Radioiodide imaging and radiovirotherapy of multiple myeloma using VSV(Δ51)-NIS, an attenuated vesicular stomatitis virus encoding the sodium iodide symporter gene

Abstract

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 ...

Comparison of expressed human and mouse sodium/iodide symporters reveals differences in transport properties and subcellular localization

“…The study reported here is of particular interest in the recent and highly promising field of NIS-based gene therapy for non-thyroidal cancers (Chung 2002), especially when NIS is used in synergy with other genes such as canstatin (an angiogenic inhibitor; Magnon et al 2007) or with virotherapy (Dingli et al 2004, Goel et al 2007). The targeted transduction and the expression of NIS in cancer cells can allow tumor cell destruction by radioiodine treatment as well as in vivo imaging for the generation and investigation of safe and efficient gene delivery systems.…”

“…Therefore, important therapeutic effects can be achieved without uniform systemic gene delivery into all tumor cells. However, despite the highly promising results obtained recently (Goel et al 2007, Magnon et al 2007, it is still critical to develop better gene delivery systems and to improve the iodide uptake capacity of targeted cells in order to lower the administered radiation doses. As with our experiments, the above-mentioned gene therapy approach is based on the transient expression of NIS in target cells.…”

Safety Studies on Intrahepatic or Intratumoral Injection of Oncolytic Vesicular Stomatitis Virus Expressing Interferon-β in Rodents and Nonhuman Primates

“…To enhance the oncolytic potency of VSV, investigators have genetically modified the virus to express a variety of transgenes such as chemokine-binding protein, IL-12, and fusogenic glycoproteins (Ebert et al, 2004;Shin et al, 2007;Wu et al, 2008). In addition, Goel and colleagues have demonstrated that addition of the human thyroidal sodium iodide symporter gene to the VSV genome permits radioiodine imaging of the sites of viral infection as well as enhancement of the antitumor activity of VSV by using 131 I, a b particle-emitting radionuclide (Goel et al, 2007). Although there has been intensive preclinical work developing VSV for cancer therapy, clinical translation of VSV has lagged behind, mainly because of concerns about the neurovirulence of VSV when administered to animals (Clarke et al, 2006).…”

Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

“…13,15 A similar strategy was employed with VSV expressing the human sodium iodine symporter that resulted in the accumulation of radioactive iodine at the tumor site. 16 Both of these recombinant VSV strategies were shown to delay tumor growth in murine models; however, their action is restricted to cells that are directly infected by VSV.…”