恶性淋巴瘤免疫治疗进展ppt课件

恶性淋巴瘤免疫治疗进展,1,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,2,霍奇金淋巴瘤：背景,HL,Classictype,95%past40years,86%willlive5yearsafterdiagnosis.20%to30%relapseafterinitialtreatmentorwillnotrespondtotherapyatall.Suchpatients:autologousstem-celltransplantation(ASCT).newertreatmentregimen+brentuximabvedotin,manypatientseventuallyworsens.,3,CBT治疗HL有效的机制RoemerMG,AdvaniRH,LigonAH,etal:PDL1andPD-L2geneticalterationsdeneclassicalHodgkinlymphomaandpredictoutcome.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,4,CBT治疗HL有效的机制RoemerMG,AdvaniRH,LigonAH,etal:PDL1andPD-L2geneticalterationsdeneclassicalHodgkinlymphomaandpredictoutcome.JClinOncol34:2690-2697,2016.,病理类型影响PD-L1、2表达86%nodularsclerosis,11%mixed-cellularity3%nototherwisespecied.病期影响基因扩增、预后Amplicationof9p24.1ismorecommoninpatientswithadvancedstagedisease（III/IV）andassociatedwithshorterPFSinthisseries.,5,CBT治疗HL有效的机制RoemerMG,AdvaniRH,LigonAH,etal:PDL1andPD-L2geneticalterationsdeneclassicalHodgkinlymphomaandpredictoutcome.JClinOncol34:2690-2697,2016.,chromosome9p24.1,resultinginoverexpressionofthePD-1ligandsPD-L1andPD-L2onthetumourcellsurface.JAK2isalsolocatedonchromosome9p24.1,andalterationsinthisgeneincreaseJAKSTATsignalling,furtherinducingPD-L1overexpression.,6,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-L1Andorskyetal.2011primarymediastinalB-celllymphoma(PMBL)which,similartoHL，frequentlyharbors9p22amplificationleadingtooverexpressionofPD-L1/PD-L2Shietal.2014.,7,R/RcHL-纳武单抗YounesA,SantoroA,ShippM,etal:NivolumabforclassicalHodgkinslymphomaafterfailureofbothautologousstem-celltransplantationandbrentuximabvedotin:Amulticentre,multicohort,single-armphase2trial.LancetOncol17:1283-1294,2016,single-armphase2studyECOG0or1,nivolumabintravenouslyover60minat3mg/kgevery2weeksuntilprogressionAug26,2014Feb20,2015,34hospitalsandacademiccentresacrossEuropeandNorthAmerica.primaryendpointwasobjectiveresponse,medianfollow-upof89months.,8,R/RcHL-纳武单抗YounesA,SantoroA,ShippM,etal:NivolumabforclassicalHodgkinslymphomaafterfailureofbothautologousstem-celltransplantationandbrentuximabvedotin:Amulticentre,multicohort,single-armphase2trial.LancetOncol17:1283-1294,2016,lymphomawentintoremissionin53(66%)of80patientsanddisappearedentirelyinseven.NearlyallpatientswithclassicHLwhorespondedtothetreatmenthadatleasta50%reduction,andresponseslasted8months.Nivolumabwasgenerallywelltolerated.Themostcommonadverseeffectsofanygradewerefatigue,infusion-relatedreaction,andrash.,9,R/RcHL-纳武单抗YounesA,SantoroA,ShippM,etal:NivolumabforclassicalHodgkinslymphomaafterfailureofbothautologousstem-celltransplantationandbrentuximabvedotin:Amulticentre,multicohort,single-armphase2trial.LancetOncol17:1283-1294,2016,Severeadverseeffects,suchaslowbloodcounts(neutropenia)andliverenzymeabnormalities(increasedlipase),occurredinonly5%ofpatients.Nivolumab，cHLrelapsingorprogressingafterautologousHSCTandpost-transplantationbrentuximabvedotin，FDA，May2016USFoodandDrugAdministration:Nivolumab(Opdivo)forHodgkinlymphoma./Drugs/InformationOnDrugs/ApprovedDrugs/ucm501412.htm.,10,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),Discontinuationpermitted24wks,Pembrolizumab10mg/kgIVQ2W,CR,PRorSD,PD,Txto24mosorPDorintolerabletoxicity,Discontinuation,ArmandP,etal.ASH2015.Abstract584；ArmandP,etal.JCO,34:3733-3739,2016.,11,R/RcHL-派姆单抗KEYNOTE-013:BaselineCharacteristics,ArmandP,etal.ASH2015.Abstract584；ArmandP,etal.JCO,34:3733-3739,2016.,12,90%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,34:3733-3739,2016,13,NHL-CTLA4antibodyipilimumab,theORRtocheckpointblockadeinNHLisgenerallylowercomparedwithHLandPMBL.phaseItrialofipilimumabin18patientswithR/RNHL,anORRof11%wasobservedAnselletal.2009.Notably,responses,althoughlow,werequitedurablewithanongoingCRlastingmorethan31and19monthsinoneDLBCLandoneFLpatient,respectively.,14,NHL-nivolumab/pembrolizumab,phaseI,nivolumabinvarioussubtypesofNHL(n=54)revealedthehighestrateofORRwasachievedinpatientswithFLat40%,closelyfollowedbyDLBCLat36%Lesokhinetal.2016.PatientswithT-celllymphomas(n=23)werealsoincluded,butdidnotfareaswellwithvariableresponses:15%ORR(allPR)inmycosisfungoidesand40%inperipheralT-celllymphoma.SimilarstudieswithpembrolizumabinpatientswithNHLarecurrentlyongoing.,15,存在的问题-研究本身,s