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OncoImmunology
Publication details, including instructions for authors and subscription information:http://www.tandfonline.com/loi/koni20Oncolytic virus expressing RANTES and IL-15 enhancesfunction of CAR-modified T cells in solid tumors
Nobuhiro Nishio & Gianpietro Dotti
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Center for Cell and Gene Therapy; Baylor College of Medicine; Houston, TX USA Department of Immunology; Baylor College of Medicine; Houston, TX USA
Department of Medicine; Baylor College of Medicine; Houston, TX USAPublished online: 06 Mar 2015.
Click for updatesTo cite this article: Nobuhiro Nishio & Gianpietro Dotti (2015) Oncolytic virus expressing RANTES and IL-15 enhances functionof CAR-modified T cells in solid tumors , OncoImmunology, 4:2, e988098, DOI: 10.4161/21505594.2014.988098To link to this article: http://dx.doi.org/10.4161/21505594.2014.988098PLEASE SCROLL DOWN FOR ARTICLE
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OncoImmunology4:2,e988098;February2015;©2015Taylor&FrancisGroup,LLC
OncolyticvirusexpressingRANTESandIL-15enhancesfunctionofCAR-modifiedTcells
insolidtumors
NobuhiroNishio1andGianpietroDotti1,2,3,*
1CenterforCellandGeneTherapy;BaylorCollegeofMedicine;Houston,TXUSA;2DepartmentofImmunology;BaylorCollegeofMedicine;Houston,TXUSA;
3DepartmentofMedicine;BaylorCollegeofMedicine;Houston,TXUSA
Keywords:chimericantigenreceptor,GD2antigen,IL-15,oncolyticvirus,RANTES
Weimprovedthemigrationandsurvivalofchimericantigenreceptor(CAR)-modifiedTcellsinsolidtumorsbycombiningCAR-Tcellswithanarmedoncolyticvirus.LocaldeliveryofthechemokineRANTESandthecytokineIL-15bytheoncolyticvirusenhancedthetraffickingandpersistenceoftheCAR-Tcells,resultinginimprovedantitumoreffects.Downloaded by [McMaster University] at 18:54 15 May 2015 AdoptivetransferofTcellsmodifiedtoexpresschimericantigenreceptors(CARs)hashadclinicalsuccessinB-lymphocytederivedmalignancies.1However,theclini-calefficacyofCAR-Tcellsremainslim-itedinsolidtumors.ThisunfavorableoutcomecouldbeduetotheinsufficientmigrationoftheinfusedTcellstothetumorsiteaswellastotheimmunosup-pressivecharacteristicsofthetumorenvi-ronmentthatinhibitstheeffectorfunctionandproliferationofthosefewTcellsthatdoreachthetumor.
CARmoleculeshavebeenfurtherengi-neeredtoexpressco-stimulatoryendodo-mainssuchasthosederivedfromCD28andtumornecrosisfactorreceptorsuper-familymember9(TNFRSF9,betterknownas4–1BB)topromoteT-cellpro-liferationandpersistenceuponencounter-ingtumorcells.CD28hasproveneffectiveininducingCAR-Tcellexpan-sioninB-cellmalignancies.2,3Theincor-porationof4–1BBseems,however,tosustainmorerobustengraftmentofCD19-specificCAR-Tcells.1Theincor-porationoftheseco-stimulatorymoleculesinCARstargetingantigensexpressedbysolidtumorsisanticipatedtoplayasimi-larlycrucialrole.
CAR-TcellstargetingCD19seemtotrafficphysiologicallytothebonemar-rowandlymphnodes,theprimarysitesofhematologicmalignancies.1,3Inaddition,theycanencounterbothnor-malBlymphocytesandleukemiccellsdirectlyinthecirculation.Bycontrast,T-cellmigrationremainsarelevantprob-lemforsolidtumors.Forinstance,whiletumor-infiltratingTlymphocytes(TILs)isolatedfromtumorbiopsiesandexpandedexvivoshowdramaticmigra-tiontomelanomalesions,polyclonalTlymphocytesisolatedfromtheperipheralbloodandengineeredwithaT-cellreceptorseemlesseffective.Thisdispar-itysuggeststhatTILsandperipheralbloodTcellsmayhaveadifferentpatternofhomingmolecules.4IfthecurrentCAR-Tcellstudiesinsolidtumorssuchasneuroblastoma,prostatecancer,pan-creaticcancer,andmesotheliomarevealsuboptimalmigration,countermeasurestoincreaseT-cellmigrationshouldbeapplied.RadiationorchemotherapybeforetheinfusionofCAR-TcellsinpatientswithsolidtumorsmayfavorablyalterthepatternofT-cellmigration.However,severalpreclinicalmodelshavealreadydemonstratedthatengineeringCAR-Tcellstoexpresschemokinerecep-torsthatpairwithchemokinesproducedbytumorcellsisastrategythatcanover-comethetraffickingissue.5WhenCAR-Tcellsreachthetumorbedinasufficientnumber,tumor-associatedinhibitorymechanismsaretheretoshutdowneffectiveimmuneresponses.Inthetreatmentofsmalltumors,infusionofCAR-Tcellsafterchemoorradiother-apymaypartiallyreducetheimpactoftheseinhibitorymechanisms.Inaddition,therecentintroductionofantibodiesthatblockT-cellinhibitorymechanisms,suchasthoseabrogatingtheimmunecheck-pointCTLA-4andPD1-PDL-1pathways,showsgreatpotential.CombinationsofCAR-Tcelltherapieswiththeseantibodiesareanticipatedtomakeasubstantialdif-ferenceinthenearfuture.SimilarlytothegeneticmodificationofCAR-Tcellsaimedtoexpressspecificchemokinerecep-tors,aplethoraofgeneticmodificationshasbeenproposedtoincreasethefitnessofCAR-Tcellswithinthetumorenviron-ment.5Someoftheproposedmodifica-tionsarecurrentlyunderclinicalinvestigation.Althougheachsinglemodi-ficationseemstohavespecificbeneficialeffects,multiplemechanismsofresistancecanbedevelopedbytumors.Tcellsmustaccomplishsimultaneouslyoptimaltraf-fickingandpersistence,whilealsoretain-inganacceptablesafetyprofile.Inourrecentstudy,6wedevelopedanengineer-ingstrategywhereanarmedoncolyticvirus(OV),anothersinglebiologicalagent,createsafavorabletumorenviron-mentforCAR-Tcells.
OVsselectivelyinfect,lyseandrepli-cateinmalignantcellswithoutaffectingnon-malignantcells.7Inaddition,OVs
*Correspondenceto:GianpietroDotti;Email:gdotti@bcm.eduSubmitted:11/08/2014;Accepted:11/12/2014http://dx.doi.org/10.4161/21505594.2014.988098www.tandfonline.comOncoImmunologye988098-1
Downloaded by [McMaster University] at 18:54 15 May 2015 havesufficientcargocapacitytoinsertmultipleectopicgenesthatcanbebenefi-cialforCAR-Tcells.ToinvestigatetheeffectofcombiningarmedOVandCAR-Tcells,wechoosetheneuroblastomamodelsincethistumormodelhasbeenpreviouslytargetedwithCAR-Tcellsspe-cificfortheGD2antigen.8Wealsoselectedanoncolyticadenovirus(Ad5D24)thathasbeenextensivelyusedintheclinic.WeexploitedthetropismoftheOVforthetumorcellsandengineeredthevirustoexpressbothachemokineandagrowthfactorfortheTcellsinordertoachieveoptimaltraffickingoftheengi-neeredTcellstothetumorsiteandtogenerateacytokinemilieuthatsustainsT-cellgrowthandsurvival.Therefore,wearmedAd5D24withchemokine(C-Cmotif)ligand5(CCL5,betterknownasRANTES)andinterleukin(IL)-15(Fig.1),2immunomodulatorymoleculesselectedonthebasisofbothclinicalandpreclinicaldata.RANTESisalsoaverypotentchemokineanditsreceptorsaremaintainedinTcellsexpandedexvivo.Usingthisstrategy,weanticipatedthattumorcells,regardlessoftheirtissueori-gin,couldbeforcedtoectopicallyexpressRANTESafterinfectionwiththearmedOV.WehypothesizedthatthisstrategywouldpromoteefficientmigrationoftheinfusedCAR-Tcellswithouttheneedtoselectachemokine/chemokinereceptorpathwayspecificforeachsingletumortype.ThecytokineIL-15wasselectedforitsmultiplebeneficialeffectsonTcells,anditsoverallabilitytoincreaseT-cellantitumorfunctions.Inourexperimentaldesign,wedemonstratedthatneuroblas-tomacellsinfectedwithAd5D24.RANTES.IL-15producefunctionallevelsofRANTESandIL-15bothinvitroandinvivo,whilethecytopathiceffectofthevirusisconserved.Inaxenogenicmousemodel,combinedtherapywithAd5D24.
RANTES.IL-15andGD2.CAR-Tcellssignificantlyenhancedthesurvivalofmiceascomparedwitheitherofthemono-therapies.Furthermore,bothRANTESandIL-15releasedbythearmedOVwerepredominantlydetectedatthetumorsite,ratherthanintheserum,indicatingapref-erentiallocalexpressionofbothfactors.Thisstrategytherebycircumventedthetoxicitiesassociatedwithsystemicadmin-istrationofcytokines.6Inconclusion,ourpreclinicalstudydemonstratesthatoptimaltraffickingandsurvivalofCAR-TcellscanbeobtainedinsolidtumorsbyengineeringanOVwith-outcompromisingitscytopathiceffect.Inprinciple,similargeneticmodificationscanbeappliedtoOVssuchasvacciniavirusesandmeaslesvirusthathavebeenadministeredintravenouslyintopatientstotreatmetastatictumorsalready.9,10Armingthesevirusesusingthisproposedstrategywillnotonlyfavortherapidrecruitmentof
tumor-specificTcellstotheprimarylesionssoinfectedbutwillalsoenhancethespreadofthevirustoothertumorcells,thusamplifyingthetherapeuticeffectoftheviruses.Inaddition,consid-eringthecargocapacityoftheseviruses,otherrelevantgenesthatmayfurtherover-comeinhibitorymechanismscanbeaccommodated.
DisclosureofPotentialConflictsofInterest
Nopotentialconflictsofinterestweredisclosed.
Acknowledgment
TheauthorswouldliketothankCatherineGillespieforeditingtheinvitedautocommentary.
Funding
Figure1.CombinedtherapywithCAR-TcellsandAd5D24armedwithRANTESandIL-15.Oncolyticviruses(OVs)selectivelyinfectandlysetumorcells,andthenspreadtoneighboringtumorcells.Virus-infectedtumorcellsreleasebothproteinsandundergoapoptosis.ThechemokineRANTESattractscirculatingchimericantigenreceptor(CAR)modifiedTcells(CAR-T)tothevirusinfectedtumorsiteandmigratedCAR-Tcellspersistbyvirtueofinterleukin15(IL-15)andspecificantigenstimulation.ThisworkwassupportedinpartbyR01CA142636NationalInstituteofHealth-NCIandW81XWH-10–10425DepartmentofDefenseandTechnology/TherapeuticDevelopmentAward.
e988098-2OncoImmunologyVolume4Issue2
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