Curative one-shot systemic virotherapy in murine myeloma

• Published in: Leukemia Vol. 26; no. 8; pp. 1870 - 1878
• Main Authors: NAIK, S, NACE, R, FEDERSPIEL, M. J, BARBER, G. N, PENG, K.-W, RUSSELL, S. J
• Format: Journal Article
• Language: English
• Published: Avenel, NJ Nature Publishing Group 01.08.2012
• Subjects: Animals; Antibodies; Antiviral agents; Autoradiography; Biological and medical sciences; Blood vessels; Cancer therapies; Care and treatment; Cell Line, Tumor; Chemical compounds; Cricetinae; Cytotoxicity; Diagnosis; Drug dosages; Gene mutations; Genetic Therapy; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Genomes; Hematologic and hematopoietic diseases; Image resolution; Immune response; Immune system; Immunocompetence; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunohistochemistry; Immunopathology; Immunosuppressive agents; Immunotherapy; Interferon-beta - genetics; Interferon-beta - metabolism; Intravenous administration; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocytes; Lymphocytes T; Medical sciences; Medicine; Mice; Mice, Inbred C57BL; Multiple myeloma; Multiple Myeloma - genetics; Multiple Myeloma - immunology; Multiple Myeloma - therapy; Neurotoxicity; Oncogenic viruses; Oncolysis; Oncolytic Virotherapy; Oncolytic Viruses - genetics; Pharmacology; Physiological aspects; Stomatitis; Symporters - genetics; Symporters - metabolism; Transplantation, Isogeneic; Tumors; Vesicular stomatitis Indiana virus - genetics; Vesicular stomatitis virus; Viruses; United States; United States > US; Intravenous administration; Virotherapy; Myeloma; Vesicular stomatitis virus; intravenous; Immunoglobulinopathy; Rhabdoviridae; Lymphoproliferative syndrome; Immunotherapy; oncolytic virotherapy; Immunopathology; multiple myeloma; Hematology; Rodentia; B cell neoplasm; Malignant hemopathy; Lymphoid neoplasm; Virus; Mononegavirales; Vertebrata; Vesiculovirus; Mammalia; Treatment; Mouse; Animal; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2012.70

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.