F3 Expression Drives Sensitivity to the Antibody-Drug Conjugate Tisotumab Vedotin in Glioblastoma

TL;DR

This study shows that the drug tisotumab vedotin is more effective against a type of brain cancer called glioblastoma that expresses high levels of a protein called Tissue Factor.

Contribution

The study is the first to evaluate tisotumab vedotin's effectiveness in gliomas and reveals its activity is mainly due to the drug conjugate, not Tissue Factor signaling inhibition.

Findings

Tisotumab vedotin was more effective against IDHwt GBM cells than IDHmut glioma cells.

Tisotumab vedotin extended survival in mice with IDHwt GBM but not in those with IDHmut glioma.

Tisotumab vedotin was associated with hemorrhage in flank tumors, indicating potential hemostasis complications.

Abstract

Glioma is the most common type of cancer arising in the adult brain. Patients with the most deadly type of glioma, glioblastoma (GBM), have a median survival time of only 15–18 months. New treatments are therefore needed. We previously showed that gliomas with mutations in isocitrate dehydrogenase 1 and 2 (IDHmut) methylate and suppress F3, the gene encoding Tissue Factor (TF), and that this contributes to the reduced aggressiveness of IDHmut gliomas compared to high TF-expressing GBM. Recent studies showed that tisotumab vedotin, a TF antibody conjugated to monomethyl auristatin E, targets cancers with high TF levels. However, this has not yet been evaluated in gliomas. Our preclinical data indicate that tisotumab vedotin is more effective against GBM than IDHmut glioma, but that intra/peritumoral hemorrhage is a side effect. This provides valuable insight into the limited therapeutic potential of tisotumab vedotin in GBM patients.

Background/Objectives: The gene F3, 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 IDHwt vs. IDHmut gliomas. Methods: We treated IDHwt and IDHmut patient-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 IDHwt and IDHmut gliomas and mice flank engrafted with IDHwt GBM. Results: TisVed was more active against cultured IDHwt GBM cells than IDHmut glioma cells. This activity was increased by the daily washout of soluble TF secreted by IDHwt GBM cells. Unconjugated Tis had less effect than TisVed, and TF signaling was minimally inhibited. TisVed extended the survival of mice intracranially engrafted with IDHwt GBM (p = 0.006), but not mice with IDHmut glioma (p = 0.88). TisVed also reduced the growth of IDHwt GBM 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 IDHwt GBM, but not low-TF-expressing IDHmut glioma. This is predominately through the vedotin conjugate rather than inhibition of TF signaling. Though the effect size is modest, TisVed shows anticancer effects against IDHwt GBM. However, there could be complications related to hemostasis and hemorrhage.

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