Improving T Cell Therapy for Cancer

ANRV306-IY25-10ARI19February20079:30ImprovingTCellTherapyforCancerAnnM.Leen,1,2ClionaM.Rooney,1,2,3,4andAaronE.Foster1,21CenterforCellandGeneTherapy,Departmentsof2Pediatrics,3Immunology,and4Virology,BaylorCollegeofMedicine,TheMethodistHospitalandTexasChildren’sHospital,Houston,Texas77030;email:[e-mail].2007.25:243–65FirstpublishedonlineasaReviewinAdvanceonNovember27,2006TheAnnualReviewofImmunologyisonlineatimmunol.annualreviews.orgThisarticle’sdoi:10.1146/annurev.immunol.25.022106.141527Copyrightc2007byAnnualReviews.Allrightsreserved0732-0582/07/0423-0243$20.00KeyWordsimmunotherapy,genetherapy,tumorimmunologyAbstractAdoptivetransferofantigen-specificTlymphocytesisapowerfultherapyforthetreatmentofopportunisticdiseaseandsomevirus-associatedmalignanciessuchasEpstein-Barrvirus–positivepost-transplantlymphoproliferativedisease.However,thisstrategyhasbeenlesssuccessfulinpatientswithnonviralcancersowingtotheirmanyandvariedimmuneevasionmechanisms.Thesemechanismsincludedownregulationoftargetantigensandantigen-presentingmachinery,secretionofinhibitorycytokines,andrecruitmentofreg-ulatoryimmunecellstothetumorsite.Withincreasedunderstand-ingofthetumormicroenvironmentandthebehaviorandpersis-tenceofexvivo–manipulated,adoptivelytransferredTcells,twonovelapproachesforincreasingtheefficacyofTcelltherapyhavebeenproposed.Thefirstinvolvesgeneticmodificationoftumor-specificTcellstoimprovetheirbiologicalfunction,forexamplebyaugmentingtheirabilitytorecognizetumorcellsortheirresis-tancetotumor-mediatedimmunosuppression.ThesecondrequiresmodificationstothehostenvironmenttoimprovethehomeostaticexpansionofinfusedTcellsortoeliminateinhibitoryTcellsubsets.Inthisreview,wediscusscurrent,promisingstrategiestoimproveadoptiveTcelltherapyforthetreatmentofcancer.243Annu.Rev.Immunol.2007.25:243-265.Downloadedfromarjournals.annualreviews.orgbyOregonHealth&ScienceUniversityon05/27/07.Forpersonaluseonly.ANRV306-IY25-10ARI19February20079:30CMV:cytomegalovirusCTL:cytotoxicTlymphocyteAdoptiveTcelltherapy:theinvitroisolationandinfusionofantigen-specificTcellsintopatientsEBV:Epstein-BarrvirusTGF-β:transforminggrowthfactor-βINTRODUCTIONTheinvitroactivationandexpansionofantigen-specificTcellsfortherapeuticpur-poseshaveyieldedimpressiveresultsinthecontextofprophylaxisandtreatmentofvirus-associatedinfectionanddiseasepost-transplant.Riddellandcolleagues(1)in-fusedcytomegalovirus(CMV)-specificCD8+Tcellclonesintorecipientsofallogeneichematopoieticstemcelltransplants(HSCT)andfoundthattheinfusedcellsweresafeandcapableofrestoringCMV-specificcytotoxicTlymphocyte(CTL)responsesinrecipientsofallogeneicbonemarrowtransplants.How-ever,thesecellsdidnotpersistinvivointheabsenceofendogenousCD4+Tcellrecov-ery.Subsequently,Einseleandcolleagues(2)infusedpolyclonalCMV-specificCTLlinesintoeightHSCTrecipientswhohadper-sistingorrecurringCMVinfectiondespitetheprolongeduseofantiviralmedications.FollowingTcelltherapy,viralload,asde-terminedbyquantitativepolymerasechainreaction,showedsignificantreductionsin7/7evaluablepatients.Thisreductioninvi-ralloadwaspersistentinfiveandtransientintwopatients;interestingly,thesetwopa-tientshadreceivedintenseimmunosuppres-sionforgraft-versus-hostdiseasearoundthetimeofTcelltherapy(1).Thus,adoptiveTcelltherapyissuccessfulatreconstitut-ingimmunitytoCMV,butmaybecompro-misedinpatientsreceivinghigh-doseimmunesuppression.TheresultsofadoptiveimmunotherapytrialsfortheprophylaxisandtreatmentofEBV-associatedpost-transplantlymphopro-liferativedisease(PTLD)weresimilarlysuc-cessful.Rooneyandcolleagues(3)havein-fuseddonor-derivedpolyclonalEBV-specificTcelllinesintomorethan60HSCTrecipi-entsasprophylaxisforPTLD.Sixadditionalpatientsreceivedvirus-specificCTLaftertheonsetoflymphoma.NoneofthepatientsintheprophylaxisgroupdevelopedPTLD,incontrasttoanincidenceof11.5%inahis-toricaluntreatedcontrolgroup.AnalysisofEBV-DNAlevelspostinfusionshoweddirectevidenceofantiviralactivity,asDNAlevelsdecreasedbyuptofourlogswithinthreeweeksofthefirstTcellinfusion.Further-more,adoptivelytransferredTcellswereabletopersistandsustainlong-termprotectionagainstviralreactivation(4).Ofthesixpa-tientswithevidentlymphoma,fiveachievedcompleteremission,whereasintheremain-ingpatientcomprehensiveinvitroanalysisrevealedtheincreaseddominanceofavirusdeletionmutantafterCTLinfusion(5).Thus,adoptiveimmunotherapyforthepreventionandtreatmentofvirus-associateddiseasesinimmunocompromisedpatientsissafe,effective,andprotectiveinvivo.Thesesuccessespromptedtheextensionofthismethodforthetreatmentoftumorsinimmunocompetentindividuals.Initialap-proachesforthetreatmentofpatientswithmetastaticmelanomabyinfusionofhighlyactivetumor-specificTcellclonesfailedtodemonstrateengraftmentandpersistenceofthetransferredcells(6,7).InthecaseofEBV-associatedHodgkin’sdisease(HD)andnasopharyngealcarcinoma(NPC),infusedEBV-specificCTLswereshowntopersistinvivo,traffictotumorsites,andproduceantitumorresponses.However,inpatientswithbulkydisease,responseswerelimitedandtransient(8,9).Therefore,itappearsthatthecellularimmunitydirectedag