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Neuroblastomas vary widely in their sensitivities to herpes simplex virotherapy unrelated to virus receptors and susceptibility

Gene Therapy volume 23, pages 135–143 (2016)Cite this article

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Abstract

Although most high-risk neuroblastomas are responsive to chemotherapy, relapse is common and long-term survival is <40%, underscoring the need for more effective treatments. We evaluated the responsiveness of 12 neuroblastoma cell lines to the Δγ134.5 attenuated oncolytic herpes simplex virus (oHSV), Seprehvir (HSV1716), which is currently used in pediatric phase I trials. We found that entry of Seprehvir in neuroblastoma cells is independent of the expression of nectin-1 and the sum of all four known major HSV entry receptors. We observed varying levels of sensitivity and permissivity to Seprehvir, suggesting that the cellular anti-viral response, not virus entry, is the key determinant of efficacy with this virus. In vivo, we found significant anti-tumor efficacy following Seprehvir treatment, which ranged from 6/10 complete responses in the CHP-134 model to a mild prolonged median survival in the SK-N-AS model. Taken together, these data suggest that anti-tumor efficacy cannot be solely predicted based on in vitro response. Whether or not this discordance holds true for other viruses or tumor types is unknown. Our results also suggest that profiling the expression of known viral entry receptors on neuroblastoma cells may not be entirely predictive of their susceptibility to Seprehvir therapy.

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Acknowledgements

We thank Brian Geier for analysis of the Pediatric Preclinical Testing Program gene expression database, and Peter Houghton (Greehey Children’s Cancer Research Institute) for cell lines. This work was supported in part by Alex’s Lemonade Stand Foundation for Childhood Cancer (PYW), the Research Institute at Nationwide Children’s Hospital and NIH grant R21-CA133663-01A1 (TPC). Oncolytic HSV Seprehvir used in the study was from Virttu Biologics, Ltd (Glasgow, UK).

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Authors and Affiliations

  1. Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA

    P-Y Wang, H M Swain, A L Kunkler, C-Y Chen, B J Hutzen & T P Cripe

  2. Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, The Ohio State University, Columbus, OH, USA

    M A Arnold

  3. Division of Hematology/Oncology/Blood and Marrow Transplant, Nationwide Children’s Hospital, The Ohio State University, Columbus, OH, USA

    K A Streby, J R Stanek & T P Cripe

  4. Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    M H Collins & B Dipasquale

  5. Virttu Biologics, Ltd, Glasgow, UK

    J Conner

  6. Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands

    T H van Kuppevelt

  7. Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    J C Glorioso & P Grandi

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  1. P-Y Wang
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  2. H M Swain
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Correspondence to P-Y Wang.

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Competing interests

JC is an employee of Virttu Biologics Ltd. The remaining authors declare no conflict of interest.

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Supplementary Information accompanies this paper on Gene Therapy website .

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Wang, PY., Swain, H., Kunkler, A. et al. Neuroblastomas vary widely in their sensitivities to herpes simplex virotherapy unrelated to virus receptors and susceptibility. Gene Ther 23, 135–143 (2016). https://doi.org/10.1038/gt.2015.105

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