title: Reovirus as a viable therapeutic option for the treatment of multiple myeloma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Oncology, University of Calgary, Calgary, Canada.
authors: Chandini M
authors: CM
authors: Thirukkumaran
authors: Zhong Qiao
authors: ZQ
authors: Shi
authors: Joanne
authors: J
authors: Luider
authors: Karen
authors: K
authors: Kopciuk
authors: He
authors: H
authors: Gao
authors: Nizar
authors: N
authors: Bahlis
authors: Paola
authors: P
authors: Neri
authors: Mark
authors: M
authors: Pho
authors: Douglas
authors: D
authors: Stewart
authors: Adnan
authors: A
authors: Mansoor
authors: Don G
authors: DG
authors: Morris
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D001853:Bone Marrow / Q000473:pathology; D045744:Cell Line, Tumor; D003588:Cytopathogenic Effect, Viral; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000821:virology; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses; D012087:Reoviridae; D023041:Xenograft Model Antitumor Assays