恶性淋巴瘤免疫治疗进展课件

精选ppt1恶性淋巴瘤免疫治疗进展精选ppt1ElertE.Nature.2013;504:S2-S3.1796:First use of immunotherapy,Jenner smallpox vaccine1976:BCG vaccine for bladder cancer1863:Connection between immunotherapy and cancer recognized1985:Interferon first approved for hairy cell leukemia1992:IL-2 approved for RCC1997:First mAb for cancer approved,rituximab2008:First cancer vaccine approved for RCC2010:Sipuleucel-T approved for prostate cancer2011:CTLA-4 inhibitor approved for melanoma 2014-2015:PD-1 inhibitors approved for melanoma,squamous NSCLC2015:First oncolytic virus approved for melanoma 2016:PD-1 inhibitor approved for cHLPD-L1 inhibitor approved for UC精选ppt2HistoryofImmunotherapyElertHL,Classictype,95%past40years,86%willlive5yearsafterdiagnosis.20%to30%relapseafterinitialtreatmentorwillnotrespondtotherapyatall.Suchpatients:1.autologousstem-celltransplantation(ASCT).2.newertreatmentregimen+brentuximabvedotin,3.manypatientseventuallyworsens.精选ppt3霍奇金淋巴瘤：背景HL,Classictype,95%Reed-Sternbergcellsfromgeneticchanges.WhichresultinanabundanceofimmunecheckpointmoleculesPD-L1andPD-L2.cHL,PD-L1andPD-L2moleculeswerefoundin97%ofthe108specimenstestedresponseratestoPD-1inhibitorsarehigherinclassicHLthaninanyothertypeofcancerstudiedtodate.CBT，checkpointblockadetherapy，(免疫)检查点阻滞治疗精选ppt4CBT治疗HL有效的机制RoemerMG,Advan病理类型影响PD-L1、2表达86%nodularsclerosis,11%mixed-cellularity3%nototherwisespecified.病期影响基因扩增、预后Amplificationof9p24.1ismorecommoninpatientswithadvancedstagedisease（III/IV）andassociatedwithshorterPFSinthisseries.精选ppt5CBT治疗HL有效的机制RoemerMG,Advanchromosome9p24.1,resultinginoverexpressionofthePD-1ligandsPD-L1andPD-L2onthetumourcellsurface.JAK2isalsolocatedonchromosome9p24.1,andalterationsinthisgeneincreaseJAKSTATsignalling,furtherinducingPD-L1overexpression.精选ppt6CBT治疗HL有效的机制RoemerMG,Advan25%ofDLBCLtumorsexpressPD-1/PD-L1Andorskyetal.2011primarymediastinalB-celllymphoma(PMBL)which,similartoHL，frequentlyharbors9p22amplificationleadingtooverexpressionofPD-L1/PD-L2Shietal.2014.精选ppt7PD-1免疫检查点抑制剂有效的机制：NHL表达PD-L1single-armphase2studyECOG0or1,nivolumabintravenouslyover60minat3mg/kgevery2weeksuntilprogressionAug26,2014Feb20,2015,34hospitalsandacademiccentresacrossEuropeandNorthAmerica.primaryendpointwasobjectiveresponse,medianfollow-upof89months.精选ppt8R/RcHL-纳武单抗YounesA,Santorolymphomawentintoremissionin53(66%)of80patientsanddisappearedentirelyinseven.NearlyallpatientswithclassicHLwhorespondedtothetreatmenthadatleasta50%reduction,andresponseslasted8months.Nivolumabwasgenerallywelltolerated.Themostcommonadverseeffectsofanygradewerefatigue,infusion-relatedreaction,andrash.精选ppt9R/RcHL-纳武单抗YounesA,SantoroSevereadverseeffects,suchaslowbloodcounts(neutropenia)andliverenzymeabnormalities(increasedlipase),occurredinonly5%ofpatients.Nivolumab，cHLrelapsingorprogressingafterautologousHSCTandpost-transplantationbrentuximabvedotin，FDA，May2016USFoodandDrugAdministration:Nivolumab(Opdivo)forHodgkinlymphoma.http:/www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501412.htm.精选ppt10R/RcHL-纳武单抗YounesA,SantoroMulticenter,multicohortphaseIbtrial,open-label,December2013toSeptember2014.Primaryendpoints:safety,CRSecondaryendpoints:OR,DoR,PFS,OS,biomarkersResponsetotreatmentwasassessedatweek12andevery8weeksthereafter.cHLptswithECOGPS0/1,previousbrentuximabvedotinfailure,ASCTfailureorineligibility(N=31)Discontinuation permitted 24 wksPembrolizumab 10mg/kgIVQ2WCRPRorSDPDTx to 24 mos orPD or intolerable toxicityDiscontinuationArmandP,etal.ASH2015.Abstract584；ArmandP,etal.JCO,34:3733-3739,2016.精选ppt11R/RcHL-派姆单抗KEYNOTE-013:StCharacteristicCharacteristicPembrolizumabPembrolizumab(N=31)(N=31)Median age,yrs(range)32(20-67)Pathology,n(%)Nodular sclerosisMixed cellularity30(97)1(3)Previous radiation therapy,n(%)10(32)Previous systemic therapy,n(%)2-4 514(45)17(55)Previous brentuximab vedotin failure,n(%)31(100)ASCT,n(%)FailureIneligibility/refusal22(71)9(29)ArmandP,etal.ASH2015.Abstract584；ArmandP,etal.JCO,34:3733-3739,2016.精选ppt12R/RcHL-派姆单抗KEYNOTE-013:Bas90%of pts had decreases in 90%of pts had decreases in target lesion burdentarget lesion burdenincreases circulating numbers increases circulating numbers of T and NK cells,of T and NK cells,upregulates TCR/IFN-upregulates TCR/IFN-signalingsignalingOf 20 pts with CR/PR:Of 20 pts with CR/PR:Still on treatment:n=7Still on treatment:n=7Discontinued treatmentDiscontinued treatmentCRCR:n=1:n=1PR switched tx:n=1PR switched tx:n=1AE:n=1AE:n=1Allogeneic SCT:n=3Allogeneic SCT:n=3PD:n=7PD:n=7Endpoint,%Endpoint,%Total Total(N=(N=31)31)Transplant Transplant FailureFailure(n=22)(n=22)Transplant Ineligibility/Refusal(n=9)ORRCRPR651648731459442222SD231833PD13922DoR 24 wksResponses occurring by 12 wks7180PFS at 24 wks69ArmandP,etal.ASH2015.Abstract584.；ArmandP,etal.JCO,34:3733-3739,2016精选ppt1390%ofptshaddecreasesintatheORRtocheckpointblockadeinNHLisgenerallylowercomparedwithHLandPMBL.phaseItrialofipilimumabin18patientswithR/RNHL,anORRof11%wasobservedAnselletal.2009.Notably,responses,althoughlow,werequitedurablewithanongoingCRlastingmorethan31and19monthsinoneDLBCLandoneFLpatient,respectively.精选ppt14NHL-CTLA4antibodyipilimumabphaseI,nivolumabinvarioussubtypesofNHL(n=54)revealedthehighestrateofORRwasachievedinpatientswithFLat40%,closelyfollowedbyDLBCLat36%Lesokhinetal.2016.PatientswithT-celllymphomas(n=23)werealsoincluded,butdidnotfareaswellwithvariableresponses:15%ORR(allPR)inmycosisfungoidesand40%inperipheralT-celllymphoma.SimilarstudieswithpembrolizumabinpatientswithNHLarecurrentlyongoing.精选ppt15NHL-nivolumab/pembrolizumabp1.single-armstudy2.long-termfollow-upwillberequiredtodeterminethedurabilityofresponses3.ongoinghostimmunereactionswithintumoursmighthavecontributedtopersistentF-FDGuptake精选ppt16存在的问题-研究本身single-armstudy精选pp1.PD-L1、2表达程度是否影响疗效？2.治疗持续多长时间最合适？3.获得CR后的终止治疗，何时开始？4.CR不是很高，治愈的可能性？5.PR的意义有多大？6.比起其他的治疗，如放疗其他治疗，孰优？性价比？精选ppt17存在的问题PD-L1、2表达程度是否影响疗效？精选ppt17for relapsed as well as for relapsed as well as newly diagnosednewly diagnosed classic HL is classic HL is under way.under way.KEYNOTE-204 phase III trialKEYNOTE-204 phase III trial，compare pembrolizumab vs compare pembrolizumab vs BV in pts with R/R cHL(NCT02684292)BV in pts with R/R cHL(NCT02684292)nivolumab with brentuximab vedotin and ipilimumab nivolumab with brentuximab vedotin and ipilimumab(ClinicalTrials.gov identi(ClinicalTrials.gov identifiers:NCT02758717,ers:NCT02758717,NCT01896999,and NCT02304458).NCT01896999,and NCT02304458).other hematologic malignancies,as well as in other hematologic malignancies,as well as in multiple myeloma(ClinicalTrial.gov identimultiple myeloma(ClinicalTrial.gov identifier:er:NCT01953692).NCT01953692).精选ppt18进一步研究forrelapsedaswellasn 谢谢聆听!精选ppt19谢谢聆听!精选ppt19