Reovirus as a Viable Therapeutic Option for the Treatment of Multiple Myeloma

• Published in: Clinical cancer research Vol. 18; no. 18; pp. 4962 - 4972
• Main Authors: THIRUKKUMARAN, Chandini M, ZHONG QIAO SHI, MORRIS, Don G, LUIDER, Joanne, KOPCIUK, Karen, HE GAO, BAHLIS, Nizar, NERI, Paola, PHO, Mark, STEWART, Douglas, MANSOOR, Adnan
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-09-2012
• Subjects: Animals; Antineoplastic agents; Apoptosis; Autophagy; Biological and medical sciences; Bone Marrow - pathology; Cell Line, Tumor; Cytopathogenic Effect, Viral; Female; Hematologic and hematopoietic diseases; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - virology; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; Multiple Myeloma - therapy; Oncolytic Virotherapy; Oncolytic Viruses; Pharmacology. Drug treatments; Reoviridae; Reovirus; Xenograft Model Antitumor Assays; Immunopathology; Treatment; Immunoglobulinopathy; Lymphoproliferative syndrome; Malignant hemopathy; Myeloma; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-11-3085

Despite the recent advances made in the treatment of multiple myeloma, the disease still remains incurable. The oncolytic potential of reovirus has previously been shown and is currently in phase III clinical trials for solid tumors. We tested the hypothesis that reovirus can successfully target human multiple myeloma in vitro, ex vivo, and in vivo without affecting human hematopoietic stem cell (HHSC) re-population/differentiation in a murine model that partially recapitulates human multiple myeloma.
Human myeloma cell lines and ex vivo tumor specimens were exposed to reovirus and oncolysis and mechanisms of cell death were assessed. RPMI 8226(GFP+) cells were injected intravenously to non-obese diabetic/severe combined immune deficient (NOD/SCID) mice and treated with live reovirus (LV) or dead virus (DV). Multiple myeloma disease progression was evaluated via whole-body fluorescence and bone marrow infiltration. HHSCs exposed to LV/DV were injected to NOD/SCID mice and re-population/differentiation was monitored.
A total of six of seven myeloma cell lines and five of seven patient tumor specimens exposed to reovirus showed significant in vitro sensitivity. Tumor response of multiple myeloma by LV, but not DV, was confirmed by comparison of total tumor weights (P = 0.05), and bone marrow infiltration (1/6, LV; 5/6, DV). Mice injected with LV- or DV-exposed HHSCs maintained in vivo re-population/lineage differentiation showing a lack of viral effect on the stem cell compartment. Reovirus oncolysis was mediated primarily by activation of the apoptotic pathways.
The unique ability of reovirus to selectively kill multiple myeloma while sparing HHSCs places it as a promising systemic multiple myeloma therapeutic for clinical testing.