Targeted BiTE expression by an oncolytic vector augments therapeutic efficacy against solid tumors

• Verfasst von: Speck, Tobias [VerfasserIn]
• Verfasst von: Heidbüchel, Johannes P. W. [VerfasserIn]
• Verfasst von: Veinalde, Rūta [VerfasserIn]
• Verfasst von: Jäger, Dirk [VerfasserIn]
• Verfasst von: Kalle, Christof von [VerfasserIn]
• Verfasst von: Ball, Claudia R. [VerfasserIn]
• Verfasst von: Ungerechts, Guy [VerfasserIn]
• Verfasst von: Engeland, Christine Elisabeth [VerfasserIn]
• Titel: Targeted BiTE expression by an oncolytic vector augments therapeutic efficacy against solid tumors
• Verf.angabe: Tobias Speck, Johannes P.W. Heidbuechel, Rūta Veinalde, Dirk Jaeger, Christof von Kalle, Claudia R. Ball, Guy Ungerechts, Christine E. Engeland
• E-Jahr: 2018
• Jahr: February 6, 2018
• Umfang: 10 S.
• Fussnoten: Gesehen am 04.04.2019
• Titel Quelle: Enthalten in: Clinical cancer research
• Ort Quelle: Philadelphia, Pa. [u.a.] : AACR, 1995
• Jahr Quelle: 2018
• Band/Heft Quelle: 24(2018), 18, Seite 2128-2137
• ISSN Quelle: 1557-3265
• DOI: doi:10.1158/1078-0432.CCR-17-2651
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1570435626

Abstract

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.