Image-guided radiovirotherapy for multiple myeloma using a recombinant measles virus expressing the thyroidal sodium iodide symporter

Abstract

The Edmonston vaccine strain of measles virus (MV-Edm) propagates efficiently in a broad range of human tumor cells, killing them selectively. However, the oncolytic potency of MV-Edm in different human tumor xenograft therapy models is highly variable and there is no convenient way to map the distribution of virus-infected tissues in vivo. To enhance the oncolytic potency of MV-Edm against radiosensitive malignancies and to facilitate noninvasive imaging of infected tissues, we generated a recombinant MV-Edm encoding the human thyroidal iodide symporter (NIS). MV-NIS replicated almost as efficiently as unmodified MV-Edm, and human tumor cells efficiently concentrated radioiodine when infected with MV-NIS. Intratumoral spread of MV-NIS was noninvasively demonstrated by serial gammacamera imaging of iodine-123 ( 123 I) uptake both in MV-sensitive KAS-6/1 myeloma xenografts, which regressed completely after a single intravenous dose of MV-NIS, and in MM1 myeloma xenografts, which were unresponsive to MV-NIS therapy. However, MV-resistant MM1 tumors regressed completely when 131 I was administered 9 days after a single intravenous injection of MV-NIS (radiovirotherapy). 131 I alone had no effect on MM1 tumor growth. While the potential hematopoietic toxicity of this new therapy requires further evaluation, image-guided radiovirotherapy is a promising new approach to the treatment of multiple myeloma, an incurable but highly radiosensitive plasma cell malignancy. Testing in other radiosensitive cancers is warranted. IntroductionMultiple myeloma is a disseminated malignancy of antibodysecreting plasma cells that reside in active bone marrow. Clinical features of the disease include bone pain, lytic lesions, pathologic fractures, hypercalcemia, anemia, suppression of humoral immunity, and renal dysfunction caused by the tumor-derived monoclonal immunoglobulin. 1 In most patients, the fraction of proliferating cells is less than 1% until late in the disease. 2 Standard therapy is with alkylating agents (melphalan, cyclophosphamide) plus prednisone or combination chemotherapy (vincristine, doxorubicin, and dexamethasone) followed by high-dose melphalan with stem cell rescue. 1,3 At relapse, patients can be offered thalidomide or investigational drugs such as PS-341. [3][4][5] The disease, however, remains incurable and new therapeutic approaches are required.Myeloma cells are highly radiosensitive, and local radiotherapy provides effective palliation for painful bone lesions. 6 However, the disseminated nature of myeloma precludes curative external beam radiation therapy due to unacceptable end organ toxicity. 7 Bone-seeking radioisotopes that bind to bone mineral are being tested in multiple myeloma, 8 but their appeal and efficacy are limited by their inability to penetrate into the centers of myelomatous bone marrow deposits.Replicating viruses have considerable potential as cytoreductive agents for cancer. 9,10 Of the oncolytic viruses currently under investigation, measles virus (MV) is naturally lymphotrophic 11 ...

History of Oncolytic Viruses: Genesis to Genetic Engineering

“…Measles virus, for example, was first attenuated by serial passage in cultured cells, then genetically engineered to enhance its oncolytic potency and tumor specificity. [98][99][100][101][102] By and large, through a variety of mechanisms that have recently been reviewed [103][104][105][106][107][108][109][110] these clinically tested oncolytic viruses have shown strong specificity for neoplastic tissue.…”

Stratégies génétiques, immunologiques et pharmacologiques au service d’une nouvelle génération de virus anticancéreux

“…D'une manière similaire, la virulence de plusieurs souches de virus de la vaccine (VV) est supérieure à celle de la souche Wyeth utilisée pour élaborer le virus oncolytique de première génération JX-594. Par exemple, le virus oncolytique JX-963 a été développé à partir de la souche Western Reserve dont les gènes TK et VGF (vaccinia growth factor) ont été supprimés, et des cellules tumorales infectées conduit à une accumulation cytoplasmique d'iode 131, dont les radiations s'ajoutent au potentiel oncolytique du virus, augmentant l'efficacité thérapeutique [19,20]. Cette modalité peut aussi être utilisée pour visualiser, par tomographie par émission de positons, les tissus infectés.…”

Cell carriers to deliver oncolytic viruses to sites of myeloma tumor growth

“…Furthermore, there was complete regression of a measles resistant myeloma tumor model when MV-NIS was combined with a therapeutic dose of radioiodine in the form of 131 I. 33 MV-NIS is currently being administered intravenously to patients with MM in a phase I clinical trial at Mayo Clinic. 34 …”