Targeted BiTE expression by an oncolytic vector augments therapeutic efficacy against solid tumors
PURPOSE: Immunotherapy with bispecific T cell engagers has achieved striking success against hematological malignancies, but efficacy against solid tumors has been limited. We hypothesized that oncolytic measles viruses encoding bispecific T cell engagers (MV-BiTEs) represent a safe and effective tr...
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| Hauptverfasser: | , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
February 6, 2018
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| In: |
Clinical cancer research
Year: 2018, Jahrgang: 24, Heft: 18, Pages: 2128-2137 |
| ISSN: | 1557-3265 |
| DOI: | 10.1158/1078-0432.CCR-17-2651 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1158/1078-0432.CCR-17-2651 Verlag, kostenfrei, Volltext: http://clincancerres.aacrjournals.org/content/early/2018/02/06/1078-0432.CCR-17-2651 
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| Verfasserangaben: | Tobias Speck, Johannes P.W. Heidbuechel, Rūta Veinalde, Dirk Jaeger, Christof von Kalle, Claudia R. Ball, Guy Ungerechts, Christine E. Engeland |
| Zusammenfassung: | PURPOSE: Immunotherapy with bispecific T cell engagers has achieved striking success against hematological malignancies, but efficacy against solid tumors has been limited. We hypothesized that oncolytic measles viruses encoding bispecific T cell engagers (MV-BiTEs) represent a safe and effective treatment against solid tumors through local BiTE expression, direct tumor cell lysis and in situ tumor vaccination. EXPERIMENTAL DESIGN: To test this hypothesis, we generated MV-BiTEs from the Edmonston B vaccine strain to target two model antigens. Replicative and oncolytic potential were assessed by infection and cell viability assays, respectively. Functionality of virus-derived BiTEs was tested in vitro by complementary binding and cytotoxicity assays. In vivo efficacy of MV-BiTE was investigated using both syngeneic and xenograft mouse models of solid cancers. RESULTS: We verified secretion of functional BiTE antibodies by MV-BiTE-infected cells. Further, we demonstrated therapeutic efficacy of MV-BiTE against established tumors in fully immunocompetent mice. MV-BiTE efficacy was associated with increased intratumoral T cell infiltration and induction of protective anti-tumor immunity. Additionally, we showed therapeutic efficacy of MV-BiTE in xenograft models of patient-derived primary colorectal carcinoma spheroids with transfer of PBMCs. CONCLUSION: MV-BiTE treatment was effective in two distinct models of solid tumors without signs of toxicity. This provides strong evidence for therapeutic benefits of tumor-targeted BiTE expression by oncolytic MV. Thus, this study represents proof of concept for an effective strategy to treat solid tumors with BiTEs. |
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| Beschreibung: | Gesehen am 04.04.2019 |
| Beschreibung: | Online Resource |
| ISSN: | 1557-3265 |
| DOI: | 10.1158/1078-0432.CCR-17-2651 |