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Arming oncolytic reovirus with GM-CSF gene to enhance immunity

Cancer Gene Therapy volume 26, pages 268–281 (2019)Cite this article

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Abstract

Oncolytic reovirus administration has been well tolerated by cancer patients in clinical trials. However, its anti-cancer efficacy as a monotherapy remains to be augmented. We and others have previously demonstrated the feasibility of producing replication-competent reoviruses expressing a heterologous transgene. Here, we describe the production of recombinant reoviruses expressing murine (mm) or human (hs) GM-CSF (rS1-mmGMCSF and rS1-hsGMCSF, respectively). The viruses could be propagated up to 10 passages while deletion mutants occurred only occasionally. In infected cell cultures, the secretion of GM-CSF protein (up to 481 ng/106 cells per day) was demonstrated by ELISA. The secreted mmGM-CSF protein was functional in cell culture, as demonstrated by the capacity to stimulate the survival and proliferation of the GM-CSF-dependent dendritic cell (DC) line D1, and by its ability to generate DCs from murine bone marrow cells. Importantly, in a murine model of pancreatic cancer we found a systemic increase in DC and T-cell activation upon intratumoral administration of rS1-mmGMCSF. These data demonstrate that reoviruses expressing functional GM-CSF can be generated and have the potential to enhance anti-tumor immune responses. The GM-CSF reoviruses represent a promising new agent for use in oncolytic virotherapy strategies.

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Author notes

  1. Vera Kemp

    Present address: Department of Pathobiology, Utrecht University, 3584 CL, Utrecht, The Netherlands

Authors and Affiliations

  1. Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands

    Vera Kemp, Diana J. M. van den Wollenberg & Rob C. Hoeben

  2. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands

    Marcel G. M. Camps

  3. Department of Medical Oncology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands

    Thorbald van Hall, Priscilla Kinderman & Nadine Pronk-van Montfoort

Authors
  1. Vera Kemp
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  2. Diana J. M. van den Wollenberg
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  3. Marcel G. M. Camps
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  4. Thorbald van Hall
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  5. Priscilla Kinderman
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  6. Nadine Pronk-van Montfoort
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  7. Rob C. Hoeben
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Contributions

VK, DJMvdW, MGMC, TvH, PK, NPvM, and RCH all compiled data and jointly wrote the manuscript.

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Correspondence to Vera Kemp.

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The authors declare that they have no conflict of interest.

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Kemp, V., van den Wollenberg, D.J.M., Camps, M.G.M. et al. Arming oncolytic reovirus with GM-CSF gene to enhance immunity. Cancer Gene Ther 26, 268–281 (2019). https://doi.org/10.1038/s41417-018-0063-9

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  • DOI: https://doi.org/10.1038/s41417-018-0063-9

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