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dc.contributor.authorMüller, LME
dc.contributor.authorHolmes, M
dc.contributor.authorMichael, JL
dc.contributor.authorScott, GB
dc.contributor.authorWest, EJ
dc.contributor.authorScott, KJ
dc.contributor.authorParrish, C
dc.contributor.authorHall, K
dc.contributor.authorStäble, S
dc.contributor.authorJennings, VA
dc.contributor.authorCullen, M
dc.contributor.authorMcConnell, S
dc.contributor.authorLangton, C
dc.contributor.authorTidswell, EL
dc.contributor.authorShafren, D
dc.contributor.authorSamson, A
dc.contributor.authorHarrington, KJ
dc.contributor.authorPandha, H
dc.contributor.authorRalph, C
dc.contributor.authorKelly, RJ
dc.contributor.authorCook, G
dc.contributor.authorMelcher, AA
dc.contributor.authorErrington-Mais, F
dc.date.accessioned2019-08-05T08:18:22Z
dc.date.issued2019-07
dc.identifier.citationJournal for immunotherapy of cancer, 2019, 7 (1), pp. 164 - ?
dc.identifier.issn2051-1426
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3309
dc.identifier.eissn2051-1426
dc.identifier.doi10.1186/s40425-019-0632-y
dc.description.abstractBACKGROUND:The oncolytic virus, coxsackievirus A21 (CVA21), has shown promise as a single agent in several clinical trials and is now being tested in combination with immune checkpoint blockade. Combination therapies offer the best chance of disease control; however, the design of successful combination strategies requires a deeper understanding of the mechanisms underpinning CVA21 efficacy, in particular, the role of CVA21 anti-tumor immunity. Therefore, this study aimed to examine the ability of CVA21 to induce human anti-tumor immunity, and identify the cellular mechanism responsible. METHODS:This study utilized peripheral blood mononuclear cells from i) healthy donors, ii) Acute Myeloid Leukemia (AML) patients, and iii) patients taking part in the STORM clinical trial, who received intravenous CVA21; patients receiving intravenous CVA21 were consented separately in accordance with local institutional ethics review and approval. Collectively, these blood samples were used to characterize the development of innate and adaptive anti-tumor immune responses following CVA21 treatment. RESULTS:An Initial characterization of peripheral blood mononuclear cells, collected from cancer patients following intravenous infusion of CVA21, confirmed that CVA21 activated immune effector cells in patients. Next, using hematological disease models which were sensitive (Multiple Myeloma; MM) or resistant (AML) to CVA21-direct oncolysis, we demonstrated that CVA21 stimulated potent anti-tumor immune responses, including: 1) cytokine-mediated bystander killing; 2) enhanced natural killer cell-mediated cellular cytotoxicity; and 3) priming of tumor-specific cytotoxic T lymphocytes, with specificity towards known tumor-associated antigens. Importantly, immune-mediated killing of both MM and AML, despite AML cells being resistant to CVA21-direct oncolysis, was observed. Upon further examination of the cellular mechanisms responsible for CVA21-induced anti-tumor immunity we have identified the importance of type I IFN for NK cell activation, and demonstrated that both ICAM-1 and plasmacytoid dendritic cells were key mediators of this response. CONCLUSION:This work supports the development of CVA21 as an immunotherapeutic agent for the treatment of both AML and MM. Additionally, the data presented provides an important insight into the mechanisms of CVA21-mediated immunotherapy to aid the development of clinical biomarkers to predict response and rationalize future drug combinations.
dc.formatElectronic
dc.format.extent164 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectDendritic Cells
dc.subjectT-Lymphocytes, Cytotoxic
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectEnterovirus
dc.subjectIntercellular Adhesion Molecule-1
dc.subjectAdult
dc.subjectAged
dc.subjectAged, 80 and over
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectOncolytic Virotherapy
dc.subjectOncolytic Viruses
dc.subjectLeukemia, Myeloid, Acute
dc.subjectImmunity, Innate
dc.subjectAdaptive Immunity
dc.titlePlasmacytoid dendritic cells orchestrate innate and adaptive anti-tumor immunity induced by oncolytic coxsackievirus A21.
dc.typeJournal Article
dcterms.dateAccepted2019-06-06
rioxxterms.versionofrecord10.1186/s40425-019-0632-y
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-07
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfJournal for immunotherapy of cancer
pubs.issue1
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy/Translational Immunotherapy (TL)
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy/Translational Immunotherapy (TL)
pubs.publication-statusPublished
pubs.volume7
pubs.embargo.termsNo embargo
icr.researchteamTargeted Therapyen_US
icr.researchteamTranslational Immunotherapyen_US
dc.contributor.icrauthorHarrington, Kevinen
dc.contributor.icrauthorMelcher, Alanen


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