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Interleukin-15 (IL-15) and IL-15 receptor alpha fusion protein enhances antitumor activity of myxoma virus

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Title:
Interleukin-15 (IL-15) and IL-15 receptor alpha fusion protein enhances antitumor activity of myxoma virus
Creator:
Tosic, Vesna
Thomas, Diana L.
Kranz, David M.
Liu, Jia
Mc-Fadden, Grant
MacNeil, Amy L.
Roy, Edward J.
Publisher:
BioMed Central (Journal for ImmunoTherapy of Cancer)
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Language:
English

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Abstract:
© 2013 Tosic et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
General Note:
Tosic et al. Journal for ImmunoTherapy of Cancer 2013, 1(Suppl 1):P137 http://www.immunotherapyofcancer.org/content/1/S1/P137
General Note:
doi:10.1186/2051-1426-1-S1-P137 Cite this article as: Tosic et al.: Interleukin-15 (IL-15) and IL-15 receptor alpha fusion protein enhances antitumor activity of myxoma virus. Journal for ImmunoTherapy of Cancer 2013 1(Suppl 1):P137.

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University of Florida
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University of Florida
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POSTERPRESENTATION OpenAccessInterleukin-15(IL-15)andIL-15receptoralpha fusionproteinenhancesantitumoractivityof myxomavirusVesnaTosic1*,DianaLThomas2,DavidMKranz3,JiaLiu5,GrantMcFadden5,AmyLMacNeill4,EdwardJRoy1,2From SocietyforImmunotherapyofCancer28thAnnualMeeting NationalHarbor,MD,USA.8-10November2013Myxomavirus,arabbitpoxvirus,canefficientlyinfect variousclassesofmouseandhumancancercells.Itisa strictrabbit-specificpathogen,safetouseinallnon-rabbit hoststestedincludingmiceandhumans.Recombinant viruseswerepreviouslyeng ineeredtoexpresstdTomatoRedfluorescentprotein(vMyx-tdTr)andmouse interleukin-15(vMyx-IL15-tdTr).IL15isanimmunomodulatorycytokinewithagreatpotentialforstimulating TlymphocytesandNKcells.IthasbeenshownthatcoexpressionofIL15withthe a subunitofIL15receptor (IL15R a )greatlyenhancesIL15stabilityandbioavailability.Ourpreviousstudieshaveshownthatearliergenerationrecombinantmyxomaviruses(vMyx-tdTrand vMyx-IL15-tdTr)selectivel yinfectedtumors,buthad limitedtherapeuticeffectinvivo.Inordertousemyxoma virusasavehicletodeliverimmuno-stimulatorycytokine totumors,weengineeredanewrecombinantmyxoma virus(vMyx-IL15Ra-tdTr),whichexpressesIL15R a -IL15 fusionproteinandtdTomatoRedfluorescentprotein. Multi-stepgrowthcurvesshowproductiveinfectionof variouscancercelllinestested.Melanoma(B16-F10and B16.SIY)andglioma(GL261andGL261.SIY)celllinesare permissivetomyxomainfection.RK-13cellsinfectedwith vMyx-IL15Ra-tdTr(MOI=5)expressandsecretethe IL15R a -IL15fusionprotein.Functionalactivityofthe secretedfusionproteininvitroisconfirmedbystimulating proliferationofthecytokine-dependentCTLL-2cells. Invivoexperiments,inwhichRAG-/-micewithsubcutaneousB16-F10tumorsweretreatedtwiceinratumorally with2.6x107ffuvMyx-IL15Ra-tdTr,showedasignificant survivalbenefitforthetreatedgroupcomparedtothePBS controlandthecontrolvirus(vMyx-tdTr).Fusion-protein expressingvirusattenuatedtumorgrowthandprolonged survival(mediansurvivalof29,23and17daysforvMyxIL15Ra-tdTr,vMyx-tdTrandPBStreatedgroups,respectively).Immunohostologicalanalysisofthesubcutaneous tumorsshoweddramaticallyincreasedinfiltrationofNK cellsinvMyx-IL15Ra-tdTrtreatedtumorscomparedto bothcontrols.Wehypothesizedthatthethreevirotherapeuticeffectsofthevirus(oncolysis,deliveryofIL15R a -IL15, andimmuneactivationfromTolllikereceptor-mediated inflammation)willaugmenttheantitumoractivities ofhost simmunesystem.OurresultssuggestthatIL15R a IL15componentdoesimprovetherapeuticeffectovervirus aloneandthattheeffectislikelymediatedbyNKcell componentoftheimmunesystem.Authors details1MIP,UniversityofIllinois,Urbana,IL,USA.2Neuroscience,Universityof Illinois,Urbana,IL,USA.3Biochemistry,UniversityofIllinois,Urbana,IL,USA.4PathobiologyatCollegeofVeterinaryMedicine,UniversityofIllinois, Urbana,IL,USA.5MolecularGeneticsandMicrobiology,UniversityofFlorida, Gainesville,FL,USA. Published:7November2013doi:10.1186/2051-1426-1-S1-P137 Citethisarticleas: Tosic etal .: Interleukin-15(IL-15)andIL-15receptor alphafusionproteinenhancesantitumoractivityofmyxomavirus. JournalforImmunoTherapyofCancer 2013 1 (Suppl1):P137. 1MIP,UniversityofIllinois,Urbana,IL,USA FulllistofauthorinformationisavailableattheendofthearticleTosic etal JournalforImmunoTherapyofCancer 2013, 1 (Suppl1):P137 http://www.immunotherapyofcancer.org/content/1/S1/P137 2013Tosicetal;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommons AttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,andreproductionin anymedium,providedtheoriginalworkisproperlycited.


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