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Myeloma

Curative one-shot systemic virotherapy in murine myeloma

Leukemia volume 26, pages 1870–1878 (2012)Cite this article

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Abstract

Current therapy for multiple myeloma is complex and prolonged. Antimyeloma drugs are combined in induction, consolidation and/or maintenance protocols to destroy bulky disease, then suppress or eradicate residual disease. Oncolytic viruses have the potential to mediate both tumor debulking and residual disease elimination, but this curative paradigm remains unproven. Here, we engineered an oncolytic vesicular stomatitis virus to minimize its neurotoxicity, enhance induction of antimyeloma immunity and facilitate noninvasive monitoring of its intratumoral spread. Using high-resolution imaging, autoradiography and immunohistochemistry, we demonstrate that the intravenously administered virus extravasates from tumor blood vessels in immunocompetent myeloma-bearing mice, nucleating multiple intratumoral infectious centers that expand rapidly and necrose at their centers, ultimately coalescing to cause extensive tumor destruction. This oncolytic tumor debulking phase lasts only for 72 h after virus administration, and is completed before antiviral antibodies become detectable in the bloodstream. Antimyeloma T cells, cross-primed as the virus-infected cells provoke an antiviral immune response, then eliminate residual uninfected myeloma cells. The study establishes a curative oncolytic paradigm for multiple myeloma where direct tumor debulking and immune eradication of minimal disease are mediated by a single intravenous dose of a single therapeutic agent. Clinical translation is underway.

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Acknowledgements

This work was supported by funds from Mayo Clinic, NIH/NCI (R01 CA100634 and R01 CA129966), the Richard M Schulze Family Foundation and a gift from Al and Mary Agnes McQuinn. We are grateful to Guy Griesmann and Sharon Stephan in the Viral Vector Production Laboratory (Mayo Clinic), Theresa Decklever (Department of Nuclear Medicine) and Wendy Ferguson (Mayo Clinic) for their technical assistance.

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Authors and Affiliations

  1. Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA

    S Naik, R Nace, M J Federspiel, K-W Peng & S J Russell

  2. Department of Medicine and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL, USA

    G N Barber

  3. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    S J Russell

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  1. S Naik
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Correspondence to S J Russell.

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Naik, S., Nace, R., Federspiel, M. et al. Curative one-shot systemic virotherapy in murine myeloma. Leukemia 26, 1870–1878 (2012). https://doi.org/10.1038/leu.2012.70

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