{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T01:07:07Z","timestamp":1785460027738,"version":"3.56.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010076","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T00:00:00Z","timestamp":1671494400000}}],"reference-count":37,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T00:00:00Z","timestamp":1670284800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["ERC Advanced Grant No. 789240"],"award-info":[{"award-number":["ERC Advanced Grant No. 789240"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"CAPES","doi-asserted-by":"crossref","award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Abel Tasman Talent Program scholarship","award":["PhD Scholarship"],"award-info":[{"award-number":["PhD Scholarship"]}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Oncolytic virotherapy is a promising form of cancer treatment that uses native or genetically engineered viruses to target, infect and kill cancer cells. Unfortunately, this form of therapy is not effective in a substantial proportion of cancer patients, partly due to the occurrence of infection-resistant tumour cells. To shed new light on the mechanisms underlying therapeutic failure and to discover strategies that improve therapeutic efficacy we designed a cell-based model of viral infection. The model allows us to investigate the dynamics of infection-sensitive and infection-resistant cells in tumour tissue in presence of the virus. To reflect the importance of the spatial configuration of the tumour on the efficacy of virotherapy, we compare three variants of the model: two 2D models of a monolayer of tumour cells and a 3D model. In all model variants, we systematically investigate how the therapeutic outcome is affected by the properties of the virus (e.g. the rate of viral spread), the tumour (e.g. production rate of resistant cells, cost of resistance), the healthy stromal cells (e.g. degree of resistance to the virus) and the timing of treatment. We find that various therapeutic outcomes are possible when resistant cancer cells arise at low frequency in the tumour. These outcomes depend in an intricate but predictable way on the death rate of infected cells, where faster death leads to rapid virus clearance and cancer persistence. Our simulations reveal three different causes of therapy failure: rapid clearance of the virus, rapid selection of resistant cancer cells, and a low rate of viral spread due to the presence of infection-resistant healthy cells. Our models suggest that improved therapeutic efficacy can be achieved by sensitizing healthy stromal cells to infection, although this remedy has to be weighed against the toxicity induced in the healthy tissue.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010076","type":"journal-article","created":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T14:08:54Z","timestamp":1670335734000},"page":"e1010076","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["Modelling the spatial dynamics of oncolytic virotherapy in the presence of virus-resistant tumour cells"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0923-2353","authenticated-orcid":true,"given":"Darshak Kartikey","family":"Bhatt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4162-1140","authenticated-orcid":true,"given":"Thijs","family":"Janzen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0166-512X","authenticated-orcid":true,"given":"Toos","family":"Daemen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3281-663X","authenticated-orcid":true,"given":"Franz J.","family":"Weissing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,12,6]]},"reference":[{"key":"pcbi.1010076.ref001","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.cell.2020.03.001","article-title":"The Emerging Landscape of Immune Cell Therapies","volume":"181","author":"EW Weber","year":"2020","journal-title":"Cell"},{"key":"pcbi.1010076.ref002","article-title":"Oncolytic viruses as engineering platforms for combination immunotherapy","author":"K Twumasi-Boateng","year":"2018","journal-title":"Nature Reviews Cancer"},{"key":"pcbi.1010076.ref003","article-title":"A systematic analysis on the clinical safety and efficacy of Onco-Virotherapy","author":"DK Bhatt","year":"2021","journal-title":"Molecular Therapy\u2014Oncolytics"},{"key":"pcbi.1010076.ref004","article-title":"Down-regulation of type I interferon receptor sensitizes bladder cancer cells to vesicular stomatitis virus-induced cell death","author":"K Zhang","year":"2010","journal-title":"Int J Cancer"},{"key":"pcbi.1010076.ref005","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1517\/14712590903170653","article-title":"Engineering oncolytic viruses to exploit tumor specific defects in innate immune signaling pathways","volume":"9","author":"S Naik","year":"2009","journal-title":"Expert Opinion on Biological Therapy"},{"key":"pcbi.1010076.ref006","doi-asserted-by":"crossref","first-page":"e001486","DOI":"10.1136\/jitc-2020-001486","article-title":"Clinical landscape of oncolytic virus research in 2020","volume":"8","author":"N Macedo","year":"2020","journal-title":"J Immunother Cancer"},{"key":"pcbi.1010076.ref007","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.omto.2019.10.007","article-title":"Oncolytic Viruses for Cancer Therapy: Barriers and Recent Advances.","volume":"15","author":"M Zheng","year":"2019","journal-title":"Molecular Therapy\u2014Oncolytics"},{"key":"pcbi.1010076.ref008","first-page":"21","article-title":"Assessing and Overcoming Resistance Phenomena against a Genetically Modified Vaccinia Virus in Selected Cancer Cell Lines.","author":"S Berchtold","year":"2020","journal-title":"Int J Mol Sci"},{"key":"pcbi.1010076.ref009","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1038\/srep02375","article-title":"Induction of antiviral genes by the tumor microenvironment confers resistance to virotherapy","volume":"3","author":"Y-P Liu","year":"2013","journal-title":"Sci Rep"},{"key":"pcbi.1010076.ref010","article-title":"STING and IRF3 in stromal fibroblasts enable sensing of genomic stress in cancer cells to undermine oncolytic viral therapy","author":"EN Arwert","year":"2020","journal-title":"Nat Cell Biol"},{"key":"pcbi.1010076.ref011","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.3390\/vaccines9101166","article-title":"Resistance Mechanisms Influencing Oncolytic Virotherapy, a Systematic Analysis.","volume":"9","author":"DK Bhatt","year":"2021","journal-title":"Vaccines"},{"key":"pcbi.1010076.ref012","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1158\/0008-5472.CAN-08-2173","article-title":"A multiscale mathematical model for oncolytic virotherapy","volume":"69","author":"LR Paiva","year":"2009","journal-title":"Cancer Res"},{"key":"pcbi.1010076.ref013","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1039\/B917597K","article-title":"In silico evolutionary dynamics of tumour virotherapy","volume":"2","author":"CL Reis","year":"2010","journal-title":"Integr Biol (Camb)."},{"key":"pcbi.1010076.ref014","doi-asserted-by":"crossref","first-page":"e1002547","DOI":"10.1371\/journal.pcbi.1002547","article-title":"Complex Spatial Dynamics of Oncolytic Viruses In Vitro: Mathematical and Experimental Approaches","volume":"8","author":"D Wodarz","year":"2012","journal-title":"PLoS Comput Biol."},{"key":"pcbi.1010076.ref015","doi-asserted-by":"crossref","first-page":"110052","DOI":"10.1016\/j.jtbi.2019.110052","article-title":"Enhancing oncolytic virotherapy: Observations from a Voronoi Cell-Based model","volume":"485","author":"AL Jenner","year":"2020","journal-title":"Journal of Theoretical Biology"},{"key":"pcbi.1010076.ref016","doi-asserted-by":"crossref","first-page":"e1006773","DOI":"10.1371\/journal.pcbi.1006773","article-title":"In vitro and in silico multidimensional modeling of oncolytic tumor virotherapy dynamics","volume":"15","author":"DR Berg","year":"2019","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1010076.ref017","doi-asserted-by":"crossref","first-page":"e1005241","DOI":"10.1371\/journal.pcbi.1005241","article-title":"Complex Dynamics of Virus Spread from Low Infection Multiplicities: Implications for the Spread of Oncolytic Viruses","volume":"13","author":"IA Rodriguez-Brenes","year":"2017","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1010076.ref018","first-page":"92","article-title":"Secretome Screening Reveals Fibroblast Growth Factors as Novel Inhibitors of Viral Replication","author":"SD van Asten","year":"2018","journal-title":"J Virol"},{"key":"pcbi.1010076.ref019","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/BF01840357","article-title":"A sweepline algorithm for Voronoi diagrams","volume":"2","author":"S. Fortune","year":"1987","journal-title":"Algorithmica"},{"key":"pcbi.1010076.ref020","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1021\/j100540a008","article-title":"Exact stochastic simulation of coupled chemical reactions","volume":"81","author":"DT Gillespie","year":"1977","journal-title":"J Phys Chem"},{"key":"pcbi.1010076.ref021","doi-asserted-by":"crossref","first-page":"10123","DOI":"10.1128\/JVI.01102-12","article-title":"Cell-free transmission of human adenovirus by passive mass transfer in cell culture simulated in a computer model","volume":"86","author":"A Yakimovich","year":"2012","journal-title":"J Virol"},{"key":"pcbi.1010076.ref022","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1038\/nrmicro1972","article-title":"Avoiding the void: cell-to-cell spread of human viruses","volume":"6","author":"Q. Sattentau","year":"2008","journal-title":"Nat Rev Microbiol"},{"key":"pcbi.1010076.ref023","first-page":"1317","article-title":"Validation and analysis of a mathematical model of a replication-competent oncolytic virus for cancer treatment: implications for virus design and delivery","volume":"63","author":"LM Wein","year":"2003","journal-title":"Cancer Res"},{"key":"pcbi.1010076.ref024","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/cgt.2013.78","article-title":"Different responses of human pancreatic adenocarcinoma cell lines to oncolytic Newcastle disease virus infection","volume":"21","author":"PRA Buijs","year":"2014","journal-title":"Cancer Gene Ther"},{"key":"pcbi.1010076.ref025","doi-asserted-by":"crossref","first-page":"71249","DOI":"10.18632\/oncotarget.19531","article-title":"Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy","volume":"8","author":"RFV Medrano","year":"2017","journal-title":"Oncotarget"},{"key":"pcbi.1010076.ref026","doi-asserted-by":"crossref","first-page":"872","DOI":"10.4161\/cbt.6.6.4088","article-title":"Interferon-\u03b1 Induces TRAIL Expression and Cell Death Via an IRF-1-Dependent Mechanism in Human Bladder Cancer Cells.","volume":"6","author":"A Papageorgiou","year":"2007","journal-title":"Cancer Biology & Therapy"},{"key":"pcbi.1010076.ref027","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/ijc.20236","article-title":"Interferon receptor expression regulates the antiproliferative effects of interferons on cancer cells and solid tumors","volume":"111","author":"TC Wagner","year":"2004","journal-title":"Int J Cancer"},{"key":"pcbi.1010076.ref028","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1038\/s41586-019-1730-1","article-title":"A view on drug resistance in cancer","volume":"575","author":"N Vasan","year":"2019","journal-title":"Nature"},{"key":"pcbi.1010076.ref029","doi-asserted-by":"crossref","first-page":"104395","DOI":"10.1016\/j.isci.2022.104395","article-title":"Agent-based computational modeling of glioblastoma predicts that stromal density is central to oncolytic virus efficacy","volume":"25","author":"AL Jenner","year":"2022","journal-title":"iScience"},{"key":"pcbi.1010076.ref030","doi-asserted-by":"crossref","first-page":"5314","DOI":"10.3390\/cancers13215314","article-title":"An Agent-Based Model of Combination Oncolytic Viral Therapy and Anti-PD-1 Immunotherapy Reveals the Importance of Spatial Location When Treating Glioblastoma","volume":"13","author":"KM Storey","year":"2021","journal-title":"Cancers"},{"key":"pcbi.1010076.ref031","doi-asserted-by":"crossref","first-page":"e0184347","DOI":"10.1371\/journal.pone.0184347","article-title":"Oncolytic potency and reduced virus tumor-specificity in oncolytic virotherapy. A mathematical modelling approach","volume":"12","author":"KJ Mahasa","year":"2017","journal-title":"PLoS One"},{"key":"pcbi.1010076.ref032","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/s41417-018-0074-6","article-title":"JAK\/STAT inhibition with ruxolitinib enhances oncolytic virotherapy in non-small cell lung cancer models","volume":"26","author":"MR Patel","year":"2019","journal-title":"Cancer Gene Ther"},{"key":"pcbi.1010076.ref033","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.virol.2015.08.003","article-title":"Breaking resistance of pancreatic cancer cells to an attenuated vesicular stomatitis virus through a novel activity of IKK inhibitor TPCA-1","volume":"485","author":"M Cataldi","year":"2015","journal-title":"Virology"},{"key":"pcbi.1010076.ref034","doi-asserted-by":"crossref","first-page":"2352","DOI":"10.1158\/1078-0432.CCR-08-2082","article-title":"Mathematical modeling of herpes simplex virus distribution in solid tumors: implications for cancer gene therapy","volume":"15","author":"W Mok","year":"2009","journal-title":"Clin Cancer Res"},{"key":"pcbi.1010076.ref035","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.omtm.2019.12.013","article-title":"Point Mutations in Retargeted gD Eliminate the Sensitivity of EGFR\/EGFRvIII-Targeted HSV to Key Neutralizing Antibodies","volume":"16","author":"C Tuzmen","year":"2020","journal-title":"Mol Ther Methods Clin Dev"},{"key":"pcbi.1010076.ref036","doi-asserted-by":"crossref","first-page":"5992","DOI":"10.1158\/0008-5472.CAN-18-0447","article-title":"In Vivo Estimation of Oncolytic Virus Populations within Tumors","volume":"78","author":"M-Y Jung","year":"2018","journal-title":"Cancer Res"},{"key":"pcbi.1010076.ref037","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.ygyno.2012.01.048","article-title":"Myxoma virus-mediated oncolysis of ascites-derived human ovarian cancer cells and spheroids is impacted by differential AKT activity","volume":"125","author":"RJM Correa","year":"2012","journal-title":"Gynecol Oncol"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1010076","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T00:00:00Z","timestamp":1671494400000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010076","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T13:42:46Z","timestamp":1671543766000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010076"}},"subtitle":[],"editor":[{"given":"Philip K.","family":"Maini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,12,6]]},"references-count":37,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12,6]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1010076","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.04.06.487254","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,6]]}}}