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精选ppt1ElertE.Nature.2013;504:S2-S3.1796:Firstuseofimmunotherapy,Jennersmallpoxvaccine1976:BCGvaccineforbladdercanc

er1863:Connectionbetweenimmunotherapyandcancerrecognized1985:Interferonfirstapprovedforhairycellleukem

ia1992:IL-2approvedforRCC1997:FirstmAbforcancerapproved,rituximab2008:FirstcancervaccineapprovedforRCC2010:

Sipuleucel-Tapprovedforprostatecancer2011:CTLA-4inhibitorapprovedformelanoma2014-2015:PD-1inhibitorsapprovedformelanoma,squamousN

SCLC2015:Firstoncolyticvirusapprovedformelanoma2016:PD-1inhibitorapprovedforcHLPD-L1inhibitorapprovedforUC精选ppt2HL,Classictype,95%past40ye

ars,86%willlive5yearsafterdiagnosis.20%to30%relapseafterinitialtreatmentorwillnotrespondtotherapyatall.Suchpatients:1.

autologousstem-celltransplantation(ASCT).2.newertreatmentregimen+brentuximabvedotin,3.manypatientseventuallyworsens.精选ppt3Reed

-Sternbergcellsfromgeneticchanges.WhichresultinanabundanceofimmunecheckpointmoleculesPD-L1andPD-L2.cHL,PD-L1andPD-L2mol

eculeswerefoundin97%ofthe108specimenstestedresponseratestoPD-1inhibitorsarehigherinclassicHLthaninanyothertypeofcancerstudiedtodate.CBT，checkpoi

ntblockadetherapy，(免疫)检查点阻滞治疗精选ppt4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ppt5chrom

osome9p24.1,resultinginoverexpressionofthePD-1ligandsPD-L1andPD-L2onthetumourcellsurface.JAK2isalsolocatedonchromosome9p24.1,andalterationsinthis

geneincreaseJAK–STATsignalling,furtherinducingPD-L1overexpression.精选ppt625%ofDLBCLtumorsexpressPD-1/PD-L

1[Andorskyetal.2011]primarymediastinalB-celllymphoma(PMBL)which,similartoHL，frequentlyharbors9p22amplificationleadingt

ooverexpressionofPD-L1/PD-L2[Shietal.2014].精选ppt7single-armphase2studyECOG0or1,nivolumabintravenouslyover60minat3mg/kgevery2weeks

untilprogressionAug26,2014～Feb20,2015,34hospitalsandacademiccentresacrossEuropeandNorthAmerica.primaryendpointwasobjectiveresponse,med

ianfollow-upof8·9months.精选ppt8lymphomawentintoremissionin53(66%)of80patientsanddisappearedentirelyin

seven.NearlyallpatientswithclassicHLwhorespondedtothetreatmenthadatleasta50%reduction,andresponseslasted8months.Nivol

umabwasgenerallywelltolerated.Themostcommonadverseeffectsofanygradewerefatigue,infusion-relatedreaction,andrash.精选ppt9Severeadverseeffec

ts,suchaslowbloodcounts(neutropenia)andliverenzymeabnormalities(increasedlipase),occurredinonly5%ofpatients.Nivolumab，

cHLrelapsingorprogressingafterautologousHSCTandpost-transplantationbrentuximabvedotin，FDA，May2016[USFoodand

DrugAdministration:Nivolumab(Opdivo)forHodgkinlymphoma.http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501412.h

tm].精选ppt10Multicenter,multicohortphaseIbtrial,open-label,December2013toSeptember2014.Primaryendpoints:safety,CRSecondaryendpoints:OR,DoR,PFS,OS,

biomarkersResponsetotreatmentwasassessedatweek12andevery8weeksthereafter.cHLptswithECOGPS0/1,previousbrentuximabvedotinfail

ure,ASCTfailureorineligibility(N=31)Discontinuationpermitted≥24wksPembrolizumab10mg/kgIVQ2WCRPRorSDP

DTxto24mosorPDorintolerabletoxicityDiscontinuationArmandP,etal.ASH2015.Abstract584；ArmandP,etal.JCO,34:3733-3739,2016.精选ppt11CharacteristicPemb

rolizumab(N=31)Medianage,yrs(range)32(20-67)Pathology,n(%)•Nodularsclerosis•Mixedcellularity30(97)1(3)Previousradiationtherapy,n(%)10(32)Previou

ssystemictherapy,n(%)•2-4•≥514(45)17(55)Previousbrentuximabvedotinfailure,n(%)31(100)ASCT,n(%)•Failure•Ineli

gibility/refusal22(71)9(29)ArmandP,etal.ASH2015.Abstract584；ArmandP,etal.JCO,34:3733-3739,2016.精选ppt1290%ofptsh

addecreasesintargetlesionburdenincreasescirculatingnumbersofTandNKcells,upregulatesTCR/IFN-γsignalingOf20ptswithCR/PR:Stillontreatment:n=7Discont

inuedtreatmentCR:n=1PRswitchedtx:n=1AE:n=1AllogeneicSCT:n=3PD:n=7Endpoint,%Total(N=31)TransplantFailure(n=22)TransplantIneligibility/Refus

al(n=9)ORR•CR•PR651648731459442222SD231833PD13922DoR≥24wks•Responsesoccurringby12wks7180PFSat24wks69ArmandP,etal.ASH2015.Abstract584.；ArmandP,eta

l.JCO,34:3733-3739,2016精选ppt13theORRtocheckpointblockadeinNHLisgenerallylowercomparedwithHLandPMBL.phaseItrialofipilimumabin18patientsw

ithR/RNHL,anORRof11%wasobserved[Anselletal.2009].Notably,responses,althoughlow,werequitedurablewithanongoingCRlastingmorethan31and19

monthsinoneDLBCLandoneFLpatient,respectively.精选ppt14phaseI,nivolumabinvarioussubtypesofNHL(n=54)revealedthehighestrateofORRwasachiev

edinpatientswithFLat40%,closelyfollowedbyDLBCLat36%[Lesokhinetal.2016].PatientswithT-celllymphomas(n=23)werealsoincluded,butdi

dnotfareaswellwithvariableresponses:15%ORR(allPR)inmycosisfungoidesand40%inperipheralT-celllymphoma.Similar

studieswithpembrolizumabinpatientswithNHLarecurrentlyongoing.精选ppt151.single-armstudy2.long-termfollow-upwillberequiredtodeterminethedurabilityofres

ponses3.ongoinghostimmunereactionswithintumoursmighthavecontributedtopersistent¹⁸F-FDGuptake精选ppt161.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forrelapsedaswellasnewlydiagnosedclassicHLisund

erway.KEYNOTE-204phaseIIItrial，comparepembrolizumabvsBVinptswithR/RcHL(NCT02684292)nivolumabwithbrentuximabvedot

inandipilimumab(ClinicalTrials.govidentifiers:NCT02758717,NCT01896999,andNCT02304458).otherhematologicmalignancies,aswellasinmultiplemye

loma(ClinicalTrial.govidentifier:NCT01953692).精选ppt18谢谢聆听!精选ppt19