肺癌免疫治疗进展

肺癌免疫治疗进展FutureOutlookUpdateofcheckpointInhibitorsinlungcancertherapyCancerImmunotherapy123OutlineFutureOutlookUpdateofcheckpointInhibitorsinlungcancertherapyCancerImmunotherapy123Outline肿瘤免疫治疗—攻克肿瘤的新希望人类抗击肿瘤的历史肿瘤免疫治疗具有特异性和靶向性，一直为临床医师高度关注，近年进步显著，使得免疫治疗成为更具期待的领域靶向治疗进入21世纪，分子靶向治疗如火如荼eKeyeventsinthehistoryofcancerimmunotherapy1890s1stCAvaccinedeveloped(coley)1973discoveryofthedendriticcell(steinman)19761ststudywithBCGinbladderCA1978DiscoveryoftumorspecificmABs19851ststudywithadoptiveT-celltransferinCA1986IFNα(cytokine)approvedforCA1990sDiscoveryofroleofcheckpointsinCA1992Il-2(Cytokine)approvedforCA19971stmABapprovedforCA20101stcellularimmunotherapyapprovedforCA20111stcheckpointinhibitorapprovedforCA20142ndcheckpointinhibitorapprovedforCAEnthusiasmphase1976-1985Skepticismphase1986-1992Renaissancephase1997-美国《Science》杂志:2013年六大值得关注的科学领域单细胞测序“普朗克”探测微波背景辐射人类连接组计划探索南极冰下世界癌症免疫疗法基础植物研究Breakthroughofyear2013Science.2013Dec20;342(6165):1432-3Immunity.39(1)25July2013,Pages1–10StimulatoryandInhibitoryFactorsintheCancer-ImmunityCycleCTLA-4andPD-1/PD-L1checkpointblockadeforcancertreatmentCTLA-4andPD-1/PD-L1CheckpointBlockadeforCancerTreatment○ImmunecheckpointblockadeincludesagentstargetingthenegativeregulatorsCTLA-4andPD-1○CTLA-4attenuatestheearlyactivationofnaiveandmemoryTcellsinthelymphnodesAgentstargetingCTLA-4includeipilimumabandtremelimumab○Incontrast,PD-1modulatestheeffectorphaseofTcellactivityinperipheraltissuesviainteractionwithPD-L1andPD-L2○AgentstargetingPD-1includenivolumabandMK-3475○AgentstargetingPD-L1includeMPDL3280AandMEDI4736KyiC,etal.FEBSLett.2014;588:368-376ComparingCTLA-4andPD-1CTLA-4PD-1BiologicalfunctionInhibitoryreceptorInhibitoryreceptorExpressiononTcellsatthetimeofinitialresponsetoantigen(activatedCD8+Tcells)ActivatedTcells,Bcells,NKcellsTILsindifferenttumortypesMajorroleRegulatestheearlystageofT-cellactivationLimitsT-cellactivityinperipheraltissueafterinflammatoryresponseLimitsautoimmunityLigandsB7.1(CD80)B7.2(CD86)PD-L1(B7-H1/CD274)PD-L2(B7-CD/CD273)MechanismofactionAfterligandbinding:BindingwithPI3K,phosphatasesSHP-2andPP2ABlockadeoflipid-raftexpressionBlockadeofmicroclusterformationAfterligandbinding:Recruitsinhibitoryphosphatase,SHP-2DecreasesexpressionofcellsurvivalproteinBcl-xLInhibitskinases(PI3K/AKT)involvedinT-cellactivationCritRevOncolHematol.2014;89:140-165.CTLA-4andPD-1haveseparatebutcomplimentaryrolesinimmuneresponsesFutureOutlookUpdateofcheckpointInhibitorsinlungcancertherapyCancerImmunotherapy123Outline•CTLA-4CheckpointInhibitorAnti-CTLA-4antibodiescaninduceclinicalresponseinabroadvarietyofcancerAdaptedformLebbeetal.ESMO2008PresentedByLawrenceFongat2014ASCOAnnualMeetingBladderRenalEsophagealCNSColorectalGlioblastomaLeukemiaSoftTissueSarcomaJClinOncol.2012Jun10;30(17):2046-54AnnOncol.2013Jan;24(1):75-83JClinOncol.2012Jun10;30(17):2046-54IpilimumabincombinationwithPCasfirst-linetherapyinstageIIIB/IVNSCLCKaplan–MeierplotsforOSJClinOncol.2012Jun10;30(17):2046-54Deaths/patients51/6651/68Median(95%CI),months8.28(6.80to12.39)12.22(9.26to14.39)HR(95%CI)0.87(0.59to1.28)Log-rankP0.23ControlPhasedIpiDeaths/patients51/6651/70Median(95%CI),months8.28(6.80to12.39)9.69(7.59to12.48)HR(95%CI)0.99(0.67to1.46)Log-rankP0.48ConcurrentlpiControlEvents/patients61/6658/70Median(95%CI),mo4.21(2.76to5.32)4.11(2.76to5.32)HR(95%CI)0.88(0.61to1.27)Log-rankP.25JClinOncol.2012Jun10;30(17):2046-54Kaplan–MeierplotsforPFSperimmune-related(ir)responsecriteria(irPFS)andmodifiedWHOcriteria(mWHO-PFS).Events/patients56/6654/68Median(95%CI),4.63m(4.14to5.52)5.68(4.76to7.79)HR(95%CI)0.72(0.50to1.06)Log-rankP.05ControlPhasedIpiEvents/patients56/6655/70Median(95%CI),4.63m(4.14to5.52)5.52(4.17to6.74)HR(95%CI)0.81(0.55to1.17)Log-rankP.13ControlConcurrentlpiEvents/patients61/6656/68Median(95%CI),mo4.21(2.76to5.32)5.13(4.17to5.72)HR(95%CI)0.69(0.48to1.00)Log-rankP.02ControlPhasedIpiControlConcurrentlpiAdverseEventsJClinOncol.2012Jun10;30(17):2046-54Follow-UPEvery12wksForsurvivalSCREENINGINDUCTIONMAINTENANCEFOLLOW-UPCA184-104:phaseIIItrialcomparingthetheefficacyofipilimumab(Ipi)withPCversusplacebowithPCinpatients(pts)withstageIV/recurrentNSCLCofsquamoushistologyTumorassessmentEvery12wksIpi10mg/kg+PCWks7,10,13,16stageIV/recurrentsquamousNSCLCECOG≤1Placebo+PCWks7,10,13,162cyclePCWks1,4Ipi10mg/kgEvery12wksPlaceboEvery12wksRJClinOncol31,2013(suppl;abstrTPS8117)primaryendpointOSsecondaryendpointsOSamongptswhoreceiveblindedtherapyPFSbestoverallresponserateTumorassessmentWks7,13,19,25ExclusionCriteria:BrainMetastasesAutoimmunediseasesPCPaclitaxel(175mg/m2,IV)+Carboplatin(AUC=6,IV)CA184-156:PhaseIIITrialComparingtheEfficacyofIpiPlusEtoposide/PlatinumVersusEtoposide/PlatinuminSubjectsWithNewlyDiagnosedED-SCLCJClinOncol30,2012(suppl;abstrTPS7113)Ipi+EPQ3W2cycleED-SCLCECOG0-1Placebo+EPQ3W2cycleSCREENINGINDUCTIONMAINTENANCE2cycleEPIpi10mg/kgQ12WPlaceboQ12WRprimaryendpointOSsecondaryendpointsOSamongptswhoreceiveblindedtherapyimmune-relatedandmWHOPFSbestoverallresponseratedurationofresponseExclusionCriteria:Priorsystemictherapy