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恶性淋巴瘤免疫治疗进展陈振东陈振东安徽医科大学第二附属医院肿瘤中心安徽医科大学第二附属医院肿瘤中心HistoryofImmunotherapyElert E.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霍奇金淋巴瘤：背景霍奇金淋巴瘤：背景HL,Classictype,95%past 40 years,86%will live 5 years afterdiagnosis.20%to30%relapseafterinitialtreatmentorwill not respond to therapy at all.Suchpatients:1.autologousstem-celltransplantation(ASCT).2.newertreatment regimen+brentuximabvedotin,3.manypatientseventuallyworsens.CBT治疗治疗HL有效的机制有效的机制RoemerMG,AdvaniRH,LigonAH,etal:PDL1andPD-L2geneticalterationsdefineclassicalHodgkinlymphomaandpredictoutcome.JClinOncol34:2690-2697,2016.Reed-Sternberg cells from genetic changes.Which result in an abundance of immunecheckpointmoleculesPD-L1andPD-L2.cHL,PD-L1andPD-L2moleculeswerefoundin97%ofthe108specimenstestedresponseratestoPD-1inhibitorsarehigherinclassicHLthaninanyothertypeofcancerstudiedtodate.CBT，checkpointblockadetherapy，(免疫免疫)检查点阻滞治疗检查点阻滞治疗CBT治疗治疗HL有效的机制有效的机制RoemerMG,AdvaniRH,LigonAH,etal:PDL1andPD-L2geneticalterationsdefineclassicalHodgkinlymphomaandpredictoutcome.JClinOncol34:2690-2697,2016.病理类型影响病理类型影响PD-L1、2表达表达86%nodularsclerosis,11%mixed-cellularity3%nototherwisespecified.病期影响基因扩增、预后病期影响基因扩增、预后Amplificationof9p24.1ismorecommoninpatientswithadvancedstagedisease（III/IV）andassociatedwithshorterPFSinthisseries.CBT治疗治疗HL有效的机制有效的机制RoemerMG,AdvaniRH,LigonAH,etal:PDL1andPD-L2geneticalterationsdefineclassicalHodgkinlymphomaandpredictoutcome.JClinOncol34:2690-2697,2016.chromosome9p24.1,resultinginoverexpression of the PD-1 ligandsPD-L1andPD-L2onthetumourcellsurface.JAK2isalsolocatedonchromosome9p24.1,and alterations in this geneincreaseJAKSTATsignalling,furtherinducingPD-L1overexpression.PD-1免疫检查点抑制剂有效的机制：免疫检查点抑制剂有效的机制：NHLNHL表达表达PD-L1PD-L1、2 2与与cHLcHL不同不同25%ofDLBCLtumorsexpressPD-1/PD-L1Andorskyetal.2011primary mediastinal B-cell lymphoma(PMBL)which,similartoHL，frequently harbors 9p22 amplificationleadingtooverexpressionofPD-L1/PD-L2Shietal.2014.R/RcHL-纳武单抗纳武单抗YounesA,SantoroA,ShippM,etal:NivolumabforclassicalHodgkinslymphomaafterfailureofbothautologousstem-celltransplantationandbrentuximabvedotin:Amulticentre,multicohort,single-armphase2trial.LancetOncol17:1283-1294,2016single-armphase2studyECOG0or1,nivolumabintravenouslyover60minat3mg/kgevery2weeksuntilprogressionAug 26,2014 Feb 20,2015,34hospitalsandacademiccentresacrossEuropeandNorthAmerica.primaryendpointwasobjectiveresponse,median follow-up of 89months.R/RcHL-纳武单抗纳武单抗YounesA,SantoroA,ShippM,etal:NivolumabforclassicalHodgkinslymphomaafterfailureofbothautologousstem-celltransplantationandbrentuximabvedotin:Amulticentre,multicohort,single-armphase2trial.LancetOncol17:1283-1294,2016lymphoma went into remission in 53(66%)of 80 patients and disappearedentirely in seven.Nearly all patientswithclassicHLwhorespondedtothetreatmenthadatleasta50%reduction,andresponseslasted8months.Nivolumab was generally well tolerated.The most common adverse effects ofanygradewerefatigue,infusion-relatedreaction,andrash.R/RcHL-纳武单抗纳武单抗YounesA,SantoroA,ShippM,etal:NivolumabforclassicalHodgkinslymphomaafterfailureofbothautologousstem-celltransplantationandbrentuximabvedotin:Amulticentre,multicohort,single-armphase2trial.LancetOncol17:1283-1294,2016Severe adverse effects,such as low bloodcounts(neutropenia)andliverenzymeabnormalities(increasedlipase),occurredinonly5%ofpatients.Nivolumab，cHLrelapsingorprogressingafterautologous HSCT and post-transplantationbrentuximabvedotin，FDA，May2016US FoodandDrugAdministration:Nivolumab(Opdivo)forHodgkinlymphoma.http:/www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501412.htm.R/RcHL-派姆单抗派姆单抗KEYNOTE-013:StudyDesignMulticenter,multicohort phase Ib trial,open-label,December2013toSeptember2014.Primaryendpoints:safety,CRSecondaryendpoints:OR,DoR,PFS,OS,biomarkersResponse to treatment was assessed at week 12 and every 8weeksthereafter.cHL pts with ECOG PS 0/1,previous brentuximab vedotin failure,ASCT failure or ineligibility(N=31)Discontinuation permitted 24 wksPembrolizumab 10 mg/kg IV Q2WCRPR or SDPDTx to 24 mos orPD or intolerable toxicityDiscontinuationArmand P,et al.ASH 2015.Abstract 584；Armand P,et al.JCO,34:3733-3739,2016.R/R cHL-R/R cHL-派姆单抗派姆单抗 KEYNOTE-013:Baseline CharacteristicsKEYNOTE-013:Baseline CharacteristicsCharacteristicCharacteristicPembrolizumabPembrolizumab(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)Armand P,et al.ASH 2015.Abstract 584；Armand P,et al.JCO,34:3733-3739,2016.90%90%of of pts pts had had decreases decreases in in target lesion burdentarget lesion burdenincreases increases circulating circulating numbers numbers of of T T and and NK NK cells,cells,upregulates upregulates TCR/IFN-TCR/IFN-signaling signalingOf 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=7R/R cHL-R/R cHL-派姆单抗，派姆单抗，April2016,FDA,breakthroughtherapydesignationfortreatmentofrelapsedclassicHL.KEYNOTE-013:EfficacyKEYNOTE-013:EfficacyEndpoint,%Endpoint,%Total Total(N=(N=31)31)Transplant Transplant FailureFailure(n=22)(n=22)TransplantIneligibility/Refusal(n=9)ORRCRPR651648731459442222SD231833PD13922DoR 24 wksResponses occurring by 12 wks7180PFS at 24 wks69Armand P,et al.ASH 2015.Abstract 584.；Armand P,et al.JCO,34:3733-3739,2016NHL-CTLA4antibodyipilimumabtheORRtocheckpointblockadeinNHLisgenerally lower compared with HL andPMBL.phaseItrialofipilimumabin18patientswithR/R NHL,an ORR of 11%was observedAnselletal.2009.Notably,responses,althoughlow,were quite durable with an ongoingCRlastingmorethan31and19monthsinoneDLBCLandoneFLpatient,respectively.NHL-nivolumab/pembrolizumabphase I,nivolumab in various subtypes ofNHL(n=54)revealedthehighestrateofORRwasachievedinpatientswithFLat40%,closely followed by DLBCL at 36%Lesokhinetal.2016.PatientswithT-celllymphomas(n=23)werealsoincluded,butdidnotfareaswellwithvariable responses:15%ORR(all PR)inmycosisfungoidesand40%inperipheralT-celllymphoma.Similar studies with pembrolizumab inpatientswithNHLarecurrentlyongoing.存在的问题存在的问题-研究本身研究本身1.single-armstudy2.long-termfollow-upwillberequiredtodeterminethedurabilityofresponses3.ongoing host immune reactionswithintumoursmighthavecontributed to persistent F-FDGuptake存在的问题存在的问题1.PD-L1、2表达程度是否影响疗效？表达程度是否影响疗效？2.治疗持续多长时间最合适？治疗持续多长时间最合适？3.获得获得CR后的终止治疗，何时开始？后的终止治疗，何时开始？4.CR不是很高，治愈的可能性？不是很高，治愈的可能性？5.PR的意义有多大？的意义有多大？6.比比起起其其他他的的治治疗疗，如如放放疗疗其其他他治治疗疗，孰优？性价比？孰优？性价比？进一步研究进一步研究for for relapsed relapsed as as well well as as newly newly diagnoseddiagnosed classic HL is under way.classic HL is under way.KEYNOTE-204 KEYNOTE-204 phase phase III III trialtrial，compare compare pembrolizumab pembrolizumab vs vs BV BV in in pts pts with with R/R R/R cHL(NCT02684292)cHL(NCT02684292)nivolumab nivolumab with with brentuximab brentuximab vedotin vedotin and and ipilimumab ipilimumab(ClinicalTrials.gov(ClinicalTrials.gov identiidentifiers:ers:NCT02758717,NCT02758717,NCT01896999,and NCT02304458).NCT01896999,and NCT02304458).other other hematologic hematologic malignancies,malignancies,as as well well as as in in multiple multiple myeloma myeloma(ClinicalTrial.gov(ClinicalTrial.gov identiidentifier:er:NCT01953692).NCT01953692).谢谢聆听!