{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T20:04:29Z","timestamp":1785355469127,"version":"3.55.0"},"reference-count":55,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T00:00:00Z","timestamp":1675382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council Taiwan","award":["111-2115-M-126-002"],"award-info":[{"award-number":["111-2115-M-126-002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Oncolytic ability to direct target and lyse tumor cells makes oncolytic virus therapy (OVT) a promising approach to treating cancer. Despite its therapeutic potential to stimulate anti-tumor immune responses, it also has immunosuppressive effects. The efficacy of OVTs as monotherapies can be enhanced by appropriate adjuvant therapy such as anti-CTLA-4. In this paper, we propose a mathematical model to explore the interactions of combined therapy of oncolytic viruses and a checkpoint inhibitor, anti-CTLA-4. The model incorporates both the susceptible and infected tumor populations, natural killer cell population, virus population, tumor-specific immune populations, virus-specific immune populations, tumor suppressive cytokine IFN-g, and the effect of immune checkpoint inhibitor CTLA-4. In particular, we distinguish the tumor-specific immune abilities of CD8+ T, NK cells, and CD4+ T cells and describe the destructive ability of cytokine on tumor cells as well as the inhibitory capacity of CTLA-4 on various components. Our model is validated through the experimental results. We also investigate various dosing strategies to improve treatment outcomes. Our study reveals that tumor killing rate by cytokines, cytokine decay rate, and tumor growth rate play important roles on both the OVT monotherapy and the combination therapy. Moreover, parameters related to CD8+ T cell killing have a large impact on treatment outcomes with OVT alone, whereas parameters associated with IFN-g strongly influence treatment responses for the combined therapy. We also found that virus killing by NK cells may halt the desired spread of OVs and enhance the probability of tumor escape during the treatment. Our study reveals that it is the activation of host anti-tumor immune system responses rather than its direct destruction of the tumor cells plays a major biological function of the combined therapy.<\/jats:p>","DOI":"10.3390\/cells12030507","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T04:25:28Z","timestamp":1675657528000},"page":"507","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Exploring the Interactions of Oncolytic Viral Therapy and Immunotherapy of Anti-CTLA-4 for Malignant Melanoma Mice Model"],"prefix":"10.3390","volume":"12","author":[{"given":"Jui-Ling","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Data Science and Big Data Analytics, Providence University, Taichung City 43301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia R.-J.","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Statistics, Texas Tech University, Lubbock, TX 79409, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwei-Yan","family":"Liu","sequence":"additional","affiliation":[{"name":"National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli County 53053, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.2147\/OV.S39609","article-title":"Oncolytic virotherapy: The questions and the promise","volume":"2","author":"Aurelian","year":"2013","journal-title":"Oncolytic Virother."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/bjc.2015.481","article-title":"Oncolytic viruses: Finally delivering","volume":"114","author":"Seymour","year":"2016","journal-title":"Br. J. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1158\/2326-6066.CIR-14-0015","article-title":"Oncolytic viruses and their application to cancer immunotherapy","volume":"2","author":"Chiocca","year":"2014","journal-title":"Cancer Immunol. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/gt.2011.176","article-title":"Targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody specific for CTLA-4","volume":"19","author":"Dias","year":"2012","journal-title":"Gene Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1038\/mt.2014.160","article-title":"CTLA-4 and PD-L1 Checkpoint Blockade Enhances Oncolytic Measles Virus Therapy","volume":"22","author":"Engeland","year":"2014","journal-title":"Mol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/s13045-020-00922-1","article-title":"Oncolytic viruses for cancer immunotherapy","volume":"13","author":"Hemminki","year":"2020","journal-title":"J. Hematol. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1097\/COC.0000000000000239","article-title":"CTLA-4 and PD-1 Pathways Similarities, Differences, and Implications of Their Inhibition","volume":"39","author":"Buchbinder","year":"2016","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_8","unstructured":"(2022, March 01). CTLA-4. Available online: https:\/\/en.wikipedia.org\/wiki\/CTLA-4."},{"key":"ref_9","unstructured":"(2022, March 01). Ipilimumab. Available online: https:\/\/en.wikipedia.org\/wiki\/Ipilimumab."},{"key":"ref_10","unstructured":"Pollack, A. (The New York Times, 2011). Approval for Drug That Treats Melanoma, The New York Times."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1056\/NEJMe1205943","article-title":"Tumor immunotherapy directed at PD-1","volume":"366","author":"Ribas","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"15","DOI":"10.2147\/OTT.S4833","article-title":"CTLA-4 blockade: Therapeutic potential in cancer treatments","volume":"3","author":"Tarhini","year":"2010","journal-title":"Onco Targets Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1038\/bjc.2013.117","article-title":"Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer","volume":"108","author":"Quezada","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"683","DOI":"10.3389\/fimmu.2020.00683","article-title":"Combining Oncolytic Viruses With Cancer Immunotherapy: Establishing a New Generation of Cancer Treatment","volume":"11","author":"Shi","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Mahasa, K.J., Eladdadi, A., de Pillis, L., and Ouifki, R. (2017). Oncolytic potency and reduced virus tumor specificity in oncolytic virotherapy. A mathematical modelling approach. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0184347"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2932","DOI":"10.1007\/s11538-011-9653-5","article-title":"Multi-stability and multi-instability phenomena in a mathematical model of tumor-immune-virus interactions","volume":"73","author":"Eftimie","year":"2011","journal-title":"Bull. Math. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s11538-021-00903-6","article-title":"Natural Killer Cells Recruitment in Oncolytic Virotherapy: A Mathematical Model","volume":"83","author":"Senekal","year":"2021","journal-title":"Bull. Math. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Storey, K.M., and Jackson, T.L. (2021). An Agent-Based Model of Combination Oncolytic Viral Therapy and Anti-PD-1 Immunotherapy Reveals the Importance of Spatial Location When Treating Glioblastoma. Cancers, 13.","DOI":"10.3390\/cancers13215314"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1098\/rsif.2006.0195","article-title":"Dynamics of killer T cell inflation in viral infections","volume":"4","author":"Wodarz","year":"2007","journal-title":"J. R. Soc. Interface"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/gene.2013.57","article-title":"Differential CTLA-4 expression in human CD4+ versus CD8+ T cells is associated with increased NFAT1 and inhibition of CD4+ proliferation","volume":"15","author":"Chan","year":"2014","journal-title":"Genes Immun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4330","DOI":"10.1002\/mma.3370","article-title":"Qualitative behavior of systems of tumor\u2013CD4+\u2013cytokine interactions with treatments","volume":"38","author":"Anderson","year":"2015","journal-title":"Math. Methods Appl. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1084\/jem.20021683","article-title":"Immunotherapy of cytotoxic T cell-resistant tumors by T helper 2 cells: An eotaxin and STAT6-dependent process","volume":"197","author":"Mattes","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5346","DOI":"10.1182\/blood-2006-10-051318","article-title":"CD4 cells can be more efficient at tumor rejection than CD8 cells","volume":"109","author":"Joncker","year":"2007","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1002\/eji.200839152","article-title":"CD4 T-cell-mediated anti-tumor immunity can be uncoupled from autoimmunity via the STAT4\/STAT6 signaling axis","volume":"39","author":"Zhang","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1084\/jem.20091918","article-title":"Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts","volume":"207","author":"Quezada","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jtbi.2015.04.004","article-title":"Memory versus effector immune responses in oncolytic virotherapies","volume":"377","author":"Macnamara","year":"2015","journal-title":"J. Theor. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"124523","DOI":"10.1016\/j.amc.2019.06.037","article-title":"A mathematical model of tumor-immune interactions with an immune checkpoint inhibitor","volume":"362","author":"Yu","year":"2019","journal-title":"Appl. Math. Comput."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ma, Y., Li, X., and Kuang, E. (2016). Viral Evasion of Natural Killer Cell Activation. Viruses, 8.","DOI":"10.3390\/v8040095"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"151","DOI":"10.3389\/fphys.2020.00151","article-title":"Modeling Oncolytic Viral Therapy, Immune Checkpoint Inhibition, and the Complex Dynamics of Innate and Adaptive Immunity in Glioblastoma Treatment","volume":"11","author":"Storey","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"17292","DOI":"10.1073\/pnas.1004879107","article-title":"IFN-\u03b3 produced by CD8 T cells induces T-bet\u2013dependent and \u2013independent class switching in B cells in responses to alum-precipitated protein vaccine","volume":"107","author":"Mohr","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1615\/CritRevImmunol.2016017387","article-title":"Metabolic Regulation of Natural Killer Cell IFN-\u03b3 Production","volume":"36","author":"Mah","year":"2016","journal-title":"Crit. Rev. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3013","DOI":"10.1073\/pnas.042684699","article-title":"Cytotoxic T lymphocyte antigen-4 (CTLA-4) limits the expansion of encephalitogenic T cells in experimental autoimmune encephalomyelitis (EAE)-resistant BALB\/c mice","volume":"99","author":"Hurwitz","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.omto.2020.02.001","article-title":"NK cells augment oncolytic adenovirus cytotoxicity in ovarian cancer","volume":"16","author":"Leung","year":"2020","journal-title":"Mol. Ther. Oncolytics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.jtbi.2016.06.021","article-title":"A mathematical prognosis model for pancreatic cancer patients receiving immunotherapy","volume":"406","author":"Li","year":"2016","journal-title":"J. Theor. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.30707\/LiB5.2Eftimiea","article-title":"Tumour-associated macrophages and oncolytic virotherapies: A mathematical investigation into a complex dynamics","volume":"5","author":"Eftimie","year":"2018","journal-title":"Lett. Biomath."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.jtbi.2010.04.030","article-title":"Modeling anti-tumor Th1 and Th2 immunity in the rejection of melanoma","volume":"265","author":"Eftimie","year":"2010","journal-title":"J. Theor. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.jtbi.2008.01.016","article-title":"Modeling of cancer virotherapy with recombinant measles viruses","volume":"252","author":"Bajzer","year":"2008","journal-title":"J. Theor. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1038\/cgt.2009.40","article-title":"Dynamics of multiple myeloma tumor therapy with a recombinant measles virus","volume":"16","author":"Dingli","year":"2009","journal-title":"Cancer Gene Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5931","DOI":"10.4049\/jimmunol.175.9.5931","article-title":"IFN-\u03b3 Production by CD8+ T Cells Depends on NFAT1 Transcription Factor and Regulates Th Differentiation","volume":"175","author":"Texeira","year":"2005","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2852","DOI":"10.1002\/mma.7958","article-title":"A model of tumor-immune system interactions with healthy cells and immunotherapies","volume":"45","author":"Yu","year":"2022","journal-title":"Math. Methods Appl. Sci."},{"key":"ref_41","unstructured":"Jaffe, J.B. (2016). Characterizing and Modulating the Canine T-Cell Costimulatory Molecules CTLA-4 and CD28. [Master\u2019s Thesis, University of Washington]."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1142\/S0218339008002435","article-title":"Optimal control of mixed immunotherapy and chemotherapy of tumors","volume":"16","author":"Fister","year":"2008","journal-title":"J. Biol. Syst."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s10441-019-09357-9","article-title":"Investigating Macrophages Plasticity Following Tumour\u2013Immune Interactions During Oncolytic Therapies","volume":"67","author":"Eftimie","year":"2019","journal-title":"Acta Biotheor."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.matcom.2022.02.028","article-title":"Bifurcations and multistability in a virotherapy model with two time delays","volume":"198","author":"Dai","year":"2022","journal-title":"Math. Comput. Simul."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Komarova, N.L., and Wodarz, D. (2014). Targeted Cancer Treatment in Silico: Small Molecule Inhibitors and Oncolytic Viruses (Modeling and Simulation in Science, Engineering and Technology), Birkh\u00e4user.","DOI":"10.1007\/978-1-4614-8301-4"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"505","DOI":"10.4161\/cc.8.3.7608","article-title":"Does the cell number 10(9) still really fit one gram of tumor tissue?","volume":"8","author":"Monte","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.jtbi.2008.04.011","article-title":"A Methodology For Performing Global Uncertainty In addition, Sensitivity Analysis In Systems Biology","volume":"254","author":"Marino","year":"2008","journal-title":"J. Theor. Biol."},{"key":"ref_48","first-page":"239","article-title":"A Comparison of Three Methods for Selecting Values of Input Variables in the Analysis of Output from a Computer Code","volume":"21","author":"McKay","year":"1979","journal-title":"Technometrics"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"275","DOI":"10.3389\/fimmu.2020.00275","article-title":"Unleashing natural killer cells in the tumor microenvironment-the next generation of immunotherapy?","volume":"11","author":"Biber","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"702","DOI":"10.3389\/fonc.2020.00702","article-title":"Effective treatment of glioblastoma multiforme with oncolytic virotherapy: A case-series","volume":"10","author":"Gesundheit","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4927","DOI":"10.1073\/pnas.1715295115","article-title":"Complex role of NK cells in regulation of oncolytic virus-bortezomib therapy","volume":"115","author":"Kim","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1093\/jnci\/djt111","article-title":"Awaiting a moment of truth for oncolytic viruses","volume":"105","author":"Schmidt","year":"2013","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.immuni.2017.12.007","article-title":"NKp46 Receptor-Mediated Interferon-\u03b3 Production by Natural Killer Cells Increases Fibronectin 1 to Alter Tumor Architecture and Control Metastasis","volume":"48","author":"Glasner","year":"2018","journal-title":"Immunity"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3695","DOI":"10.4049\/jimmunol.1501997","article-title":"TLR-Mediated Innate Production of IFN-\u03b3 by CD8+ T Cells Is Independent of Glycolysis","volume":"196","author":"Salerno","year":"2016","journal-title":"J. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/s41577-019-0221-9","article-title":"Defining \u2018T cell exhaustion\u2019","volume":"19","author":"Blank","year":"2019","journal-title":"Nat. Rev. Immunol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/3\/507\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:23:30Z","timestamp":1760120610000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/3\/507"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,3]]},"references-count":55,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["cells12030507"],"URL":"https:\/\/doi.org\/10.3390\/cells12030507","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,3]]}}}