Curative one-shot systemic virotherapy in murine myeloma

S. Naik, R. Nace, Mark J Federspiel, G. N. Barber, Kah-Whye Peng, Stephen J Russell

Research output: Contribution to journalArticle

46 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1870-1878
Number of pages9
JournalLeukemia
Volume26
Issue number8
DOIs
StatePublished - Aug 2012

Fingerprint

Disease Eradication
Viruses
Multiple Myeloma
Antiviral Agents
Oncolytic Viruses
Vascular Tissue Neoplasms
Neoplasms
Vesicular Stomatitis
Residual Neoplasm
Autoradiography
Immunity
Necrosis
Immunohistochemistry
Maintenance
T-Lymphocytes
Antibodies
Therapeutics
Pharmaceutical Preparations

Keywords

  • immunotherapy
  • intravenous
  • multiple myeloma
  • oncolytic virotherapy
  • vesicular stomatitis virus

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Curative one-shot systemic virotherapy in murine myeloma. / Naik, S.; Nace, R.; Federspiel, Mark J; Barber, G. N.; Peng, Kah-Whye; Russell, Stephen J.

In: Leukemia, Vol. 26, No. 8, 08.2012, p. 1870-1878.

Research output: Contribution to journalArticle

Naik, S. ; Nace, R. ; Federspiel, Mark J ; Barber, G. N. ; Peng, Kah-Whye ; Russell, Stephen J. / Curative one-shot systemic virotherapy in murine myeloma. In: Leukemia. 2012 ; Vol. 26, No. 8. pp. 1870-1878.
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