Oncolytic adenoviruses encoding bispecific T cell engagers or a novel trispecific T cell engager for dual-targeting of c-MET and EGFR
This study reports a strategy to overcome immune escape of tumors during viro-immunotherapy due to tumor heterogeneity. We pursued a dual-targeting approach of epidermal growth factor receptor (EGFR) and cellular mesenchymal epithelial transition factor (c-MET) facilitated by two bispecific T cell e...
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| Main Authors: | , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
19 March 2026
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| In: |
Molecular therapy. Oncology
Year: 2026, Volume: 34, Issue: 1, Pages: 1-19 |
| ISSN: | 2950-3299 |
| DOI: | 10.1016/j.omton.2025.201106 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.omton.2025.201106 Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2950329925001754 
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| Author Notes: | Martin A. Boos, Oliver Seifert, Stefanie Sawall, Jessica Genz, Annika Huber, Ilse Hofmann, Roland E. Kontermann, Guy Ungerechts, and Dirk M. Nettelbeck |
| Summary: | This study reports a strategy to overcome immune escape of tumors during viro-immunotherapy due to tumor heterogeneity. We pursued a dual-targeting approach of epidermal growth factor receptor (EGFR) and cellular mesenchymal epithelial transition factor (c-MET) facilitated by two bispecific T cell engagers (TCEs) or one trispecific TCE encoded by oncolytic adenoviruses (oAds). Different bi- and trispecific TCE formats were generated and characterized. We showed efficacy of bispecific TCEs single-chain diabody (scDb)-cMET and tandem scFv (taFv)-EFGR in vitro, encouraging the design of the diabody-based trispecific TCE (Db-TriTE) scDb-cMET-scFv-EGFR. The Db-TriTE exhibited effective dual-targeting, i.e., the induction of cytotoxicity for single-positive cells of both targets and superior efficacy on double-positive cells. Therefore, a panel of oAds was produced to test different TCE (co-)expression strategies. Our results showed no or minor attenuation of viruses harboring the transgenes for one of the analyzed insertion strategies, expression of TCEs, and specific induction of both T cell activation and cytotoxicity in co-cultures of infected tumor cells with peripheral blood mononuclear cells (PBMCs). Importantly, we demonstrated dual-targeting by oAds encoding the two bispecific TCEs or the Db-TriTE with the latter featuring superior genomic stability and the overall highest efficacy. Taken together, we report novel bi- and trispecific TCEs and proof of principle for their application as dual-targeted viro-antibody therapy. |
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| Item Description: | Online verfügbar: 9. Dezember 2025, Artikelversion: 30. Dezember 2025 Gesehen am 10.03.2026 |
| Physical Description: | Online Resource |
| ISSN: | 2950-3299 |
| DOI: | 10.1016/j.omton.2025.201106 |