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Enhancing the bystander killing effect of an oncolytic HSV by arming it with a secretable apoptosis activator

Gene Therapy volume 22, pages 237–246 (2015)Cite this article

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Abstract

Although oncolytic viruses have shown great promise as cancer therapeutics, results from a recent phase III clinical trial indicate that their potency may need further improvement for a clear clinical benefit. Here, we report a novel strategy to increase the bystander effect of virotherapy by arming an oncolytic virus with a secreted form of a Her2 single chain antibody linked to a self-multimerizing Fas ligand extracellular domain (Her2-COL-sFasL). The rationale is that, due to its much smaller size, this apoptosis activator can overcome obstacles such as the dense collagen in the tumor tissues to spread more freely than the viral particles. When measured in vitro, Her2-COL-sFasL was found to efficiently induce caspase cleavage, resulting in an 80% reduction in cell viability. Once incorporated into the genome of an oncolytic type 2 herpes simplex virus, FusOn-H3, Her2-COL-sFasL potentiates the therapeutic efficacy of the virus in an aggressive syngeneic mammary tumor model. Our data suggest that arming an oncolytic virus with a secretable and self-multimerizing apoptosis inducer is a feasible strategy to improve the potency of virotherapy.

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Acknowledgements

We thank Xinping Fu, Lihua Tao, Armando Rivera, Kim Anthony-Gonda and Jeffrey Spencer for the sharing of their expertise for a variety of techniques. Also, we further thank Armando Rivera, Kim Anthony-Gonda and Jeffrey Spencer for reading of the manuscript before submission. This work was supported by the National Cancer Institute grants R01CA106671 and R01CA132792 and also by a grant from the William and Ella Owens Medical Research Foundation (to XZ).

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  1. Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA

    S M W Loya & X Zhang

  2. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA

    S M W Loya

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Correspondence to X Zhang.

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Loya, S., Zhang, X. Enhancing the bystander killing effect of an oncolytic HSV by arming it with a secretable apoptosis activator. Gene Ther 22, 237–246 (2015). https://doi.org/10.1038/gt.2014.113

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