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Replication restricted vaccinia as a cytokine gene therapy vector in cancer: persistent transgene expression despite antibody generation

Mukherjee, Sutapa; Haenel, Thomas; Himbeck, Robyn; Scott, Bernadette; Ramshaw, Ian; Lake, Richard A; Harnett, J; Phillips, Peter; Morey, Sue; Smith, David; Davidson, J Andrew; Musk, Arthur W; Robinson, Bruce

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Background: As antitumoral immunity requires the generation of local immunity directed against tissue proteins, we attempted to recreate within tumors the same environment found within tissues affected by autoimmune diseases (i.e., prolonged cytokine expression). Vaccinia virus (VV) has not been widely used as a cytokine gene therapy vector because of presumed high immunogenicity that would likely make repeated injections impossible; therefore, we modified it by inserting the cytokine gene into...[Show more]

dc.contributor.authorMukherjee, Sutapa
dc.contributor.authorHaenel, Thomas
dc.contributor.authorHimbeck, Robyn
dc.contributor.authorScott, Bernadette
dc.contributor.authorRamshaw, Ian
dc.contributor.authorLake, Richard A
dc.contributor.authorHarnett, J
dc.contributor.authorPhillips, Peter
dc.contributor.authorMorey, Sue
dc.contributor.authorSmith, David
dc.contributor.authorDavidson, J Andrew
dc.contributor.authorMusk, Arthur W
dc.contributor.authorRobinson, Bruce
dc.date.accessioned2015-12-13T23:18:13Z
dc.date.available2015-12-13T23:18:13Z
dc.identifier.issn0929-1903
dc.identifier.urihttp://hdl.handle.net/1885/90063
dc.description.abstractBackground: As antitumoral immunity requires the generation of local immunity directed against tissue proteins, we attempted to recreate within tumors the same environment found within tissues affected by autoimmune diseases (i.e., prolonged cytokine expression). Vaccinia virus (VV) has not been widely used as a cytokine gene therapy vector because of presumed high immunogenicity that would likely make repeated injections impossible; therefore, we modified it by inserting the cytokine gene into the thymidine kinase region, rendering it replication-restricted. The cytokine chosen was human interleukin-2 (IL-2), a molecule with powerful antitumoral effects. Methods: Six patients with the treatment-resistant tumor malignant mesothelioma received intratumoral (i.t.) VV-IL-2 therapy for 12 weeks by injection of 107 plaque-forming units of W-IL-2 per dose. Serial tumor biopsies, sputum, urine, and blood samples were tested for VV-IL-2 mRNA expression; VV culture and T-cell infiltrates were evaluated by immunohistochemistry. Patients and of patients were monitored for changes in VV immunoglobulin G (IgG) levels and clinical evidence of VV infection. Results: VV-IL-2 was not excreted and was only cultured in one patient from tumor biopsies. A T-cell infiltrate was detected in 50% of tumor biopsies. VV-IL-2 mRNA expression was highest on days 1-3 postinjection and was detected for up to 3 weeks after each injection even though VV IgG levels rose in all patients. No significant toxicities, infection of patient contacts, or tumor regressions were observed. Conclusions: I.t. VV-IL-2 administration is safe, is associated with minimal toxicity, and results in i.t. expression of VV-IL-2 for up to 3 weeks postinjection regardless of the level of anti-VV IgG titers generated. This suggests that VV may be a good vector for repeated cytokine gene therapy of solid human cancer.
dc.publisherNature Publishing Group
dc.sourceCancer Gene Therapy
dc.subjectKeywords: cytokine; interleukin 2; messenger RNA; vaccinia vaccine; virus vector; adult; aged; article; clinical article; female; gene expression; gene therapy; human; human cell; immunohistochemistry; male; mesothelioma; nonhuman; nucleotide sequence; polymerase c Gene therapy; Interleukin-2; Malignant mesothelioma; Vaccinia virus
dc.titleReplication restricted vaccinia as a cytokine gene therapy vector in cancer: persistent transgene expression despite antibody generation
dc.typeJournal article
local.description.notesImported from ARIES
local.description.refereedYes
local.identifier.citationvolume7
dc.date.issued2000
local.identifier.absfor100401 - Gene and Molecular Therapy
local.identifier.ariespublicationMigratedxPub20337
local.type.statusPublished Version
local.contributor.affiliationMukherjee, Sutapa, University of Western Australia
local.contributor.affiliationHaenel, Thomas, University of Western Australia
local.contributor.affiliationHimbeck, Robyn, University of Western Australia
local.contributor.affiliationScott, Bernadette, University of Western Australia
local.contributor.affiliationRamshaw, Ian, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationLake, Richard A, University of Western Australia
local.contributor.affiliationHarnett, J, University of Technology Sydney
local.contributor.affiliationPhillips, Peter, Western Australian Center for Pathology and Medical Research
local.contributor.affiliationMorey, Sue, Sir Charles Gairdner Hospital
local.contributor.affiliationSmith, David, Western Australian Center for Pathology and Medical Research
local.contributor.affiliationDavidson, J Andrew, University of Western Australia
local.contributor.affiliationMusk, Arthur W, Sir Charles Gairdner Hospital
local.contributor.affiliationRobinson, Bruce, University of Western Australia
local.bibliographicCitation.issue5
local.bibliographicCitation.startpage663
local.bibliographicCitation.lastpage670
dc.date.updated2015-12-12T08:55:50Z
local.identifier.scopusID2-s2.0-0034106260
CollectionsANU Research Publications

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