《惡性淋巴瘤免疫治療進(jìn)展ppt課件.ppt》由會員分享，可在線閱讀，更多相關(guān)《惡性淋巴瘤免疫治療進(jìn)展ppt課件.ppt（19頁珍藏版）》請?jiān)趨R文網(wǎng)上搜索。

1、惡性淋巴瘤免疫治療進(jìn)展惡性淋巴瘤免疫治療進(jìn)展陳振東陳振東安徽醫(yī)科大學(xué)第二附屬醫(yī)院腫瘤中心安徽醫(yī)科大學(xué)第二附屬醫(yī)院腫瘤中心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 hair

2、y 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

3、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-celltransplantat

4、ion(ASCT).2.newertreatment regimen+brentuximabvedotin,3.manypatientseventuallyworsens.CBT治療治療HL有效的機(jī)制有效的機(jī)制RoemerMG,AdvaniRH,LigonAH,etal:PDL1andPD-L2geneticalterationsdefineclassicalHodgkinlymphomaandpredictoutcome.JClinOncol34:2690-2697,2016.Reed-Sternberg cells from genetic changes.Which result in

5、an abundance of immunecheckpointmoleculesPD-L1andPD-L2.cHL,PD-L1andPD-L2moleculeswerefoundin97%ofthe108specimenstestedresponseratestoPD-1inhibitorsarehigherinclassicHLthaninanyothertypeofcancerstudiedtodate.CBT，checkpointblockadetherapy，(免疫免疫)檢查點(diǎn)阻滯治療檢查點(diǎn)阻滯治療CBT治療治療HL有效的機(jī)制有效的機(jī)制RoemerMG,AdvaniRH,LigonA

6、H,etal:PDL1andPD-L2geneticalterationsdefineclassicalHodgkinlymphomaandpredictoutcome.JClinOncol34:2690-2697,2016.病理類型影響病理類型影響PD-L1、2表達(dá)表達(dá)86%nodularsclerosis,11%mixed-cellularity3%nototherwisespecified.病期影響基因擴(kuò)增、預(yù)后病期影響基因擴(kuò)增、預(yù)后Amplificationof9p24.1ismorecommoninpatientswithadvancedstagedisease（III/IV）and

7、associatedwithshorterPFSinthisseries.CBT治療治療HL有效的機(jī)制有效的機(jī)制RoemerMG,AdvaniRH,LigonAH,etal:PDL1andPD-L2geneticalterationsdefineclassicalHodgkinlymphomaandpredictoutcome.JClinOncol34:2690-2697,2016.chromosome9p24.1,resultinginoverexpression of the PD-1 ligandsPD-L1andPD-L2onthetumourcellsurface.JAK2isals

8、olocatedonchromosome9p24.1,and alterations in this geneincreaseJAKSTATsignalling,furtherinducingPD-L1overexpression.PD-1免疫檢查點(diǎn)抑制劑有效的機(jī)制：免疫檢查點(diǎn)抑制劑有效的機(jī)制：NHLNHL表達(dá)表達(dá)PD-L1PD-L1、2 2與與cHLcHL不同不同25%ofDLBCLtumorsexpressPD-1/PD-L1Andorskyetal.2011primary mediastinal B-cell lymphoma(PMBL)which,similartoHL，frequen

9、tly harbors 9p22 amplificationleadingtooverexpressionofPD-L1/PD-L2Shietal.2014.R/RcHL-納武單抗納武單抗YounesA,SantoroA,ShippM,etal:NivolumabforclassicalHodgkinslymphomaafterfailureofbothautologousstem-celltransplantationandbrentuximabvedotin:Amulticentre,multicohort,single-armphase2trial.LancetOncol17:1283-

10、1294,2016single-armphase2studyECOG0or1,nivolumabintravenouslyover60minat3mg/kgevery2weeksuntilprogressionAug 26,2014 Feb 20,2015,34hospitalsandacademiccentresacrossEuropeandNorthAmerica.primaryendpointwasobjectiveresponse,median follow-up of 89months.R/RcHL-納武單抗納武單抗YounesA,SantoroA,ShippM,etal:Nivol

11、umabforclassicalHodgkinslymphomaafterfailureofbothautologousstem-celltransplantationandbrentuximabvedotin:Amulticentre,multicohort,single-armphase2trial.LancetOncol17:1283-1294,2016lymphoma went into remission in 53(66%)of 80 patients and disappearedentirely in seven.Nearly all patientswithclassicHL

12、whorespondedtothetreatmenthadatleasta50%reduction,andresponseslasted8months.Nivolumab was generally well tolerated.The most common adverse effects ofanygradewerefatigue,infusion-relatedreaction,andrash.R/RcHL-納武單抗納武單抗YounesA,SantoroA,ShippM,etal:NivolumabforclassicalHodgkinslymphomaafterfailureofbot

13、hautologousstem-celltransplantationandbrentuximabvedotin:Amulticentre,multicohort,single-armphase2trial.LancetOncol17:1283-1294,2016Severe adverse effects,such as low bloodcounts(neutropenia)andliverenzymeabnormalities(increasedlipase),occurredinonly5%ofpatients.Nivolumab，cHLrelapsingorprogressingaf

14、terautologous HSCT and post-transplantationbrentuximabvedotin，F(xiàn)DA，May2016US FoodandDrugAdministration:Nivolumab(Opdivo)forHodgkinlymphoma.http:/www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501412.htm.R/RcHL-派姆單抗派姆單抗KEYNOTE-013:StudyDesignMulticenter,multicohort phase Ib trial,open-label,Dec

15、ember2013toSeptember2014.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 wksPemb

16、rolizumab 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-派姆單抗派姆單抗 KEYNOTE-013:Baseline CharacteristicsKEYNOTE-013:Baseline CharacteristicsCharacteristicCharacteristicPembroli

17、zumabPembrolizumab(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)Ar

18、mand 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/IF

19、N-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-派姆單抗，派姆單抗，April2016,FDA,b

20、reakthroughtherapydesignationfortreatmentofrelapsedclassicHL.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

21、 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,res

22、ponses,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%Lesokhinet

23、al.2016.PatientswithT-celllymphomas(n=23)werealsoincluded,butdidnotfareaswellwithvariable responses:15%ORR(all PR)inmycosisfungoidesand40%inperipheralT-celllymphoma.Similar studies with pembrolizumab inpatientswithNHLarecurrentlyongoing.存在的問題存在的問題-研究本身研究本身1.single-armstudy2.long-termfollow-upwillber

24、equiredtodeterminethedurabilityofresponses3.ongoing host immune reactionswithintumoursmighthavecontributed to persistent F-FDGuptake存在的問題存在的問題1.PD-L1、2表達(dá)程度是否影響療效？表達(dá)程度是否影響療效？2.治療持續(xù)多長時(shí)間最合適？治療持續(xù)多長時(shí)間最合適？3.獲得獲得CR后的終止治療，何時(shí)開始？后的終止治療，何時(shí)開始？4.CR不是很高，治愈的可能性？不是很高，治愈的可能性？5.PR的意義有多大？的意義有多大？6.比比起起其其他他的的治治療療，如如放放療療

25、其其他他治治療療，孰優(yōu)？性價(jià)比？孰優(yōu)？性價(jià)比？進(jìn)一步研究進(jìn)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

26、/R cHL(NCT02684292)cHL(NCT02684292)nivolumab nivolumab with with brentuximab brentuximab vedotin vedotin and and ipilimumab ipilimumab(ClinicalTrials.gov(ClinicalTrials.gov identiidentififiers: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 identiidentififier:er:NCT01953692).NCT01953692).謝謝聆聽!