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Updated: Aug 6, 2026
Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Molecular Profiling of Tisotumab Vedotin-Treated Patients Identifies Immune Pathways Associated With Clinical
Sriram Sridhar1, Guy Roukens2, Christina Y Yu3
1Genmab (Netherlands) Princeton United States.
Purpose:
Tisotumab vedotin (TV) is a tissue factor (TF)-specific antibody-drug conjugate that was evaluated in the innovaTV 204 study in patients with recurrent or metastatic cervical cancer (r/mCC). Although TF expression is required for TV binding to tumor cells, clinical responses were found to be independent of TF levels. This study aimed to evaluate whether baseline tumor gene expression signatures consistent with the proposed mechanisms of action of TV were associated with clinical outcomes.
Patients And Methods:
Pretreatment tumor samples from patients enrolled in innovaTV 204 (NCT03438396), a phase 2, single-arm, multicenter trial of TV in r/mCC following chemotherapy, were profiled for molecular biomarkers. Gene expression analyses of immune-related signatures were stratified by clinical response. In vitro antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity assays were performed using tumor cell lines with variable TF expression.
Results:
TF expression was confirmed in most patients but did not associate with response. Higher expression of gene signatures linked to natural killer cells and myeloid cells was associated with improved clinical outcomes. In vitro, TV induced tumor cell death through myeloid-mediated antibody-dependent cellular phagocytosis and natural killer-mediated antibody-dependent cellular cytotoxicity across various TF expression levels.
Conclusions:
This work provides supportive evidence for TV mechanisms of action that involve antitumor effects through direct cytotoxic and immune effector-mediated mechanisms. The association of immune-related gene signatures with improved clinical outcomes supports a multimodal mechanism of action for TV in the clinic and provides further rationale for antibody-drug conjugate efficacy in tumors with heterogeneous target expression.
Insights
Tisotumab vedotin (TV) shows efficacy in recurrent or metastatic cervical cancer by engaging immune cells, not just tissue factor (TF) levels. Gene expression signatures related to natural killer and myeloid cells predict better outcomes.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Tisotumab vedotin (TV) is an antibody-drug conjugate targeting tissue factor (TF) for recurrent or metastatic cervical cancer (r/mCC).
- Previous studies indicated clinical responses to TV were independent of TF expression levels.
- Understanding TV's mechanism of action beyond TF binding is crucial for optimizing its use.
Purpose of the Study:
- To investigate the association between baseline tumor gene expression signatures and clinical outcomes in patients treated with TV.
- To explore the role of immune-related gene signatures in predicting response to TV.
- To further elucidate the mechanisms of action of TV in r/mCC.
Main Methods:
- Analysis of pretreatment tumor samples from the innovaTV 204 trial (NCT03438396) in r/mCC patients.
- Gene expression profiling focusing on immune-related signatures, stratified by clinical response.
- In vitro assays (antibody-dependent cellular phagocytosis and cytotoxicity) to assess TV's effects on tumor cells with varying TF expression.
Main Results:
- Tissue factor (TF) expression was common but did not correlate with clinical response to TV.
- Elevated expression of gene signatures associated with natural killer cells and myeloid cells correlated with improved clinical outcomes.
- In vitro studies demonstrated TV-induced tumor cell death via myeloid and natural killer cell-mediated mechanisms, irrespective of TF levels.
Conclusions:
- TV exerts antitumor effects through direct cytotoxicity and immune effector-mediated mechanisms.
- Immune-related gene signatures are associated with enhanced clinical outcomes, supporting a multimodal mechanism of action for TV.
- These findings support the efficacy of antibody-drug conjugates in tumors with heterogeneous target expression.
