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An armed, YB-1-dependent oncolytic adenovirus as a candidate for a combinatorial anti-glioma approach of virotherapy, suicide gene therapy and chemotherapeutic treatment

Cancer Gene Therapy volume 22, pages 30–43 (2015)Cite this article

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Abstract

We investigated the novel recombinant oncolytic adenovirus Ad-delo-sr39TK-RGD, armed with a mutant herpes simplex virus type 1 thymidine kinase (HSV1-sr39TK) as a suicide gene, and explored its antitumor efficacy in combination with HSV1-sr39TK/ganciclovir (GCV) gene therapy and temozolomide (TMZ). Ad-delo-sr39TK-RGD is an E1-mutated conditionally replicating adenovirus dependent on the human Y-box binding protein 1 (YB-1). Thus, we utilized the YB-1 dependency of the vector to target human glioma cells in vitro, using two-dimensional cell culture and three-dimensional multicellular spheroids, and demonstrated the strong replication competence and oncolytic potential of the virus. The cytotoxicity mediated by HSV1-sr39TK and its prodrug GCV enhanced the oncolytic effect even at <0.1 μg ml–1 GCV and induced cell killing of > 95% after adding GCV 0–1 days following infection. An increased bystander effect of viral replication and GCV in co-cultured infected and uninfected cells was observed. Co-administrating Ad-delo-sr39TK-RGD with TMZ and GCV, spheroid growth was reduced drastically. Gamma counting of infected spheroids demonstrated successful accumulation of the radiotracer 18F-labeled 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine mediated by HSV1-sr39TK. Hence, our results show that the combination of YB-1-dependent virotherapy with suicide genes and TMZ effectively induces glioma cell killing and may allow for in vivo non-invasive imaging within a limited time frame.

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Acknowledgements

We thank Katja Dumler and Anja Wolf for excellent technical assistance. Hans-Jürgen Wester and Michael Herz, Department of Nuclear medicine, are acknowledged for providing [18F]-FHBG, and William Summers, Yale University, for providing the HSV1-TK antibody. This work was supported by BMBF grant 01GU0613 of the Federal Ministry of Education and Research.

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  1. K Mantwill & P S Holm

    Present address: 2Present address: Department of Urology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.,

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  1. Institute for Experimental Oncology and Therapy Research, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany

    Y Kostova, K Mantwill, P S Holm & M Anton

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PSH is founder and owner of XVir Therapeutics GmbH. The remaining authors declare no conflict of interest.

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Kostova, Y., Mantwill, K., Holm, P. et al. An armed, YB-1-dependent oncolytic adenovirus as a candidate for a combinatorial anti-glioma approach of virotherapy, suicide gene therapy and chemotherapeutic treatment. Cancer Gene Ther 22, 30–43 (2015). https://doi.org/10.1038/cgt.2014.67

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