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- W2507708049 abstract "Mumps virus belongs to the family of Paramyxoviridae and has the potential to be an oncolytic agent. Mumps virus Urabe strain had been tested in the clinical setting as a treatment for human cancer four decades ago in Japan. These clinical studies demonstrated that mumps virus could be a promising cancer therapeutic agent that showed significant antitumor activity against various types of cancers. Since oncolytic virotherapy was not in the limelight until the beginning of the 21st century, the interest to pursue mumps virus for cancer treatment slowly faded away. Recent success stories of oncolytic clinical trials prompted us to resurrect the mumps virus and to explore its potential for cancer treatment. We have obtained the Urabe strain of mumps virus from Osaka University, Japan, which was used in the earlier human clinical trials. In this report we describe the development of a reverse genetics system from a major isolate of this Urabe strain mumps virus stock, and the construction and characterization of several recombinant mumps viruses with additional transgenes. We present initial data demonstrating these recombinant mumps viruses have oncolytic activity against tumor cell lines in vitro and some efficacy in preliminary pilot animal tumor models. Mumps virus belongs to the family of Paramyxoviridae and has the potential to be an oncolytic agent. Mumps virus Urabe strain had been tested in the clinical setting as a treatment for human cancer four decades ago in Japan. These clinical studies demonstrated that mumps virus could be a promising cancer therapeutic agent that showed significant antitumor activity against various types of cancers. Since oncolytic virotherapy was not in the limelight until the beginning of the 21st century, the interest to pursue mumps virus for cancer treatment slowly faded away. Recent success stories of oncolytic clinical trials prompted us to resurrect the mumps virus and to explore its potential for cancer treatment. We have obtained the Urabe strain of mumps virus from Osaka University, Japan, which was used in the earlier human clinical trials. In this report we describe the development of a reverse genetics system from a major isolate of this Urabe strain mumps virus stock, and the construction and characterization of several recombinant mumps viruses with additional transgenes. We present initial data demonstrating these recombinant mumps viruses have oncolytic activity against tumor cell lines in vitro and some efficacy in preliminary pilot animal tumor models. Oncolytic virotherapy is a rapidly evolving field in which viruses are exploited for their targeted cell killing properties. Viruses had been utilized for cancer treatment in the 20th century,1Kelly E Russell SJ History of oncolytic viruses: genesis to genetic engineering.Mol Ther. 2007; 15: 651-659Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar but they received considerable interest only at the beginning of 21st century. Oncolytic viruses specifically infect and kill tumor cells without harming healthy cells with intact interferon pathway.2Singh PK Doley J Kumar GR Sahoo AP Tiwari AK Oncolytic viruses & their specific targeting to tumour cells.Indian J Med Res. 2012; 136: 571-584PubMed Google Scholar Currently, many viruses are being studied extensively for their oncolytic and immunotherapeutic properties in clinical and preclinical trials. Recent FDA approval of herpes virus underscores the importance of oncolytic viruses in the field of cancer therapeutics as an alternative therapeutic agent.3Ledford H Cancer-fighting viruses win approval.Nature. 2015; 526: 622-623Crossref PubMed Scopus (81) Google Scholar The reports of significant responses of human cancers to oncolytic virotherapy in clinical trials kindle the interest of many researchers to explore various viruses for their usefulness in cancer treatment. A recombinant measles virus encoding human sodium iodide symporter (MV-NIS), has shown some promising results in recent human clinical trials including a complete response of a myeloma patient in phase 1 trial at the Mayo Clinic.4Russell SJ Federspiel MJ Peng KW Tong C Dingli D Morice WG et al.Remission of disseminated cancer after systemic oncolytic virotherapy.Mayo Clin Proc. 2014; 89: 926-933Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar We were inspired to look for another equally competent virus in the same family. In this regard, we explored the safety and efficacy of another member of paramyxoviridae family, mumps virus (MuV). It belongs to the genus Rubulavirus and possess a single stranded negative sense RNA genome (~15 kb) which encodes at least nine viral proteins.5Elango N Varsanyi TM Kövamees J Norrby E Molecular cloning and characterization of six genes, determination of gene order and intergenic sequences and leader sequence of mumps virus.J Gen Virol. 1988; 69: 2893-2900Crossref PubMed Scopus (104) Google Scholar Mumps virus has 12 genotypes, designated A–N (excluding E and M) based on the sequence of the SH gene.6Mumps virus nomenclature update: 2012.Wkly Epidemiol Rec. 2012; 87: 217-224PubMed Google Scholar Mumps virus has long been used for cancer treatment as an immuno-therapeutic and antineoplastic agent.7Asada T Treatment of human cancer with mumps virus.Cancer. 1974; 34: 1907-1928Crossref PubMed Scopus (161) Google Scholar, 8Okuno Y Asada T Yamanishi K Otsuka T Takahashi M Tanioka T et al.Mumps virus therapy of neoplasms (2).Nihon Rinsho. 1977; 35: 3820-3825PubMed Google Scholar, 9Minton JP Mumps virus and BCG vaccine in metastatic melanoma.Arch Surg. 1973; 106: 503-506Crossref PubMed Scopus (12) Google Scholar Dr. Asada, a physician from Japan demonstrated oncolytic activity of Mumps virus in cancer patients. He used a near wild-type mumps virus (Urabe strain) collected from saliva of patients with epidemic parotitis, and minimally passaged on cultured cells. For later experiments, Asada used purified mumps virus grown in tissue culture (human embryonic kidney cells), from the Department of Virology, Research Institute for Microbial Diseases, Osaka University. In this clinical trial, Asada treated 90 patients with various kinds of terminal cancers. For 37 of 90 patients treated, the tumor regressed completely or decreased to less than half of the initial size. Among which 42 patients responded moderately and their tumor showed a tendency of retreat or growth suppression. Asada also compared live mumps virus with an inactivated one and found no anticancer effect which clearly shows that live replicating virus is essential for antitumor efficacy. He also noticed that oncolytic efficacy was terminated once antimumps immunity developed. Local or intratumoral administration was more effective than systemic therapy that requires a large dose of mumps virus. Many patients were in remission for a long time after discontinuation of therapy, suggesting development of antitumor immunity. He also concluded that it is essential to start virotherapy when the immune system is intact in the early stages of cancer or before other conventional therapies. A second clinical trial was conducted using the same Urabe strain mumps virus but after additional passages in cultured cells and with improved purity.10Okuno Y Asada T Yamanishi K Otsuka T Takahashi M Tanioka T et al.Studies on the use of mumps virus for treatment of human cancer.Biken J. 1978; 21: 37-49PubMed Google Scholar In this trial, patients with various cancers, most of them at terminal stages, were treated with mumps virus intravenously (i.v.) and tumor regression were observed in 26 out of 200 patients. This trial was followed by a third one, in which patients with advanced gynecologic cancer were preimmunized with mumps virus before treatment.11Shimizu Y Hasumi K Okudaira Y Yamanishi K Takahashi M Immunotherapy of advanced gynecologic cancer patients utilizing mumps virus.Cancer Detect Prev. 1988; 12: 487-495PubMed Google Scholar Marked clinical response was observed with patients treated locally and no response was noticed in unprimed patients or patients with large tumor mass. The above clinical trials strongly demonstrate the oncolytic and immune-therapeutic potential of Urabe strain mumps virus. Recently, we were able to obtain Urabe strain mumps virus that was subjected to cancer clinical trials in Japan by Dr. Asada and coworkers.7Asada T Treatment of human cancer with mumps virus.Cancer. 1974; 34: 1907-1928Crossref PubMed Scopus (161) Google Scholar Since modern day clinical trial requires preclinical studies with detailed information on safety and efficacy of oncolytic virus derived from infectious clone, we developed a reverse genetics system for this Urabe strain of mumps virus and conducted preliminary studies on oncolytic efficacy both in in-vitro and in-vivo models with the aim of translating this virus again to the clinic. An aliquot of the mumps virus Urabe strain (MuV-U) used in oncolytic virotherapy human clinical trials in Japan in the 1970’s and 1980’s was obtained. A representative clone, MuV-U Clone 1-C-3 (MuV-UC-WT) was isolated, characterized, and used in this study. A unique aspect of this MuV-UC virus stock was the minimal amplification in cultured cells that may have minimized the attenuation from the original patient isolate. A reverse genetics platform based on the nucleotide sequence of the MuV-UC isolate was constructed initially with an additional transcription unit containing the green flourescent protein (GFP) coding sequence flanked by unique restriction enzyme cloning sites between MuV-UC genes HN and L, in a plasmid vector pMuV-UC-GFP. Negative-strand RNA can be synthesized using T7 polymerase and the T7 transcription elements flanking the MuV-UC genome along with three MuV-UC-based helper plasmids expressing MuV-UC N, P and L proteins. Baby hamster kidney cells infected with a vaccinia virus vector encoding the T7 polymerase were then transfected with the infectious MuV-UC plasmid along with the three helper plasmids to rescue recombinant virus. After successful rescue in baby hamster kidney cells, the recombinant MuV-UC virus was further propagated in Vero cells to produce virus stocks (Figure 1a). When growth potential of recombinant mumps virus expressing GFP was compared with wild-type virus, it showed better growth rate (Figure 1b). To test the genomic stability and transgene expression abilities of the recombinant MuV-UC platform, we constructed several other recombinant viruses with different useful transgenes for in vivo bio-distribution and efficacy studies (Figure 2a). The GFP coding region was replaced with the luciferase gene (rMuV-UC-LUC), or the human sodium iodide symporter (NIS) gene (rMUV-UC-NIS). We also tested whether two transgenes could be inserted and expressed from the rMuV-UC platform by adding an additional transgene, mouse interferon beta (mIFNβ), in between M and F genes of rMuV-UC-GFP creating rMuV-UC-mIFNβ-GFP that should express both the mIFNβ and GFP. All the recombinant mumps viruses replicated well on Vero cells (Figure 2b). Also, as expected, the rMuV-UC-mIFNβ-GFP with two transgenes replicated to a lower titer compared with viruses with single transgenes. All transgenes delivered by the recombinant mumps viruses were well expressed (Figure 2c–e). Since oncolytic virotherapy not only expects the virus to directly kill tumor cells but then cause a unique immune response to the tumor to completely cure the patient, efficacy models that can evaluate both strategies of this two-pronged therapeutic approach are the best. Therefore, while we want to know the efficacy of mumps virus for treating human tumors, human tumor xenografts in nude mice can only evaluate the virus killing therapeutic component. Since some syngeneic mouse tumors models respond similarly to their human tumor counterparts, we next investigated the infectivity and oncolytic activity of the rMuV-UC-GFP virus on a variety of human and mouse tumor cell lines. We tested the oncolytic efficacy of rMuV-UC-GFP in various human cancer cell lines (Figure 3a). The human tumor cell lines were infected with rMuV-UC-GFP at an MOI = 10, and analyzed 5 days later by fluorescence microscopy for GFP expression. This analysis demonstrated that mumps virus could infect most human tumor cell lines tested. At the same time we found out that most of the mouse tumor cell lines are nonpermissive to robust rMuV-UC-GFP virus infection and replication, with only the N2A neuroblastoma cell line and the CT-26-LacZ colon cancer cell lines showing significant numbers of GFP positive cells (Figure 3b). Both the N2A and CT-26-LacZ tumor lines permitted some rMuV-UC-GFP replication but at significantly lower titers compared with rMuV-UC-GFP replication on human KAS6/1 tumor cells (Figure 3c). Significant cell killing was observed in most human tumor lines tested, however the extent as well as the rate of cell killing can differ substantially between individual tumor cell lines (see Supplementary Figure S1). Very little cell killing was observed in the infected mouse tumor lines with the best in the N2A and CT-26-LacZ by day 7, where the mumps virus replicated relatively well. Since the neurovirulence studies of mumps virus has been carried out in rat models, we tested the infectivity and replication of rMuV-UC-GFP in some of the rat tumor cell lines. C6 and RG2 are two rat glioma tumor cell lines, and were infected with mumps virus at different multiplicity of infection. RG2 glioma cells were more permissive to MuV infection compared with C6 cells (Figure 4a). Mumps virus multiplies better in RG2 cells reaching its peak titer (6 x 105 pfu/ml) at 72 hours post-infection (Figure 4b). The titer produced by RG2 cells is almost two logs higher than C6 cells but more than a log lower than Vero cells. In correlation with the higher rMuV-UC-GFP replication in RG2 cells compared with C6 cells, up to 60% of the RG2 cells were killed by the mumps virus compared with just 10–20% of C6 cells as determined by MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay, confirmed the higher infectivity in RG2 cells (Figure 4c). It has been shown that mumps virus infection in nonpermissive rodent cells resulted in abortive infection.12Yamada A Tsurudome M Hishiyama M Ito Y Abortive infection of mumps virus in murine cell lines.J Gen Virol. 1984; 65: 973-980Crossref PubMed Scopus (12) Google Scholar This may be caused by the presence of antiviral machinery or due to inefficient penetration of virus into the cell. Since interferon is one of the obstacles that could prevent MuV replication, we treated some of the less permissive cell lines with Janus kinase inhibitor, Ruxolitinib,13Escobar-Zarate D Liu YP Suksanpaisan L Russell SJ Peng KW Overcoming cancer cell resistance to VSV oncolysis with JAK1/2 inhibitors.Cancer Gene Ther. 2013; 20: 582-589Crossref PubMed Scopus (44) Google Scholar and then infected the treated cells with rMuV-UC-GFP. The Ruxolitinib treatment increased the viral infection significantly in rat glioma (C6), mouse lung carcinoma (LLC) cells and also to some extent in CT-26 colon carcinoma cells, but not in plasmacytoma (MPC11) and human myeloma (MM1) cells (Figure 5). This suggests that individual cell lines not only differ in the innate immune defense but also employ more than one mechanism to restrict viral replication. So the low infectivity of MuV in mouse tumor cells may be the result of multiple cellular factors rather than single one that control different steps in the mumps virus life-cycle. To test the oncolytic activity of mumps virus in immunocompetent mouse models, we conducted pilot preliminary studies using the two relatively permissive mouse cancer cell lines to mumps virus infection, colon carcinoma (CT-26-LacZ) and neuroblastoma (N2A). These tumor cells were implanted into the flanks of syngeneic mice, Balb/C, and A/J respectively. Once the tumors reached a significant size, mumps viruses were administered i.v. through the tail vein. In CT-26-LacZ model, groups of mice were treated with rMuV-UC-GFP at 106 and 107, rMuV-UC-LUC at 107, MuV-UC at 107, and a saline control. Some of the mice with CT-26-LacZ tumors treated with rMuV-UC-LUC or MuV-UC virus had delay in their tumor growth and had better overall survival with one rMuV-UC-LUC treated mouse and two MuV-UC virus treated mice having a complete response (Figure 6). However, immunohistochemical analysis of tumor tissue on day 14 does not show any mumps virus positive staining and also the luciferase imaging on day 7 and 14 yielded no positive signal (data not shown). This suggests that there may be an involvement of immune system in tumor suppression. In our pilot studies, we found out that mutating a single amino acid in polymerase gene increased the replication rate of mumps virus (nt13328, aa N to H). When this virus was compared with MuV-UC-WT and rMuV-UC-GFP, no significance difference was observed in oncolytic activity in in-vitro studies (see Supplementary Figure S2). But we decided to use this virus (rMuV-UC-L13328-GFP) for the rest of the animal studies. In the N2A model, mice were treated with rMuV-UC-LUC, rMuV-UC-L13328-GFP, MuV-UC, and equal amount of saline. No significant antitumor activity was seen in the N2A tumor model possibly due to the aggressive nature of N2A tumor with most of the mice requiring sacrifice ~10 days postinfection (Figure 7). However, one mouse survived in rMuV-UC-L13328-GFP treated group. In order to initially assess the antitumor activity of the mumps viruses, in-vivo in a human myeloma model, we implanted human myeloma tumor cells (KAS6/1) in the flanks of nude mice. Once the tumor reached an appreciable size, 107 PFU of rMuV-UC-LUC, rMuV-UC-L13328-GFP, MuV-UC or saline were injected i.v. through the tail vein, and the mice was observed for 60 days (Figure 8). In this study, unfortunately there was more variability in the growth of the individual tumor xenografts than we wanted as shown with the saline treated animals, with four of five animals succumbing to tumor load by 60 days. This variability was seen in all four groups and prevented the survival results from reaching statistical significance. However, the data clearly shows the MuV-UC isolate significantly suppressed the tumor growth in all five animals, with one animal having a complete response. The results from mice treated with the recombinant viruses were promising with a complete response and possibly two tumors controlled when treated with rMuV-UC-LUC, while two animals had a complete response to treatment with rMuV-UC-L13328-GFP. To confirm virus replication, tumors were harvested from mice on day 7 and day 12 after virus administration and analyzed for mumps virus antigens. All tumors were positive for mumps viral proteins on day 7 and showed increased staining on day 12. MuV-UC treated tumors having comparatively better infectivity and spread relative to the tumors treated with the recombinant mumps viruses (see Supplementary Figure S3). Since these studies involved single administration of mumps virus, other treatment regimens could possibly improve oncolytic efficacy significantly. Advancement of technology and approval of oncolytic viruses for cancer treatment has prompted the researchers around the globe to explore many different virus species for their usefulness in human cancer treatment. After the clinical trials in Japan, no further attempt was made to utilize the mumps virus for human cancer treatment. Currently, the FDA requires stringent preclinical efficacy and safety studies before oncolytic clinical trials are approved. Even though animal studies do not necessarily correlate well with clinical outcomes in human patients, it is unavoidable and essential to establish proof of principle in preclinical models. In order to fulfill these requirements and to bring the mumps virus back to the clinic, we established a reverse genetics system for the Urabe stain used by Asada and coworkers in cancer clinical trials. Recombinant virus rescued from infectious clone, did not show any reduction in growth potential and even grow better than parental virus. In this report, we characterized oncolytic efficacy of recombinant Urabe mumps virus both in in vitro and in vivo studies. Oncolytic activity of recombinant mumps virus (rMuV-UC-GFP) was tested in various human cancer cell lines. The rate of infectivity differs between the cell lines which is likely due to influence of one or more factors; interferon pathway-related genes, various cellular factors (cell cycle modulators, apoptotic machinery, NF-κB, and APOBEC3) or receptors and coreceptors expression levels.14Young DF Galiano MC Lemon K Chen YH Andrejeva J Duprex WP et al.Mumps virus Enders strain is sensitive to interferon (IFN) despite encoding a functional IFN antagonist.J Gen Virol. 2009; 90: 2731-2738Crossref PubMed Scopus (11) Google Scholar, 15Le Tortorec A Denis H Satie AP Patard JJ Ruffault A Jégou B et al.Antiviral responses of human Leydig cells to mumps virus infection or poly I:C stimulation.Hum Reprod. 2008; 23: 2095-2103Crossref PubMed Scopus (42) Google Scholar, 16Brgles M Bonta M Šantak M Jagušić M Forčić D Halassy B et al.Identification of mumps virus protein and lipid composition by mass spectrometry.Virol J. 2016; 13: 9Crossref PubMed Scopus (8) Google Scholar, 17Fehrholz M Kendl S Prifert C Weissbrich B Lemon K Rennick L et al.The innate antiviral factor APOBEC3G targets replication of measles, mumps and respiratory syncytial viruses.J Gen Virol. 2012; 93: 565-576Crossref PubMed Scopus (40) Google Scholar, 18Okeoma CM Petersen J Ross SR Expression of murine APOBEC3 alleles in different mouse strains and their effect on mouse mammary tumor virus infection.J Virol. 2009; 83: 3029-3038Crossref PubMed Scopus (58) Google Scholar More detailed study is warranted to understand the interaction between virus and host cell. Another interesting phenomenon of mumps virus infection is cytopathic effect (CPE). Although cell monolayer is fully infected with mumps virus, significant cell death or disruption of monolayer is noticed only around day 7. This is probably due to interaction of viral proteins with cellular factors that involve in apoptosis pathway. It was shown that mumps virus V protein and cellular STAT protein both play a major role in apoptosis.19Rosas-Murrieta NH Santos-López G Reyes-Leyva J Jurado FS Herrera-Camacho I Modulation of apoptosis by V protein mumps virus.Virol J. 2011; 8: 224Crossref PubMed Scopus (6) Google Scholar, 20Puri M Lemon K Duprex WP Rima BK Horvath CM A point mutation, E95D, in the mumps virus V protein disengages STAT3 targeting from STAT1 targeting.J Virol. 2009; 83: 6347-6356Crossref PubMed Scopus (21) Google Scholar, 21Ulane CM Rodriguez JJ Parisien JP Horvath CM STAT3 ubiquitylation and degradation by mumps virus suppress cytokine and oncogene signaling.J Virol. 2003; 77: 6385-6393Crossref PubMed Scopus (158) Google Scholar, 22Xu P Luthra P Li Z Fuentes S D'Andrea JA Wu J et al.The V protein of mumps virus plays a critical role in pathogenesis.J Virol. 2012; 86: 1768-1776Crossref PubMed Scopus (28) Google Scholar It has also been demonstrated that mumps virus small hydrophobic (SH) protein blocks TNF-α-mediated apoptosis pathway.23Wilson RL Fuentes SM Wang P Taddeo EC Klatt A Henderson AJ et al.Function of small hydrophobic proteins of paramyxovirus.J Virol. 2006; 80: 1700-1709Crossref PubMed Scopus (87) Google Scholar Cells normally initiate apoptosis as soon as it detects viral infection. On the other hand viral proteins suppress apoptosis to maximize its own production. In case of mumps virus, V and SH proteins probably block the apoptosis and prevent early cell death.20Puri M Lemon K Duprex WP Rima BK Horvath CM A point mutation, E95D, in the mumps virus V protein disengages STAT3 targeting from STAT1 targeting.J Virol. 2009; 83: 6347-6356Crossref PubMed Scopus (21) Google Scholar Even though humans are primary host for mumps virus, other animals can also be infected at least in experimental conditions. So we tested the infectivity and oncolytic efficacy of mumps virus in mouse and rat cancer cell lines. Researchers previously demonstrated that many mouse cell lines support the replication of mumps virus.24Tsurudome M Yamada A Hishiyama M Ito Y Replication of mumps virus in murine cells.Arch Virol. 1984; 81: 13-24Crossref PubMed Scopus (6) Google Scholar They also showed that variation existed in infectivity between different strains of mumps virus. In another study, researchers also demonstrated that mumps virus replication is restricted in mouse cell lines due to interferon machinery or inefficient penetration into the cell.12Yamada A Tsurudome M Hishiyama M Ito Y Abortive infection of mumps virus in murine cell lines.J Gen Virol. 1984; 65: 973-980Crossref PubMed Scopus (12) Google Scholar In this study we tested the infectivity of MuV-UC mumps virus in a panel of mouse cell lines. While most cells were not permissive to MuV-UC mumps virus infection, significant viral replication was observed in colon carcinoma and neuroblastoma cells. But the viral titer is significantly lower compared with human cell lines. It suggests the restricted replication of mumps virus in mouse cell lines and is due to one or combination of factors suggested above. At the same time mumps virus replicates well in one of the two rat cell lines tested, which warrants further study on mechanism of mumps virus infectivity in various rat cancer cell lines. To preliminarily assess the oncolytic activity of MuV-UC viruses for both tumor cell killing and a subsequent immune activation in vivo, immune compromised and immunocompetent mouse models were tested. Although MuV-UC viruses did not replicate well in most mouse tumor cell lines, there was a reasonable infection and spread of the MuV-UC viruses in CT-26-LacZ mouse colon carcinoma cell and N2A mouse neuroblastoma cells in-vitro. In the CT-26-LacZ immunocompetent model, wild-type and recombinant MuV-UC viruses showed significant tumor suppression, delay in tumor growth, and also statistically significant increase in survival rate. But we could not detect any significant viral replication in the tumor tissue by immunostaining (data not shown) probably due to the cellular restriction of mumps virus infection in the tumor tissue. The tumor suppression we observed might be due to an antitumor immunity induced by the initial viral replication in the tumor tissue and it requires more detailed investigation. We noticed that wild-type MuV-UC performed better than the GFP expressing recombinant rMuV-UC-GFP virus. We suspected that GFP might have slowed down the replication of virus in vivo even though its replication rate is better in in-vitro. We have noticed this kind of phenomenon in other oncolytic studies. To improve the performance of GFP expressing mumps virus, we made a mutation in the polymerase gene (N13328H). The mutant virus, rMuV-UC-L13328-GFP replicated to a higher titer compared with rMuV-UC-GFP in Vero cells and we subsequently used this recombinant virus. We then tested the oncolytic efficacy of mumps virus in mouse neuroblastoma immunocompetent model. Since tumor growth is extremely aggressive, most of the mice reached sacrifice criteria within a week. Due to the aggressive nature of this tumor, immunotherapeutic potential of mumps virus could not be observed. No difference was noticed in tumor growth or survival rate compared with the control group, although one mouse survived in the rMuV-UC-L13328-GFP treated group. This study demonstrated that this particular neuroblastoma tumor model may not be suitable for mumps virus oncolytic studies due to its inherent, biologically specific properties like growth rate, host species, antiviral status, etc. Finally, in an immune compromised human xenograft model, subcutaneously implanted KAS6/1 myeloma cells were treated with single i.v. injection of mumps virus. Although wild-type MuV-UC virus caused significant delay in tumor growth, the survival rate is similar to that of recombinant viruses. In this study, KAS6/1 cells took more than a month to establish recognizable subcutaneous tumor, we suspected that there might be an issue with the particular clone of KAS6/1 cells. In our future studies we plan to use different clone of KAS6/1 cells and also other human cancer lines, especially in systemic tumor models. In this study, we present initial data demonstrating the recombinant mumps viruses based on the Urabe strain which was used to treat cancer patients in Japan, have oncolytic activity in various tumor cell lines in vitro and some efficacy in preliminary pilot animal tumor models. More detailed in-vitro and in-vivo studies should be carried out to understand the true nature of this virus. We have isolated various clones of Urabe mumps virus from the initial stock and we will compare those clones for the growth potential and oncolytic efficacy. Initial clinical study conducted by Dr. Asada showed highly significant oncolytic activity in various human cancers. Although later trials demonstrated oncolytic and immunotherapeutic potential of mumps virus, nothing was as dramatic as the initial trial. We assume that this was probably due to loss of virulence while passaging the virus in cell culture. Initial studies utilized wild-type virus with minimal passage, which might have maintained virulent species that had replicated better in cancer patients. Later trials might have used highly passaged virus which probably might have lost its virulence that lead to lower efficacy compared with the initial trial. In this study, we have used plaque purified single clone which is most probably less virulent than the original stock. This may be one of the reasons why we could not see better efficacy in our animal s" @default.
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- W2507708049 title "Recombinant mumps virus as a cancer therapeutic agent" @default.
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