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9 août 2012 4 09 /08 /août /2012 09:51
Original Article

Leukemia (2012) 26, 1870–1878; doi:10.1038/leu.2012.70; published online 20 April 2012

Myeloma

Curative one-shot systemic virotherapy in murine myeloma

S Naik1, R Nace1, M J Federspiel1, G N Barber2, K-W Peng1 and S J Russell1,3

1Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
2Department of Medicine and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL, USA
3Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
Correspondence: Dr SJ Russell, Department of Molecular Medicine, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. E-mail: sjr@mayo.edu

Received 11 January 2012; Revised 20 February 2012; Accepted 22 February 2012
Accepted article preview online 19 March 2012; Advance online publication 20 April 2012

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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.

Keywords: oncolytic virotherapy; multiple myeloma; vesicular stomatitis virus; intravenous; immunotherapy

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