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Clin Cancer Res. 2018 May 1;24(9):2128-2137. doi: 10.1158/1078-0432.CCR-17-2651. Epub 2018 Feb 6.

Targeted BiTE Expression by an Oncolytic Vector Augments Therapeutic Efficacy Against Solid Tumors.

Author information

1
Department of Translational Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
2
Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
3
Department of Medical Oncology, University Hospital Heidelberg and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
4
Ottawa Hospital Research Institute, Centre for Innovative Cancer Research, Ottawa, Ontario, Canada.
5
Department of Translational Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. christine.engeland@nct-heidelberg.de.

Abstract

Purpose: Immunotherapy with bispecific T-cell engagers has achieved striking success against hematologic 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 antitumor immunity. In addition, we showed therapeutic efficacy of MV-BiTE in xenograft models of patient-derived primary colorectal carcinoma spheroids with transfer of peripheral blood mononuclear cells.Conclusions: 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. Clin Cancer Res; 24(9); 2128-37. ©2018 AACR.

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