Treatment of medulloblastoma using an oncolytic measles virus encoding the thyroidal sodium iodide symporter shows enhanced efficacy with radioiodine

Abstract

BackgroundMedulloblastoma is the most common malignant brain tumor of childhood. Although the clinical outcome for medulloblastoma patients has improved significantly, children afflicted with the disease frequently suffer from debilitating side effects related to the aggressive nature of currently available therapy. Alternative means for treating medulloblastoma are desperately needed. We have previously shown that oncolytic measles virus (MV) can selectively target and destroy medulloblastoma tumor cells in localized and disseminated models of the disease. MV-NIS, an oncolytic measles virus that encodes the human thyroidal sodium iodide symporter (NIS), has the potential to deliver targeted radiotherapy to the tumor site and promote a localized bystander effect above and beyond that achieved by MV alone.MethodsWe evaluated the efficacy of MV-NIS against medulloblastoma cells in vitro and examined their ability to incorporate radioiodine at various timepoints, finding peak uptake at 48 hours post infection. The effects of MV-NIS were also evaluated in mouse xenograft models of localized and disseminated medulloblastoma. Athymic nude mice were injected with D283med-Luc medulloblastoma cells in the caudate putamen (localized disease) or right lateral ventricle (disseminated disease) and subsequently treated with MV-NIS. Subsets of these mice were given a dose of 131I at 24, 48 or 72 hours later.ResultsMV-NIS treatment, both by itself and in combination with 131I, elicited tumor stabilization and regression in the treated mice and significantly extended their survival times. Mice given 131I were found to concentrate radioiodine at the site of their tumor implantations. In addition, mice with localized tumors that were given 131I either 24 or 48 hours after MV-NIS treatment exhibited a significant survival advantage over mice given MV-NIS alone.ConclusionsThese data suggest MV-NIS plus radioiodine may be a potentially useful therapy for the treatment of medulloblastoma.

Oncolytic measles virus as a novel therapy for malignant peripheral nerve sheath tumors

“…This may be due to the lower CD46 expression or a robust antiviral response to MV in HSCIL-1 cells as compared to the other MPNST lines; however, further study is needed to determine this difference. Similar to other preclinical cancer models (Dingli et al, 2004;Hasegawa et al, 2006;Li et al, 2012;Hutzen et al, 2012;Carlson et al, 2009;Penheiter et al, 2010), we observed that a single intratumoral administration of MV-NIS inhibited tumor xenograft growth in vivo and improved long-term survival in treated mice. Of the mice that survived to the end of the study, all but one had no appreciable tumor, indicating that one treatment of MV-NIS was capable of eradicating the MPNST-derived xenografts.…”

Measles to the Rescue: A Review of Oncolytic Measles Virus

“…Besides tracking MV replication by MV-NIS, expression of NIS increases virotherapeutic efficacy by facilitating the intracellular entry of beta-emitting radioisotopes such as I131 and Re188, specifically inducing radiation damage within the tumour microenvironment [62,67,68]. Radiovirotherapy of in vivo multiple myeloma models with relatively small doses of MV-NIS followed by iodine-131 subsequently resulted in the eradication of infected tumour cells, which are otherwise resistant to MV-mediated lysis [62].…”

Potential and clinical translation of oncolytic measles viruses

“…NIS expression in infected cells results in uptake of radioiodide isotopes or Tc99 m and thus facilitates in vitro and in vivo localization of infected cells [48–52]. In addition to permitting anatomic localization of the infected tumor cells, NIS can also function as a therapeutic transgene, allowing uptake of therapeutic radioiodine isotopes, with resultant improved tumor regression, as well as local bystander effect [47,53–57]. Attempts at maximizing therapy and monitoring with multiple transgenes have produced mixed results.…”