostasis and hemorrhage.
背景/目的：编码组织因子（TF）的F3基因在多种癌症中表达并促进其恶性进展。在成人型弥漫性胶质瘤中，IDH1/2野生型（IDHwt）胶质母细胞瘤（GBM）比IDH1/2突变型（IDHmut）胶质瘤表达更高水平的TF。Tisotumab vedotin（TisVed）是一种与单甲基奥瑞他汀E偶联的抗TF抗体，其设计旨在靶向表达TF的细胞。因此，我们试图评估TisVed在IDHwt与IDHmut胶质瘤中的治疗潜力。方法：我们在体外用对照IgG、未偶联的tisotumab（Tis）或TisVed处理IDHwt和IDHmut患者来源的胶质瘤细胞，随后进行细胞活力测定和TF信号通路评估。我们在颅内移植患者来源IDHwt和IDHmut胶质瘤的小鼠模型以及侧腹移植IDHwt GBM的小鼠模型中测试了Tis和TisVed的疗效。结果：TisVed对培养的IDHwt GBM细胞的杀伤活性高于IDHmut胶质瘤细胞。通过每日清除IDHwt GBM细胞分泌的可溶性TF可增强该活性。未偶联的Tis效果弱于TisVed，且对TF信号通路的抑制作用微弱。TisVed显著延长了颅内移植IDHwt GBM小鼠的生存期（p=0.006），但对IDHmut胶质瘤模型小鼠无显著效果（p=0.88）。TisVed还能抑制IDHwt GBM侧腹移植瘤的生长。单独使用Tis在两种模型中均未显示抗肿瘤效应。值得注意的是，TisVed和Tis均与侧腹移植瘤的出血现象相关。结论：TisVed能靶向高表达TF的IDHwt GBM，但对低表达TF的IDHmut胶质瘤无效。该作用主要通过vedotin偶联物而非抑制TF信号通路实现。尽管效应幅度有限，TisVed对IDHwt GBM显示出抗癌活性，但可能存在与止血功能和出血相关的并发症风险。
F3Expression Drives Sensitivity to the Antibody-Drug Conjugate Tisotumab Vedotin in Glioblastoma
肿瘤(癌症)患者之家