恶性淋巴瘤免疫治疗进展ppt课件.ppt

恶性淋巴瘤免疫治疗进展 陈振东安徽医科大学第二附属医院肿瘤中心 HistoryofImmunotherapy ElertE Nature 2013 504 S2 S3 1796 Firstuseofimmunotherapy Jennersmallpoxvaccine 1976 BCGvaccineforbladdercancer 1863 Connectionbetweenimmunotherapyandcancerrecognized 1985 Interferonfirstapprovedforhairycellleukemia 1992 IL 2approvedforRCC 1997 FirstmAbforcancerapproved rituximab 2008 FirstcancervaccineapprovedforRCC 2010 Sipuleucel Tapprovedforprostatecancer 2011 CTLA 4inhibitorapprovedformelanoma 2014 2015 PD 1inhibitorsapprovedformelanoma squamousNSCLC 2015 Firstoncolyticvirusapprovedformelanoma 2016 PD 1inhibitorapprovedforcHLPD L1inhibitorapprovedforUC 霍奇金淋巴瘤 背景 HL Classictype 95 past40years 86 willlive5yearsafterdiagnosis 20 to30 relapseafterinitialtreatmentorwillnotrespondtotherapyatall Suchpatients autologousstem celltransplantation ASCT newertreatmentregimen brentuximabvedotin manypatientseventuallyworsens CBT治疗HL有效的机制 RoemerMG AdvaniRH LigonAH etal PDL1andPD L2geneticalterationsde neclassicalHodgkinlymphomaandpredictoutcome JClinOncol34 2690 2697 2016 Reed Sternbergcellsfromgeneticchanges WhichresultinanabundanceofimmunecheckpointmoleculesPD L1andPD L2 cHL PD L1andPD L2moleculeswerefoundin97 ofthe108specimenstestedresponseratestoPD 1inhibitorsarehigherinclassicHLthaninanyothertypeofcancerstudiedtodate CBT checkpointblockadetherapy 免疫 检查点阻滞治疗 CBT治疗HL有效的机制 RoemerMG AdvaniRH LigonAH etal PDL1andPD L2geneticalterationsde neclassicalHodgkinlymphomaandpredictoutcome JClinOncol34 2690 2697 2016 病理类型影响PD L1 2表达86 nodularsclerosis 11 mixed cellularity3 nototherwisespeci ed 病期影响基因扩增 预后Ampli cationof9p24 1ismorecommoninpatientswithadvancedstagedisease III IV andassociatedwithshorterPFSinthisseries CBT治疗HL有效的机制 RoemerMG AdvaniRH LigonAH etal PDL1andPD L2geneticalterationsde neclassicalHodgkinlymphomaandpredictoutcome JClinOncol34 2690 2697 2016 chromosome9p24 1 resultinginoverexpressionofthePD 1ligandsPD L1andPD L2onthetumourcellsurface JAK2isalsolocatedonchromosome9p24 1 andalterationsinthisgeneincreaseJAK STATsignalling furtherinducingPD L1overexpression PD 1免疫检查点抑制剂有效的机制 NHL表达PD L1 2与cHL不同 25 ofDLBCLtumorsexpressPD 1 PD L1 Andorskyetal 2011 primarymediastinalB celllymphoma PMBL which similartoHL frequentlyharbors9p22amplificationleadingtooverexpressionofPD L1 PD L2 Shietal 2014 R RcHL 纳武单抗YounesA SantoroA ShippM etal NivolumabforclassicalHodgkin slymphomaafterfailureofbothautologousstem celltransplantationandbrentuximabvedotin Amulticentre multicohort single armphase2trial LancetOncol17 1283 1294 2016 single armphase2studyECOG0or1 nivolumabintravenouslyover60minat3mg kgevery2weeksuntilprogressionAug26 2014 Feb20 2015 34hospitalsandacademiccentresacrossEuropeandNorthAmerica primaryendpointwasobjectiveresponse medianfollow upof8 9months R RcHL 纳武单抗YounesA SantoroA ShippM etal NivolumabforclassicalHodgkin slymphomaafterfailureofbothautologousstem celltransplantationandbrentuximabvedotin Amulticentre multicohort single armphase2trial LancetOncol17 1283 1294 2016 lymphomawentintoremissionin53 66 of80patientsanddisappearedentirelyinseven NearlyallpatientswithclassicHLwhorespondedtothetreatmenthadatleasta50 reduction andresponseslasted8months Nivolumabwasgenerallywelltolerated Themostcommonadverseeffectsofanygradewerefatigue infusion relatedreaction andrash R RcHL 纳武单抗YounesA SantoroA ShippM etal NivolumabforclassicalHodgkin slymphomaafterfailureofbothautologousstem celltransplantationandbrentuximabvedotin Amulticentre multicohort single armphase2trial LancetOncol17 1283 1294 2016 Severeadverseeffects suchaslowbloodcounts neutropenia andliverenzymeabnormalities increasedlipase occurredinonly5 ofpatients Nivolumab cHLrelapsingorprogressingafterautologousHSCTandpost transplantationbrentuximabvedotin FDA May2016 USFoodandDrugAdministration Nivolumab Opdivo forHodgkinlymphoma http www fda gov Drugs InformationOnDrugs ApprovedDrugs ucm501412 htm R RcHL 派姆单抗KEYNOTE 013 StudyDesign Multicenter multicohortphaseIbtrial open label December2013toSeptember2014 Primaryendpoints safety CRSecondaryendpoints OR DoR PFS OS biomarkersResponsetotreatmentwasassessedatweek12andevery8weeksthereafter cHLptswithECOGPS0 1 previousbrentuximabvedotinfailure ASCTfailureorineligibility N 31 Discontinuationpermitted 24wks Pembrolizumab10mg kgIVQ2W CR PRorSD PD Txto24mosorPDorintolerabletoxicity Discontinuation ArmandP etal ASH2015 Abstract584 ArmandP etal JCO 34 3733 3739 2016 R RcHL 派姆单抗KEYNOTE 013 BaselineCharacteristics ArmandP etal ASH2015 Abstract584 ArmandP etal JCO 34 3733 3739 2016 90 ofptshaddecreasesintargetlesionburdenincreasescirculatingnumbersofTandNKcells upregulatesTCR IFN signalingOf20ptswithCR PR Stillontreatment n 7DiscontinuedtreatmentCR n 1PRswitchedtx n 1AE n 1AllogeneicSCT n 3PD n 7 R RcHL 派姆单抗 April2016 FDA breakthroughtherapydesignationfortreatmentofrelapsedclassicHL KEYNOTE 013 Efficacy ArmandP etal ASH2015 Abstract584 ArmandP etal JCO 34 3733 3739 2016 NHL CTLA4antibodyipilimumab theORRtocheckpointblockadeinNHLisgenerallylowercomparedwithHLandPMBL phaseItrialofipilimumabin18patientswithR RNHL anORRof11 wasobserved Anselletal 2009 Notably responses althoughlow werequitedurablewithanongoingCRlastingmorethan31and19monthsinoneDLBCLandoneFLpatient respectively NHL nivolumab pembrolizumab phaseI nivolumabinvarioussubtypesofNHL n 54 revealedthehighestrateofORRwasachievedinpatientswithFLat40 closelyfollowedbyDLBCLat36 Lesokhinetal 2016 PatientswithT celllymphomas n 23 werealsoincluded butdidnotfareaswellwithvariableresponses 15 ORR allPR inmycosisfungoidesand40 inperipheralT celllymphoma SimilarstudieswithpembrolizumabinpatientswithNHLarecurrentlyongoing 存在