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1、PERSPECTIVEStheseantigensinordertoeliminatetheOPINIONtumour.T cellactivationisinitiatedbystimulationoftheantigenreceptor(TcellNovelcancerimmunotherapyreceptor(TCR))withmajorhistocompat-ibilitycomplex(MHC)molecules,whichagentswithsurvivalbenefit:presentpeptid
2、esthatarederivedfromtumourantigens.Forproductiveactivation,recentsuccessesandnextstepsthismustbeaccompaniedbyco-stimulatorysignalsmediatedbythebindingofCD28ontheT cellsurfacetoB7proteins(suchasPadmaneeSharma,KlausWagner,JeddD. WolchokandJamesP. AllisonCD80or
3、CD86)ontheantigen-presentingcell(APC)(FIG.1a).ThesetwosignalsallowAbstract
4、TheUSFoodandDrugAdministration(FDA)recentlyapprovedtwoT cellstobegintoproliferate,toacquirenovelimmunotherapyagents,sipuleucel-Tandipilimumab,whichshowedaeffectorfunctionsandeventuall
5、ytomigrate.survivalbenefitforpatientswithmetastaticprostatecancerandmelanoma,TCRsignallingalsoinducestheproductionrespectively.ThemechanismsbywhichtheseagentsprovideclinicalbenefitareoftheCD28homologueCTLA4,whichisaT cell-specificmoleculethathasahighernotcom
6、pletelyunderstood.However,knowledgeofthesemechanismswillbebindingaffinityforB7,therebyoutcompetingcrucialforprobinghumanimmuneresponsesandtumourbiologyinordertoCD28andeventuallyinhibitingT cellactiv-understandwhatdistinguishesrespondersfromnon-responders.The
7、followingity(FIG.1b).CTLA4restrictsT cellactivityinnextstepsarenecessary:first,thedevelopmentofimmune-monitoringordertominimizedamagetonormaltissues.strategiesfortheidentificationofrelevantbiomarkers;second,theOtherinhibitorymoleculessuchasPD1arealsoexpresse
8、donT cellsafterT cellactiva-establishmentofguidelinesfortheassessmentofclinicalendpoints;andthird,tion,thusprovidingsignalsthatcontrolT celltheevaluationofcombinationtherapystrategiestoimproveclinicalbenefit.responses.T cellactivitymaybeenhancedincancerpatie
9、ntstoelicitclinicalbenefitbyTheconceptofcancerimmunesurveillancestimulatorystrategiesincludetheuseofusingtumour-specificantigenstostimulatedatesbackdecades1–3andisbasedontheantibodiestargetingth
