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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Design and Engineering of Recombinant Oncolytic Adenoviruses Expressing an Anti-EpCAM/Anti-CD3 BiTE for Targeted
Ensieh Taheri1,2, Shahriyar Abdoli1,2, Majid Shahbazi2,3
1Department of Biotechnology, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Golestan, Iran.
Background:
Oncolytic virotherapy is a novel therapeutic approach in oncology that uses viruses to target and eradicate cancer cells specifically. To improve therapeutic effectiveness, we investigated the application of genetically modified oncolytic adenoviruses (OVs) engineered to express bispecific T-cell engager (BiTE) antibodies.
Methods:
In particular, we engineered Ad5-delta24 to express an EpCAM-targeting BiTE under the major late promoter, yielding the recombinant virus Ad5D24-Anti-EpCAM-Anti-CD3-scFv (rOAd5-BiTE). Following infection of A549 lung cancer cells, rOAd5-BiTE promoted the expression and secretion of BiTE antibodies targeting EpCAM and CD3.
Results:
In co-culture experiments, rOAd5-BiTE elicited significant T-cell activation and proliferation, characterized by increased secretion of IFN-γ and IL-2, as well as augmented cytotoxic activity from neighboring bystander cells. Moreover, the combination of rOAd5-BiTE with peripheral blood mononuclear cells (PBMCs) markedly enhanced the antitumor activity against A549 cells.
Conclusion:
The results indicate that equipping OVs with BiTE molecules may address critical challenges in virotherapy by enhancing and redirecting T-cell activity within the tumor microenvironment. This strategy offers a promising avenue for developing targeted immunovirotherapy approaches for the treatment of solid tumors.
Insights
Genetically modified oncolytic adenoviruses (OVs) engineered to express bispecific T-cell engager (BiTE) antibodies enhance T-cell activity. This novel immunovirotherapy approach shows promise for treating solid tumors by improving T-cell responses within the tumor microenvironment.
Area of Science:
- Oncology
- Immunotherapy
- Virology
Background:
- Oncolytic virotherapy utilizes viruses to specifically target and eliminate cancer cells.
- Investigating genetically modified oncolytic adenoviruses (OVs) to express bispecific T-cell engager (BiTE) antibodies aims to enhance therapeutic efficacy.
Purpose of the Study:
- To engineer an oncolytic adenovirus expressing a BiTE antibody targeting EpCAM and CD3.
- To evaluate the efficacy of the engineered oncolytic virus in activating T-cells and mediating anti-tumor activity.
Main Methods:
- Engineered Ad5-delta24 to express an EpCAM-targeting BiTE, creating rOAd5-BiTE.
- Infected A549 lung cancer cells with rOAd5-BiTE to assess BiTE expression and secretion.
- Conducted co-culture experiments with T-cells and peripheral blood mononuclear cells (PBMCs).
Main Results:
- rOAd5-BiTE successfully expressed and secreted BiTE antibodies targeting EpCAM and CD3.
- Significant T-cell activation and proliferation observed, with increased IFN-γ and IL-2 secretion.
- Enhanced cytotoxic activity and anti-tumor effects when rOAd5-BiTE was combined with PBMCs.
Conclusions:
- Equipping OVs with BiTE molecules can overcome challenges in virotherapy by improving T-cell responses.
- This strategy offers a promising approach for targeted immunovirotherapy against solid tumors.
- The engineered virus redirects T-cell activity within the tumor microenvironment for enhanced cancer treatment.
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