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IncorporatingImmune-CheckpointInhibitors?into?SystemicTherapyofNSCLCSTATEOFTHEART:CONCISEREVIEWJournalofThoracicOncology?February20141.IntroductionCurrentoptionstoincurablemetastaticNSCLC

Platinum-baseddoubletchemotherapy——standardfirst-linetreatment——limitstopatientswithgoodperformancestatusTargetedtherapy——ErlotinibGefitinibCrizotinib——limitstospecificmolecularsubtypes

Immune-checkpointandtheirblockers[CTLA4]——Ipilimumab[PD-1]——Nivolumab[PDL-1]——BMS-936559Advantages:mildtoxicity;sustainedimmune-mediatedtumorcontrol.Disadvantages:limitedproportionofresponders

CombinationleadstosynergisticactivityNSCLCconventionaltherapiesarecapableofmodulatingtheimmunesystem.Conventionalandtargetedtherapiescaninducerapidtumorlysis,andimmune-checkpointblockadecanthenhelptoinduceasustainedimmune-mediatedtumorcontrol.2.ImmuneCheckpointsandTheirBlockade2.1Mechanism——ImmuneCheckpointCTLA-4——CytotoxicT-LymphocyteAntigen4,Tcells

CTLA4isexpressedexclusivelyonTcellswhereitprimarilydownregulatestheamplitudeoftheearlystagesofTcellactivation(priming).PD-1/PD-L1——Programmedcelldeathprotein1anditsligandPD-1negativelyregulatestheactivationofTcellsinperipheraltissuesandisexpressedbyactivatedTcells.

PD-L1isoneofligandsbindingtoPD-1andexpressedonantigenpresentingcellsbutalsooncancercells.EfficientAntitumorImmuneResponseinNSCLCBlockimmune-checkpointAvoid?negativeregulatorysignalsEnhanceantitumorimmuneresponseTheeffectofimmune-checkpointinhibitorsImmunosuppressiveFactorsPresentintheTumorMicroenvironmentImmunosuppressiveFactorsTRegs:suppressorTcellsMDSC:myeloid-derivedsuppressorcellImmunosuppressivecytokines:Transforminggrowthfactorβ——TGFβInterleukin11——IL11Interferonγ——IFNγ2.2MonoclonalAntibodiesTargetingImmune-CheckpointTheDistinctiveCharacterofImmune-CheckpointBlockadeTherapyResultingclinicalresponsepatternsextendbeyondthoseofcytotoxicagentsandcanmanifestafteraninitialincreaseintumorburdenortheappearanceofnewlesions(progressivedisease).Lymphocyteinfiltrationtriggeredbythetherapycouldleadtheemergenceofpreviouslyunknownsmallnestsoftumorcellsandtheenlargementofpretreatmentlesions.ComparisonbetweenWHOcriteriaandimmune-relatedresponsecriteria(irRC)Fourdistinctresponsepatternsinducedbyimmune-checkpointinhibitorsalwaysresultin:

(a)shrink-ageinbaselinelesions,withoutnewlesions;(b)durablestabledisease(followedbyaslow,steadydecline);(c)responseafteranincreaseintotaltumorburden;(d)responseinthepresenceofnewlesions.Ipilimumab——Anti-CTLA4antibodiesPaclitaxel175mg/m2CarboplatinAUC6q21dIpilimumab10mg/kgq21dplacebo10mg/kgq21dConcurrentIpilimumabRegimenPhasedIpilimumabRegimenControlRegimen70patients68patients66patientsDesign:Result:PhasedRegimenConcurrentRegimenControlRegimenirPFS5.7months5.5months4.6monthsPFS5.1months4.1months4.2monthsirBORR32%21%18%BORR32%21%14%OS12.2months9.7months8.2monthsThestudymetitsprimaryendpointofimprovedirPFSforphasedipilimumabversusthecontrol(hazardratio[HR],0.72;P=0.05),butnotforconcurrentipilimumab(HR,0.81;P=0.13).PhasedipilimumabalsoimprovedPFSaccordingtomodifiedWHOcriteria(HR,0.69;P=0.02).

Their-PFSwasimprovedinpatientsreceivingthephasedscheduleversuschemotherapyalone(HR,0.72;P=.05).Theconcurrentscheduledidnotimprovetheir-PFS.ThemedianOSof12.2monthsforinthephasedipilimumabarmwassimilartothatreportedforthecombinationofpaclitaxelandcarboplatinwithbevacizumab(12.3months).AntitumorVaccine-LikeEffectTriggeredByChemotherapyHistologymightbeapredictivefactorInthephasedipilimumabarm,improvementsinirPFSversusthoseinthecontrolarmappearedtobegreaterinpatientswithsquamoushistology(HR,0.55[95%CI,0.27to1.12])thaninpatientswithnon-squamoushistology(HR,0.82[95%CI,0.52to1.28]).Itisnotablethattumor-infiltratingTcellsaremoreabundantinsquamousNSCLC.

Nivolumab——antibodytargetingthePD-1receptorAphaseItrialtestednivolumabin296patientswithadvancedsolidcancers,including129NSCLCpatients.Regimen：Onceevery2weeksatdosesof1,3or10mg/kg,upto12cyclesuntildiseaseprogressionoracompleteresponseoccurred.Patients:

Themajorityofpatientswereheavilypretreated(99%previouslyreceivedplatinum-basedchemotherapy,28%treatedwithTKIsbefore).Results:Overallresponserate:17%(n=22);17%ofSCC(n=9of54)and18%ofNSCC(n=13of74).MedianOS:9.2monthsforSCCand9.6monthsforNSCCOSin1/2years:44%/41%SCCand44%/17%NSCCAmaximumtolerateddosewasnotdefinedatthedosestestedinthisstudy.Fifteenof296patients(5%)discontinuedtreatmentowingtotreatment-relatedadverseeventsThenotabledurabilityofobjectiveresponsesAsmeasuredbystandardRECISTcriteriainthisstudy,objectiveresponseswerelong-lasting,withresponsedurationsof1yearormorein20of31patientswhohadaresponsewith1yearormoreoffollow-up.MedianPFSofsecond-linechemotherapyinNSCLCisalwayslessthan4months.PD-L1tumorexpressionmightbeapredictivemarkerInordertoassesstheexpressionofPD-L1,immunohistochemicalanalysiswasperformedonpretreatmenttumorspecimensobtainedfrom42patients:18withmelanoma,10withnon–small-celllungcancer,7withcolorectalcancer,5withrenal-cellcancer,and2withprostatecancer.Of17patientswithPD-L1–negativetumors,nonehadanobjectiveresponse;9of25patients(36%)withPD-L1–positivetumorshadanobjectiveresponse(P=0.006).3.ImmunomodulatoryEffectsofNSCLCConventionalTherapies3.1ChemotherapeuticAgentsVaccine-likeeffectagainstthetumorbytriggeringimmunogeniccelldeathThiseffectreliesonthecoordinatedemissionofspecificsignalsfromdyingcancercellsandtheirperceptionbythehostimmunesystem.Antigenreleaseecto-CRT:facilitatesengulfmentbyDCsHMGB1:favoringantigencross-presentationandup-regulatingpro-IL-1βATP:activatestheNLRP3inflammasomebackChemotherapeuticAgentsenhanceT-cellactivation

1.Up-regulationofMHC1——paclitaxel,gemcitabine2.DCsmodulation——taxanes3.DecreasethesizeofTregpopulation——paclitaxel4.InhibitorsupressMDSCs——gemcitabine,cisplatin,docetaxel3.2ImmunomodulatoryEffectsofRadiationTherapyLow-doseradiation：negativeReducesecretionofinflammatorycytokines——TNFα,NOInducesanimmunesuppressiveenvironment——IL-10,TGF?High-doseradiation：positive

Increaseantigenexpressionandinductionofimmunogeniccelldeath

Abscopaleffect

Radiationlocallycanalsotriggersystemicimmuneactivationandleadtospontaneousregressionoftumorsormetastasesthatareoutsidetheradiationfield.3.3ImmunomodulatoryEffectsofTargetedTherapiesBevacizumab——positiveStimulateDCsmaturationInhibittheproliferationofMDSCsErlotinib——dualimmunomodulatoryeffectsIncreasetheexpressionofMHCIandMHCIIInhibitiontheT-cellproliferation4.OncogenicPathwayModulationofPD-L1Expression

PI3k/Aktpathway——glioma,breastandprostatecancersNPM/ALK——anaplasticlarge-celllymphoma

LeadtoincreasedPD-L1expressionCrizotinib?5.ModulationofPD-L1ExpressionbyChemotherapeuticAgents

Doxorubicin——down-regulatePD-L1expressionPaclitaxelandetoposide——increasePD-L1expression

Somestrategicdrugcombinationscouldpotentiallybeprofitablewhereasotherscouldbedetrimental6.RationaleforCombination6.1TriggeringanAntitumorImmuneResponseVaccinationstrategies

Tumorcellvaccines:LucanixAntigen-basedvaccines:MAGE-A3,BLP-25,TG4010,CIMAvaxEGFTodate,vaccinetrialsinNSCLChavefailedbutfurthercombinationstrategieswithimmunecheckpointscouldleadtobetterefficacy.6.2IncreasingImmuneCheckpointTargetsExpressionPaclitaxelandetoposideIncreasePD-L1expressiononNSCLCcellsSuppressantitumorimmuneresponseBMS-936559Induceasustainedimmune-mediatedtumorcontrol6.3DecreasingTumor-InducedImmunosuppressionThedirectcytotoxicactivityofthedrugs——eliminationoftumorcellsreducesitsimmunosuppressiveimpactCisplatin,taxane,gemcitabine,orbevacizumab——canhelptoinhibittheeffectofTRegsandMDSCs6.4TargetingDrug-ResistantClones

Targetedtherapyresistanceisoftenowedtodownstreamactivationofalternativepathways.Alternativesignalingcanpotentiallyleadtoup-regulationofimmunecheckpointsatthesurfaceofthedrug-resistantcell.6.5MaximizingImmuneCheckpointBlockadeIpilimumab——CTLA4——PrimingNivolumab——PD-1——Activation？Regimen：Concurrentregimen(53patients)：

Intravenousdosesofnivolumabandipilimumabinpatientsevery3weeksfor4doses,followedbynivolumabaloneevery3weeksfor4dosesSequencedregimen(33patients)：

Patientspreviouslytreatedwithipilimumabreceivednivolumabevery2weeksforupto48dosesResult:

ORR:Concurrent——40%(n=21of52)Sequenced——13%(n=4of30)

Inconcurrentregimen,onethirdofthepatients(n=16of52)hadrapidanddeeptumorregressions(≥80%tumorreductionat12-weektumorassessment).Observedresponsesweredurable:after13monthsoffollow-up,90%ofallrespondingpatientscontinuetorespond.7.CHALLENGESFORCOMBINATIONS7.1DefiningtheOptimalTreatmentCombinationSequence:PhasedorConcurrent(Chemotherapy/Radiotherapy)Theimmunesystemstimulationofconventionaltherapiesmayincreasetumor-specificimmunityandthereforeenhanceefficacy.Conventionaltherapiesmayalsodecreasethepopulationofimmunecells,mediatingtheresponsetoimmunotherapy.ConventionaltherapiesshouldbeadministratedfirstImmune-checkpointinhibitorsshouldbeaddedearly7.2ManagingToxicitiesToxicitiesofMonotherapyAnti-CTLA4Toxicities——Immune-relatedadverseevents(irAEs)Auniquesetofadverseeffects,including:mostlyskinrashes(40%)anddiarrhea(30%to40%),hypophysitis,hepatitis,pancreatitis,iridocyclitis,lymphadenopathy,neuropathies,andnephritis

Cause:InfiltrationbyCD4andCD8Tcells——revealedbyimmunohistochemistryofaffectedskinandgutIncreasedseruminflammatorycytokines——rapidresolutionwithinfliximab

Anti–PD-1/PD-L1toxicitiesaremuchmilderthanipilimumab,andcouldbewelltoleratedandmanagedPD-1/PDL-1check-pointinteractiontakesplaceperipherally,atthetumorsite,whereasCTLA4/B7interactionoccursmostlycentrallyinthelymphoidorgans.Anti–PD-L1antibodiesseemtohaveamorefavorabletoxicityprofilethananti-PD-1withnopneumonitis.ToxicitiesofCombinedTherapyTheCombinationofImmuneCheckpoint?InhibitorsandChemotherapy

Immune-relatedAEshavefewincommonwithconventionalNSCLCtherapies.Thecombinationofipilimumab/nivolumabandchemotherapyinNSCLCwasgenerallywelltoleratedandimmunecheckpoint?inhibitorsdidnotpotentiatechemotherapy-relatedtoxicity.TheCombinationofipilimumabandnivolumab

Grade3to4immune–relatedAEsoccurredin53%ofconcurrentcohorttreatedpatients(n=28of53).ThemostcommonAEswereasymptomaticlababnormalities:elevationsoflipase(13%),AST(13%),andALT(11%).Inthesequencedcohort,grade3to4–relatedadverseeventsoccurredin18%oftreatedpatients(n=6of3).Themostcommonwasasymptomaticelevationoflipase(6%)