Multiple myeloma is a radiosensitive malignancy that is currently incurable. Here, we generated a novel recombinant vesicular stomatitis virus [VSV(⌬51) - IntroductionMultiple myeloma is a malignancy of antibody-secreting plasma cells that reside predominantly in bone and bone marrow and secrete a monoclonal immunoglobulin. 1 The disease responds initially to alkylating agents, corticosteroids, and thalidomide, but eventually becomes refractory. 2 Multiple myeloma remains incurable causing more than 10 000 deaths each year in the United States. 3 Although cultured myeloma cells are relatively resistant to radiotherapy in vitro, 4,5 the malignancy is highly radiosensitive and radiation therapy is routinely used for palliation of pain, neurologic compromise, or structural instability from focal myeloma deposits. Efforts to use radiation as a systemic modality for definitive therapy of myeloma, however, have been problematic because of collateral toxicity to normal tissues especially the bone marrow progenitor cells. 6,7 Developing novel therapies for multiple myeloma based on the targeted delivery of radioisotopes to sites of active disease may have important clinical implications for myeloma therapy.Gene transfer using the thyroidal sodium iodide symporter (NIS) gene offers a novel strategy for delivery of radionuclides to disseminated cancer cells. 8 NIS is a transmembrane protein in thyroid follicular cells that actively mediates iodide uptake to a concentration gradient more than 20 to 40-fold. 9 Cloning the human NIS cDNA has aided in imaging and therapy of dedifferentiated thyroid cancer and nonthyroid cancers such as glioma, neuroblastoma, melanoma, multiple myeloma, and ovarian, breast, cervix, lung, liver, and colon carcinoma. 10 Tissue-specific NIS expression has been achieved in various cancer xenografts with minimal toxicity to normal organs by using promoters and enhancers from genes encoding immunoglobulins, prostate-specific antigen, probasin, and mucin-1. [11][12][13][14][15][16] Cancer therapy using oncolytic viruses (oncolytic virotherapy) requires agents that amplify efficiently through replication and spread causing rapid tumor lysis, yet are safe causing minimal toxicity to normal tissue enabling systemic inoculations to treat metastatic cancers. 17,18 We previously engineered the NIS gene into a lymphotropic, replication-competent attenuated strain of measles virus (MV-NIS) 19 that was subsequently used for oncolytic virotherapy of myeloma xenografts. Intratumoral spread of MV-NIS could be monitored noninvasively by radioiodine imaging and virus-resistant tumors were ablated after administration of 131 I. 20 A phase I clinical trial to evaluate the targeting properties of MV-NIS in patients with recurrent or refractory myeloma is ongoing at our institution. Several RNA viruses other than measles virus, including reovirus, Newcastle disease virus, mumps virus, and vesicular stomatitis virus (VSV), are being developed as systemic oncolytic agents for cancer therapy. 18,21 Each of these viruses ...

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 which expand rapidly and necrose at their centers, ultimately coalescing to cause extensive tumor destruction. This oncolytic tumor debulking phase lasts only for 72 hours after virus administration, and is completed before antiviral antibodies become detectable in the bloodstream. Anti-myeloma 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.

Innate responses to viral infections are complex involving i) viral detection; ii) induction of interferon and other cytokines; and iii) establishment of an antiviral state. Oncolytic viruses are engineered to be susceptible to antiviral responses in normal cells. Cancers can be partially vulnerable to these viruses because they have defective antiviral responses but the antitumor potency of physiologically targeted viruses may be significantly diminished.

Multiple myeloma (MM) is an incurable malignancy of plasma secreting B-cells disseminated in the bone marrow. Successful utilization of oncolytic virotherapy for myeloma treatment requires a systemically administered virus that selectively destroys disseminated myeloma cells in an immune-competent host. Vesicular stomatitis virus (VSV) expressing Interferon-β (IFNβ) is a promising new oncolytic agent that exploits tumor-associated defects in innate immune signaling pathways to specifically destroy cancer cells. We demonstrate here that a single, intravenous dose of VSV-IFNβ specifically destroys subcutaneous and disseminated 5TGM1 myeloma in an immune competent myeloma model. VSV-IFN treatment significantly prolonged survival in mice bearing orthotopic myeloma. Viral murine IFNβ expression further delayed myeloma progression and significantly enhanced survival compared to VSV expressing human IFNβ. Evaluation of VSV-IFNβ oncolytic activity in human myeloma cell lines and primary patient samples confirmed myeloma specific oncolytic activity but revealed variable susceptibility to VSV-IFNβ oncolysis. The results indicate that VSV-IFNβ is a potent, safe oncolytic agent that can be systemically administered to effectively target and destroy disseminated myeloma in immune competent mice. IFNβ expression improves cancer specificity and enhances VSV therapeutic efficacy against disseminated myeloma. These data show VSV-IFNβ to be a promising vector for further development as a potential therapy for treatment of Multiple myeloma.

Osteosarcoma is the most common primary tumor of bone. Osteosarcomas are rare in humans, but occur more commonly in dogs. A comparative approach to studying osteosarcoma has highlighted many clinical and biologic aspects of the disease that are similar between dogs and humans; however, important species-specific differences are becoming increasingly recognized. In this review, we describe risk factors for the development of osteosarcoma in dogs and humans, including height and body size, genetics, and conditions that increase turnover of bone-forming cells, underscoring the concept that stochastic mutational events associated with cellular replication are likely to be the major molecular drivers of this disease. We also discuss adaptive, cancer-protective traits that have evolved in large, long-lived mammals, and how increasing size and longevity in the absence of natural selection can account for the elevated bone cancer risk in modern domestic dogs.