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Oncolytic Measles Virus Strains Have Significant Antitumor Activity Against

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Oncolytic Measles Virus Strains Have Significant Antitumor Activity Against Gene Therapy (2013) 20, 444–449 & 2013 Macmillan Publishers Limited All rights reserved 0969-7128/13 www.nature.com/gt ORIGINAL ARTICLE Oncolytic measles virus strains have significant antitumor activity against glioma stem cells C Allen1, M Opyrchal1,2, I Aderca1, MA Schroeder3, JN Sarkaria3, E Domingo4, MJ Federspiel1 and E Galanis1,2 Glioblastoma (GBM) is the most common primary brain tumor in adults and has a dismal prognosis despite multimodality treatment. Given the resistance of glioma stem cells (GSC) to chemotherapy and radiation therapy, their eradication could prevent tumor recurrence. We sought to evaluate the antitumor activity of measles virus (MV) derivatives against GSC. We generated neurosphere cultures from patient-derived primary tumor GBM xenografts, and we characterized them for the GSC markers CD133, SOX2, Nestin, ATF5 and OLIG2. Using the MV-strains MV-GFP, MV-CEA and MV-NIS we demonstrated infection, viral replication and significant cytopathic effect in vitro against GSC lines. In tumorigenicity experiments, GBM44 GSC were infected with MV in vitro and subsequently implanted into the right caudate nucleus of nude mice: significant prolongation of survival in mice implanted with infected GSC was observed, compared with mock-infected controls (P ¼ 0.0483). In therapy experiments in GBM6 and GBM12 GSC xenograft models, there was significant prolongation of survival in MV-GFP-treated animals compared with inactivated virus-treated controls (GBM6 P ¼ 0.0021, GBM12 P ¼ 0.0416). Abundant syncytia and viral replication was demonstrated in tumors of MV-treated mice. Measles virus derivatives have significant antitumor activity against glioma-derived stem cells in vitro and in vivo. Gene Therapy (2013) 20, 444–449; doi:10.1038/gt.2012.62; published online 23 August 2012 Keywords: measles virus; gliomas; stem cells; MV-CEA; MV-NIS INTRODUCTION described.8–10 A schematic representation of the strains used is Glioblastoma (GBM) is the most common primary brain tumor in included in Figure 1. adults and has a dismal prognosis despite aggressive use of multimodality treatment including surgery, chemotherapy and Characterization of stem-cell marker expression in neurosphere radiation therapy.1 One potentially significant hurdle to overcome lines in the treatment of GBM pertains to eradication of glioma cells with GBM xenografts were developed in BALB/c nude mice from GBM stem-cell-like properties (GSC); these are cells with self-renewing patients as previously described.11,12 Tumors were excised from properties, able to differentiate into neurons, oligodendrocytes and mice bearing the GBM xenografts GBM6, 10, 12, 14, 23, 34, 38, 39, astrocytes, and they can initiate brain tumors in vivo. In addition, 43 and 44, mechanically disrupted and grown in NeuroCult they have been associated with the promotion of angiogenesis, and medium: formation of neurospheres was observed within 2–6 2–4 development of resistance to radiation and chemotherapy. Our weeks depending on the cell line. Neurosphere lines used in vitro laboratory has previously demonstrated that derivatives of the and in vivo experiments were further characterized for the measles virus (MV) Edmonston’s strain have significant activity expression of the glioma stem-cell markers CD133, Nestin, Sox 2, 5–7 against glioma lines and orthotopic xenografts, and a phase I ATF5 and OLIG 2. All neurosphere lines tested expressed at least trial of the measles derivative MV-CEA is currently ongoing in 3/5 stem-cell markers. Representative results for three of the recurrent GBM patients. Assessing the ability of MV-strains to neurosphere lines are shown in Figure 2. infect and eradicate glioma cells with stem-cell-like properties represents an important parameter, which could potentially affect Expression of MV receptor CD46 in neurosphere lines the antitumor activity of this novel virotherapy platform and impact on the development of combinatorial strategies. Here, we CD46 expression in neurosphere lines was tested by fluorescence- show that GSC overexpress the MV receptor CD46. Furthermore, activated cell sorting (FACS) and immunohistochemistry over- MV-strains of the Edmonston vaccine lineage have significant expression was confirmed in all 10 lines tested. Representative antitumor activity against GSCs in vitro and in vivo, and can results are shown for GBM34 and GBM22 (Figure 3). decrease their tumorigenicity; these findings can have important translational implications in glioma treatment. Assessment of cytopathic affect of MV-strains against GSC In order to access antitumor activity of measles virus strains against GSCs, neurosphere lines were infected with the MV-strains, RESULTS MV-NIS, MV-GFP and MV-CEA at multiplicity of infection (MOI) of Viral strains 0.1 or 1.0 and trypan blue exclusion assays were performed at Antitumor activity of the MV-strains MV-CEA, MV-NIS and MV-GFP multiple time points. Results were presented as percentage of the against GSC was examined. Their construction has been previously uninfected controls. MV derivatives had significant antitumor 1Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA; 2Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA; 3Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA and 4Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA. Correspondence: Dr E Galanis, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail: [email protected] Received 8 December 2011; revised 15 May 2012; accepted 6 June 2012; published online 23 August 2012 Measles virus has activity against glioma stem cells C Allen et al 445 activity against GSCs in vitro, which was dependent on MV-strain macrophage marker CD68, showed lack of a significant immune and MOI (Figure 4). infiltrate (Supplementary Figure 1), suggesting a low likelihood that innate immune response driven viral inactivation was Assessment of viral replication responsible for tumor development in this model. Virus replication was assessed using one-step viral growth curves as previously described.7 Neurosphere cultures supported robust Assessment of therapeutic efficacy in vivo growth of the MV-NIS, MV-GFP and MV-CEA virus (Figure 5). In order to assess the antitumor activity of MV-strains against neurosphere-derived xenografts, GBM6 or GBM12 derived GSCs were orthotopically implanted into the right caudate nucleus of Assessment of tumorigenicity of infected neurospheres nude mice. Animals were treated with a total dose of either GSC cells obtained from GBM44 xenografts were infected with 9 Â 105 TCID50 (GBM12) or 1.8 Â 106 TCID (GBM6) of MV-GFP. either MV-NIS (MOI of 10) and 3 Â 105 cells were implanted into Control animals received UV-inactivated virus. Significant prolon- the right caudate nucleus of BALB/C nude mice. Mock infected gation of survival of the treated animals was observed in both GBM44 GSC were used as controls. There was significant models (P ¼ 0.0416 and P ¼ 0.0021, respectively) (Figure 7). In a prolongation of survival in mice implanted with infected neuro- parallel experiment, treated and control animals bearing ortho- spheres as compared with mice implanted with mock-infected topic GBM6 GSC xenografts (a CD133-positive neurosphere line) neurospheres (P ¼ 0.04), indicating that infection of GSC in vitro were euthanized either on day 3 post-treatment completion or can modify their aggressive biologic behavior following orthotopic when moribund. Abundant syncytia were observed in MV-GFP- implantation (Figure 6). treated mice. Syncytia expressed CD133 (Figure 7d) confirming As Figure 6 illustrates some of the mice implanted with infected activity of the MV derivatives against GSC-derived tumors in vivo. neurospheres developed tumors. Examination of these tumors at In situ hybridization for the MV N (nucleoprotein)-mRNA was the time of euthanasia showed lack of syncytia, indicating that the tumors likely derived from non-infected cells. Immunofluores- cence for the natural killer cell lectin-like receptor and the CD46 expression GBM34 GSC GBM22 GSC Measles Virus Constructs MV-CEACEA N P M F H L IHC MV-GFP GFPN P M F H L MV-NIS N P M F H NIS L Figure 1. Schematic representation of the viral strains: MV-CEA: MV- FACS strain expressing the human carcinoembryonic antigen; MV-NIS: MV-strain expressing the sodium iodine symporter. N, nucleoprotein gene; MV-GFP, MV-strain expressing the enhanced green fluorescent protein; L, large protein gene; P, phosphoprotein gene; M, matrix Figure 3. Expression of MV receptor CD46 was examined by IHC and protein gene; F, fusion protein gene; H, hemagglutinin gene; CEA, flow cytometry. Significant expression of CD46 was observed in human carcinoembryonic antigen gene; NIS, sodium iodine all neurosphere lines tested. Representative ICH and FACS data in symporter gene. GBM34 and GBM22 GSC lines are presented. CD133 NESTIN SOX2 ATF5 OLIG2 GBM6 GSC GBM12 GSC GBM38 GSC Figure 2. Neurospheres derived from GSC xenograft cultures express stem-cell markers (CD133, Nestin, SOX2, ATF5 and OLIG2). Representative data for the GBM6, GBM12 and GBM38 GSC lines are shown. & 2013 Macmillan Publishers Limited Gene Therapy (2013) 444 – 449 Measles virus has activity against glioma stem cells C Allen et al 446 GBM12 GSC on GBM38 GSC day 3 post infection 100 Uninfected MV-GFP 80 MV-GFP MOI 0.1 60 MV-NIS MOI 0.1 40 MV-GFP MOI 0.1 MV-NIS MOI 0.1 Survival (%) 20 0 0 2 4 6 8 10 12 14 Days GBM10 GSC GBM12 GSC 100 MV-GFP MOI 0.1 100 80 MV-NIS MOI 0.1 80 MV-GFP MOI 0.1 60 MV-NIS MOI 0.1 60 MV-CEA MOI 0.1 MV-NIS MOI 0.1 40 MV-CEA MOI 1 40 MV-NIS MOI 1 Survival (%) Survival (%) 20 20 0 0 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 Days Days Figure 4. (a) Infection with MV-GFP resulted in abundant GFP expression in infected GBM12 neurospheres.
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