Oncolysis by paramyxoviruses: preclinical and clinical studies
2015; Elsevier BV; Volume: 2; Linguagem: Inglês
10.1038/mto.2015.17
ISSN2372-7705
AutoresO. V. Matveeva, Zong Sheng Guo, Vyacheslav M Senin, Anna V. Senina, Svetlana A. Shabalina, Peter M. Chumakov,
Tópico(s)Herpesvirus Infections and Treatments
ResumoPreclinical studies demonstrate that a broad spectrum of human malignant cells can be killed by oncolytic paramyxoviruses, which include cells of ecto-, endo-, and mesodermal origin. In clinical trials, significant reduction in size or even complete elimination of primary tumors and established metastases are reported. Different routes of viral administration (intratumoral, intravenous, intradermal, intraperitoneal, or intrapleural), and single- versus multiple-dose administration schemes have been explored. The reported side effects are grade 1 and 2, with the most common among them being mild fever. Some advantages in using paramyxoviruses as oncolytic agents versus representatives of other viral families exist. The cytoplasmic replication results in a lack of host genome integration and recombination, which makes paramyxoviruses safer and more attractive candidates for widely used therapeutic oncolysis in comparison with retroviruses or some DNA viruses. The list of oncolytic paramyxovirus representatives includes attenuated measles virus (MV), mumps virus (MuV), low pathogenic Newcastle disease (NDV), and Sendai (SeV) viruses. Metastatic cancer cells frequently overexpress on their surface some molecules that can serve as receptors for MV, MuV, NDV, and SeV. This promotes specific viral attachment to the malignant cell, which is frequently followed by specific viral replication. The paramyxoviruses are capable of inducing efficient syncytium-mediated lyses of cancer cells and elicit strong immunomodulatory effects that dramatically enforce anticancer immune surveillance. In general, preclinical studies and phase 1–3 clinical trials yield very encouraging results and warrant continued research of oncolytic paramyxoviruses as a particularly valuable addition to the existing panel of cancer-fighting approaches. Preclinical studies demonstrate that a broad spectrum of human malignant cells can be killed by oncolytic paramyxoviruses, which include cells of ecto-, endo-, and mesodermal origin. In clinical trials, significant reduction in size or even complete elimination of primary tumors and established metastases are reported. Different routes of viral administration (intratumoral, intravenous, intradermal, intraperitoneal, or intrapleural), and single- versus multiple-dose administration schemes have been explored. The reported side effects are grade 1 and 2, with the most common among them being mild fever. Some advantages in using paramyxoviruses as oncolytic agents versus representatives of other viral families exist. The cytoplasmic replication results in a lack of host genome integration and recombination, which makes paramyxoviruses safer and more attractive candidates for widely used therapeutic oncolysis in comparison with retroviruses or some DNA viruses. The list of oncolytic paramyxovirus representatives includes attenuated measles virus (MV), mumps virus (MuV), low pathogenic Newcastle disease (NDV), and Sendai (SeV) viruses. Metastatic cancer cells frequently overexpress on their surface some molecules that can serve as receptors for MV, MuV, NDV, and SeV. This promotes specific viral attachment to the malignant cell, which is frequently followed by specific viral replication. The paramyxoviruses are capable of inducing efficient syncytium-mediated lyses of cancer cells and elicit strong immunomodulatory effects that dramatically enforce anticancer immune surveillance. In general, preclinical studies and phase 1–3 clinical trials yield very encouraging results and warrant continued research of oncolytic paramyxoviruses as a particularly valuable addition to the existing panel of cancer-fighting approaches. IntroductionThe idea of using viruses in the treatment of malignancies dates back to the beginning of the 20th century when reports on cases of spontaneous tumor regression after viral diseases or vaccination started to appear.1Dock G The influence of complicating diseases upon leukemia.Am J Med Sci. 1904; 127: 563-592Crossref Google Scholar, 2De Pace N Sulla scomparsa di un enorme cancro vegetante del collo dell'utero senza cura chirurgica.Ginecologia. 1912; 9: 82-89Google Scholar, 3Levaditi C Nicolau S Vaccine et neoplasmes.Ann Inst Pasteur. 1923; 37: 443-447Google Scholar, 4Farber S Diamond LK Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid.N Engl J Med. 1948; 238: 787-793Crossref PubMed Google Scholar, 5Svejda J [Viruses and tumors].Lek List. 1950; 5: 688-689PubMed Google Scholar, 6Moore AE Effects of viruses on tumors.Annu Rev Microbiol. 1954; 8: 393-410Crossref PubMed Google Scholar However, it took several decades of intense studies of the complex relations between viruses and their hosts before viruses started to be considered as potential tools for cancer therapy.7Kelly E Russell SJ History of oncolytic viruses: genesis to genetic engineering.Mol Ther. 2007; 15: 651-659Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar Modern studies on oncolytic viruses represent a dynamic and exciting field that absorbs the most recent discoveries in molecular, cell, and cancer biology. Viruses can be quickly modified by recombinant DNA technology thereby rapidly incorporating the fast growing knowledge into oncolytic virus design. The studies involve a wide array of virus species belonging to diverse viral families, such as adenoviruses, herpesviruses, parvoviruses, enteroviruses, reoviruses, rhabdoviruses, paramyxoviruses, myxoviruses, alphaviruses, and poxviruses. Examples of clinical trials include a phase 2 trial of reovirus in combination with chemotherapy in patients with head and neck cancer8Karapanagiotou EM Roulstone V Twigger K Ball M Tanay M Nutting C et al.Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus in patients with advanced malignancies.Clin Cancer Res. 2012; 18: 2080-2089Crossref PubMed Scopus (0) Google Scholar and a phase 2 trial of genetically engineered oncolytic poxvirus JX-594 in patients with hepatocellular carcinoma.9Heo J Reid T Ruo L Breitbach CJ Rose S Bloomston M et al.Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer.Nat Med. 2013; 19: 329-336Crossref PubMed Scopus (0) Google Scholar These trials confirm that oncolytic viruses do not produce substantial side effects and have considerable antitumor efficacy that affects the overall patient survival.Recently, the first oncolytic virus treatment in the United States was authorized by the Federal Drug Administration. Government agency approval was granted after completion of phase 1–3 trials that enrolled metastatic melanoma patients. The first oncolytic virus approved by the Federal Drug Administration is a herpes simplex virus-1 construct that encodes human granulocyte-macrophage colony-stimulating factor (GM-CSF).10Dolgin E Oncolytic viruses get a boost with first FDA-approval recommendation.Nat Rev Drug Discov. 2015; 14: 369-371Crossref PubMed Scopus (0) Google ScholarInnate barriers against viral infection exist at the molecular, cellular, tissue, and organism levels. Ordered tissue organization provides strong protection against virus penetration and spreading. In contrast, cancer cells form disordered structures, which are virus accessible. They lose their duties in the organism and form a separate foreign tissue (tumor) with the sole selfish function of accelerated expansion. The transition makes cells of a tumor a preferable substrate for oncolytic viruses in general and paramyxoviruses in particular (Box 1).Box 1•Loss of normal tissue architecture eliminates the important physical barriers that efficiently contain virus spreading in the organism. Cancer tumor vasculature is generally abnormal and leaky,11De Bock K Cauwenberghs S Carmeliet P Vessel abnormalization: another hallmark of cancer? Molecular mechanisms and therapeutic implications.Curr Opin Genet Dev. 2011; 21: 73-79Crossref PubMed Scopus (0) Google Scholar which potentially favors virus spreading through the tumor mass.12Ogris M Nucleic acid therapeutics: concepts for targeted delivery to solid tumors.Ther Deliv. 2010; 1: 91-107Crossref PubMed Scopus (0) Google Scholar•The surface of a cancer cell often overexpresses certain transmembrane proteins that serve as receptors for viruses. 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Cancer cells already have high metabolic rate and therefore efficiently support propagation of viruses even if they have defects in the host-modifying functions. In response to viral infection, normal cells trigger p53-dependent suicidal programs that kill the abnormal (infected) cells before they start shedding viral progeny.26Bian T Gibbs JD Örvell C Imani F Respiratory syncytial virus matrix protein induces lung epithelial cell cycle arrest through a p53 dependent pathway.PLoS One. 2012; 7: e38052Crossref PubMed Google Scholar, 27Muñoz-Fontela C Macip S Martínez-Sobrido L Brown L Ashour J García-Sastre A et al.Transcriptional role of p53 in interferon-mediated antiviral immunity.J Exp Med. 2008; 205: 1929-1938Crossref PubMed Scopus (0) Google Scholar, 28Rivas C Aaronson SA Munoz-Fontela C Dual Role of p53 in Innate Antiviral Immunity.Viruses. 2010; 2: 298-313Crossref PubMed Scopus (0) Google Scholar, 29Takaoka A Hayakawa S Yanai H Stoiber D Negishi H Kikuchi H et al.Integration of interferon-alpha/beta signalling to p53 responses in tumour suppression and antiviral defence.Nature. 2003; 424: 516-523Crossref PubMed Scopus (525) Google Scholar, 30Zheltukhin AO Chumakov PM Constitutive and induced functions of the p53 gene.Biochemistry (Mosc). 2010; 75: 1692-1721Crossref PubMed Scopus (0) Google Scholar Functional p53 is commonly lost through different mechanisms in cancers31Chumakov PM Versatile functions of p53 protein in multicellular organisms.Biochemistry (Mosc). 2007; 72: 1399-1421Crossref PubMed Scopus (0) Google Scholar,32Levine AJ Oren M The first 30 years of p53: growing ever more complex.Nat Rev Cancer. 2009; 9: 749-758Crossref PubMed Scopus (631) Google Scholar and therefore malignant cells frequently do not commit suicide in response to viral infection and efficiently complete virus production.Virus-infected normal cells start producing interferons (IFNs) that provide antiviral protection for surrounding cells and limit virus spreading. Cancer cells are usually not only defective for the induction of IFNs, but also do not develop resistance to viruses in response to IFN treatment.In normal cells there is tight crosstalk between the IFN type 1 and p53 pathways. Acting in concert, these two pathways efficiently limit viral infection.29Takaoka A Hayakawa S Yanai H Stoiber D Negishi H Kikuchi H et al.Integration of interferon-alpha/beta signalling to p53 responses in tumour suppression and antiviral defence.Nature. 2003; 424: 516-523Crossref PubMed Scopus (525) Google Scholar,33Tanaka N Ishihara M Lamphier MS Nozawa H Matsuyama T Mak TW et al.Cooperation of the tumour suppressors IRF-1 and p53 in response to DNA damage.Nature. 1996; 382: 816-818Crossref PubMed Scopus (0) Google Scholar,34Moiseeva O Mallette FA Mukhopadhyay UK Moores A Ferbeyre G DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation.Mol Biol Cell. 2006; 17: 1583-1592Crossref PubMed Scopus (113) Google Scholar Loss of p53 functions in cancer cells voids the control mechanisms that ensure their social behavior: the p53-deficient cancer cells can be considered as separate organisms with very unstable genomes that enter the Darwinian competition/selection process. Along with mutations that promote accelerated proliferation and invasion, cancer cells get rid of functions that serve the needs of the whole organism. The induction of IFNs is compromised in multiple tumor types, in particular, through a homozygous loss of chromosome 9p21 region, which encodes type I INF genes.21Haus O The genes of interferons and interferon-related factors: localization and relationships with chromosome aberrations in cancer.Arch Immunol Ther Exp (Warsz). 2000; 48: 95-100PubMed Google ScholarFrequent loss of type I IFN response in cancer cells is greatly stimulated by the impaired function of the p53 tumor suppressor. As a transcription regulator, p53 is responsible for silencing transcription from LINE and SINE transposons. Inactivation of p53 is associated with a dramatic activation of self-complementary transcripts (double-stranded RNAs) from the widespread repetitive DNA elements such as Alu-repeats.35Leonova KI Brodsky L Lipchick B Pal M Novototskaya L Chenchik AA et al.p53 cooperates with DNA methylation and a suicidal interferon response to maintain epigenetic silencing of repeats and noncoding RNAs.Proc Natl Acad Sci USA. 2013; 110: E89-E98Crossref PubMed Scopus (61) Google Scholar The double-stranded RNAs elicit a strong type I IFN response that hinders proliferation of cancer cells thereby putting a strong selective pressure and forcing inactivation of the IFN response mechanisms so that further evolution and expansion of cancer cells35Leonova KI Brodsky L Lipchick B Pal M Novototskaya L Chenchik AA et al.p53 cooperates with DNA methylation and a suicidal interferon response to maintain epigenetic silencing of repeats and noncoding RNAs.Proc Natl Acad Sci USA. 2013; 110: E89-E98Crossref PubMed Scopus (61) Google Scholar is allowed. Cancer cells are generally better hosts for viruses as they acquire defects in the protective mechanisms that resist viral replication. The upregulation of p53 by type I IFNs plays a protective role against the emerging cancer cells.29Takaoka A Hayakawa S Yanai H Stoiber D Negishi H Kikuchi H et al.Integration of interferon-alpha/beta signalling to p53 responses in tumour suppression and antiviral defence.Nature. 2003; 424: 516-523Crossref PubMed Scopus (525) Google Scholar,34Moiseeva O Mallette FA Mukhopadhyay UK Moores A Ferbeyre G DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation.Mol Biol Cell. 2006; 17: 1583-1592Crossref PubMed Scopus (113) Google Scholar Therefore, cancer cells experience strong selection pressure against both the p53 and the type 1 IFN-mediated mechanisms. 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But the very same defects that promote tumor growth provide the opportunity to destroy cancer cells with the use of oncolytic viruses. This also relates to paramyxoviruses.For example, the oncolytic potential of measles vaccine virus (MV) in a few sarcoma cell lines was negatively correlated with upregulation of expression of RIG-I molecule and the IFN-stimulated gene IFIT1. In the MV resistant cell lines, inhibition of viral replication was going along with strong expression of these molecules. In contrast, susceptible cell lines showed a much weaker expression of IFIT1. Pretreatment with IFN-β made the susceptible cell lines more resistant to MV-mediated oncolysis.40Berchtold S Lampe J Weiland T Smirnow I Schleicher S Handgretinger R et al.Innate immune defense defines susceptibility of sarcoma cells to measles vaccine virus based oncolysis.J Virol. 2013; 9: 9Google ScholarHowever, the preferable killing of cancer cells directly by a virus is not the only mechanism of viral oncolysis. Viruses are potent inducers of innate and adaptive immune responses that greatly contribute to the process.41Bartlett DL Liu Z Sathaiah M Ravindranathan R Guo Z He Y et al.Oncolytic viruses as therapeutic cancer vaccines.Mol Cancer. 2013; 12: 103Crossref PubMed Scopus (0) Google Scholar, 42Boisgerault N Tangy F Gregoire M New perspectives in cancer virotherapy: bringing the immune system into play.Immunotherapy. 2010; 2: 185-199Crossref PubMed Scopus (0) Google Scholar, 43Prestwich RJ Errington F Diaz RM Pandha HS Harrington KJ Melcher AA et al.The case of oncolytic viruses versus the immune system: waiting on the judgment of Solomon.Hum Gene Ther. 2009; 20: 1119-1132Crossref PubMed Google ScholarBoth innate and adaptive branches of immune system act against viral spreading and persistence in the organism, which in case of oncolytic virus therapy might impose a problem. However, host immune system also recognizes and attacks cancerous cells, and viruses can greatly stimulate the process. Preclinical and clinical data suggest that oncolytic viruses can be regarded as an efficient approach to cancer immunotherapy.44Donnelly OG Errington-Mais F Steele L Hadac E Jennings V Scott K et al.Measles virus causes immunogenic cell death in human melanoma.Gene Ther. 2013; 20: 7-15Crossref PubMed Scopus (0) Google Scholar,45Sze DY Reid TR Rose SC Oncolytic virotherapy.J Vasc Interv Radiol. 2013; 24: 1115-1122Abstract Full Text Full Text PDF PubMed Google Scholar Introduction of a nonpathogenic virus strain stimulates natural immune surveillance mechanisms triggering the immune system to recognize and attack malignant cells.46Tai LH Zhang J Scott KJ de Souza CT Alkayyal AA Ananth AA et al.Perioperative influenza vaccination reduces postoperative metastatic disease by reversing surgery-induced dysfunction in natural killer cells.Clin Cancer Res. 2013; 19: 5104-5115Crossref PubMed Scopus (0) Google ScholarMany viruses, bacteria, and other pathogens have a tendency to accumulate in primary tumors and metastases.47Yu YA Shabahang S Timiryasova TM Zhang Q Beltz R Gentschev I et al.Visualization of tumors and metastases in live animals with bacteria and vaccinia virus encoding light-emitting proteins.Nat Biotechnol. 2004; 22: 313-320Crossref PubMed Scopus (246) Google Scholar While accumulated in tumors, pathogens bring into any tumor mass a lot of biological materials which is rich with foreign antigens, pathogenic RNA or DNA, and promote multiple danger signals with immuno-triggering properties. In other words, appearance of foreign proteins and genetic material in the malignant cells or near these cells in tumor masses could increase these cells visibility for the immune system.47Yu YA Shabahang S Timiryasova TM Zhang Q Beltz R Gentschev I et al.Visualization of tumors and metastases in live animals with bacteria and vaccinia virus encoding light-emitting proteins.Nat Biotechnol. 2004; 22: 313-320Crossref PubMed Scopus (246) Google Scholar Numerous cytokines, including IFNs, induced by the pathogen and virus in particular, stimulate antigen processing in immunoproteasomes and presentation of cancer specific epitopes by major histocompatability complex molecules.48Lemay CG Rintoul JL Kus A Paterson JM Garcia V Falls TJ et al.Harnessing oncolytic virus-mediated antitumor immunity in an infected cell vaccine.Mol Ther. 2012; 20: 1791-1799Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarSome oncolytic paramyxoviruses might have particular high affinity to cancer cells due to overexpression of viral receptors on their surface. NDV, mumps, and SeV use sialic acid–containing sialoglycoproteins as the cell surface receptors.49Bossart KN Fusco DL Broder CC Paramyxovirus entry.Adv Exp Med Biol. 2013; 790: 95-127Crossref PubMed Scopus (0) Google Scholar,50Matrosovich M Herrler G Klenk HD Sialic acid receptors of viruses.Top Curr Chem. 2013; 7: 73Google Scholar The abundant presence of sialoglycoproteins on the surface of cancer cells13Büll C den Brok MH Adema GJ Sweet escape: sialic acids in tumor immune evasion.Biochim Biophys Acta. 2014; 1846: 238-246Crossref PubMed Scopus (0) Google Scholar,51Büll C Stoel MA den Brok MH Adema GJ Sialic acids sweeten a tumor's life.Cancer Res. 2014; 74: 3199-3204Crossref PubMed Scopus (0) Google Scholar most likely promotes preferential association of the virus with malignant rather than with normal cells and contributes to their selective cytolytic effect in primary tumors and in metastases. UV-inactivated SeV is able to kill prostate carcinoma cells but unable to kill normal prostate epithelium cells. Perhaps, high sensitivity to SeV-mediated cell death of sialic acid–rich prostate carcinoma cells in comparison with normal prostate epithelium is explained by SeV's preferential association with malignant cells.52Kawaguchi Y Miyamoto Y Inoue T Kaneda Y Efficient eradication of hormone-resistant human prostate cancers by inactivated Sendai virus particle.Int J Cancer. 2009; 124: 2478-2487Crossref PubMed Scopus (0) Google ScholarThe attenuated measles virus (MV Edmonston strain) uses the CD46 receptor, which is a regulator of complement activation that is universally expressed in all nucleated human cells but is often overexpressed in tumor cells.53Myers R Greiner S Harvey M Soeffker D Frenzke M Abraham K et al.Oncolytic activities of approved mumps and measles vaccines for therapy of ovarian cancer.Cancer Gene Ther. 2005; 12: 593-599Crossref PubMed Scopus (33) Google Scholar MV Edmonston strain can kill cells that overexpress this receptor without significant cytopathic effect against nontransformed cells expressing low receptor levels.54Anderson BD Nakamura T Russell SJ Peng KW High CD46 receptor density determines preferential killing of tumor cells by oncolytic measles virus.Cancer Res. 2004; 64: 4919-4926Crossref PubMed Scopus (150) Google Scholar Nectin 4 has been identified as the additional receptor for MV.19Noyce RS Bondre DG Ha MN Lin LT Sisson G Tsao MS et al.Tumor cell marker PVRL4 (nectin 4) is an epithelial cell receptor for measles virus.PLoS Pathog. 2011; 7: e1002240Crossref PubMed Scopus (0) Google Scholar It is a member of adhesion receptors of the immunoglobulin super-family localized to the adherents' junctions of epithelial cells. Nectin 4 can be considered as a tumor cell marker for breast,55Fabre-Lafay S Monville F Garrido-Urbani S Berruyer-Pouyet C Ginestier C Reymond N et al.Nectin-4 is a new histological and serological tumor associated marker for breast cancer.BMC Cancer. 2007; 7: 73Crossref PubMed Scopus (0) Google Scholar lung,16Takano A Ishikawa N Nishino R Masuda K Yasui W Inai K et al.Identification of nectin-4 oncoprotein as a diagnostic and therapeutic target for lung cancer.Cancer Res. 2009; 69: 6694-6703Crossref PubMed Scopus (0) Google Scholar and ovarian cancers,17Derycke MS Pambuccian SE Gilks CB Kalloger SE Ghidouche A Lopez M et al.Nectin 4 overexpression in ovarian cancer tissues and serum: potential role as a serum biomarker.Am J Clin Pathol. 2010; 134: 835-845Crossref PubMed Scopus (0) Google Scholar suggesting that it can be partially responsible for the selectivity of MV toward cancer cells.Are there any advantages in using paramyxoviruses versus representatives of other viral families as oncolytic agents? Recently published review56Matveeva OV Guo ZS Shabalina SA Chumakov PM Oncolysis by paramyxoviruses: multiple mechanisms contribute to therapeutic efficiency.Molecular Therapy — Oncolytics. 2015; 2 (doi:10.1038/mto.2015.11): 15011Abstract Full Text Full Text PDF PubMed Google Scholar analyzes these advantages in detail, while a brief description of some of the advantages is provided below.A potential unique advantage of some paramyxoviruses is the sialidase (neuraminidase) activity of their HN protein, which has the potential to remove sialic residues from the surface of tumor cells.57Kingsbury DW The Paramyxoviruses. Plenum Press, New York1991Crossref Google Scholar,58Enders G Paramyxoviruses. University of Texas Medical Branch at Galveston, Galveston1996Google Scholar Metastatic cancer cells often express a high density of sialic acid-rich glycoproteins that increase the invasive potential.13Büll C den Brok MH Adema GJ Sweet escape: sialic acids in tumor immune evasion.Biochim Biophys Acta. 2014; 1846: 238-246Crossref PubMed Scopus (0) Google ScholarOne of the possible mechanisms linking the increased sialylation with malignant phenotype is the creation of a thick "coat" on the cell surface that hides cancer antigens and provides an escape of malignant cells from the immunosurveillance. Removing some sialic acid residues from the surface of malignant cells by sialidase can unmask cancer specific antigens and make cells visible to the immune system. The removal of sialic acids from tumor cells is associated with a reduced growth potential, an activation of NK cells, and a secretion of IFN-γ.59Cohen M Elkabets M Perlmutter M Porgador A Voronov E Apte RN et al.Sialylation of 3-methylcholanthrene-induced fibrosarcoma determines antitumor immune responses during immunoediting.J Immunol. 2010; 185: 5869-5878Crossref PubMed Scopus (0) Google Scholar The HN proteins present in SeV, NDV, and some other paramyxoviruses possess neuraminidase (sialidase) activities.57Kingsbury DW The Paramyxoviruses. Plenum Press, New York1991Crossref Google Scholar,58Enders G Paramyxoviruses. University of Texas Medical Branch at Galveston, Galveston1996Google Scholar Neuraminidase is capable of cleaving and removing sialic acid residues from the surface of malignant cells leading to a dramatic increase in their ability to induce the T-cell response.60Powell LD Whiteheart SW Hart GW Cell surface sialic acid influences tumor cell recognition in the mixed lymphocyte reaction.J Immunol. 1987; 139: 262-270PubMed Google ScholarSome oncolytic viruses including paramyxoviruses are capable of inducing syncytia formation. During this process, infected and neighboring cells (up to 50 or even 100) are fusing with each other and are forming large multinucleated cells.61Galanis E Therapeutic potential of oncolytic measles virus: promises and challenges.Clin Pharmacol Ther. 2010; 88: 620-625Crossref PubMed Scopus (0) Google Scholar We believe that the ability to trigger syncytium formation is another great advantage of oncolytic paramyxoviruses. Syncytium formation
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