惡性淋巴瘤免疫治療進(jìn)展

惡性淋巴瘤免疫治療進(jìn)展HistoryofImmunotherapyElertE.Nature.2013;504:S2-S3.1796:Firstuseofimmunotherapy,Jennersmallpoxvaccine1976:BCGvaccineforbladdercancer1863:Connectionbetweenimmunotherapyandcancerrecognized1985:Interferonfirstapprovedforhairycellleukemia1992:IL-2approvedforRCC1997:FirstmAbforcancerapproved,rituximab2008:FirstcancervaccineapprovedforRCC2010:Sipuleucel-Tapprovedforprostatecancer2011:CTLA-4inhibitorapprovedformelanoma

2014-2015:PD-1inhibitorsapprovedformelanoma,squamousNSCLC2015:Firstoncolyticvirusapprovedformelanoma2016:PD-1inhibitorapprovedforcHLPD-L1inhibitorapprovedforUC霍奇金淋巴瘤：背景HL,Classictype,95%past40years,86%willlive5yearsafterdiagnosis.20%to30%relapseafterinitialtreatmentorwillnotrespondtotherapyatall.Suchpatients:autologousstem-celltransplantation(ASCT).newertreatmentregimen+brentuximab

vedotin,manypatientseventuallyworsens.CBT治療HL有效的機(jī)制

[RoemerMG,AdvaniRH,LigonAH,etal:PDL1andPD-L2geneticalterationsde?neclassicalHodgkinlymphomaandpredictoutcome.JClinOncol34:2690-2697,2016].Reed-Sternbergcellsfromgeneticchanges.WhichresultinanabundanceofimmunecheckpointmoleculesPD-L1andPD-L2.cHL,PD-L1andPD-L2moleculeswerefoundin97%ofthe108specimenstested

responseratestoPD-1inhibitorsarehigherinclassicHLthaninanyothertypeofcancerstudiedtodate.CBT，checkpointblockadetherapy，(免疫)檢查點(diǎn)阻滯治療CBT治療HL有效的機(jī)制

[RoemerMG,AdvaniRH,LigonAH,etal:PDL1andPD-L2geneticalterationsde?neclassicalHodgkinlymphomaandpredictoutcome.JClinOncol34:2690-2697,2016].病理類(lèi)型影響PD-L1、2表達(dá)86%nodularsclerosis,11%mixed-cellularity3%nototherwisespeci?ed.病期影響基因擴(kuò)增、預(yù)后Ampli?cationof9p24.1ismorecommoninpatientswithadvancedstagedisease（III/IV）andassociatedwithshorterPFSinthisseries.CBT治療HL有效的機(jī)制

[RoemerMG,AdvaniRH,LigonAH,etal:PDL1andPD-L2geneticalterationsde?neclassicalHodgkinlymphomaandpredictoutcome.JClinOncol34:2690-2697,2016].chromosome9p24.1,resultinginoverexpressionofthePD-1ligandsPD-L1andPD-L2onthetumourcellsurface.JAK2isalsolocatedonchromosome9p24.1,andalterationsinthisgeneincreaseJAK–STATsignalling,furtherinducingPD-L1overexpression.PD-1免疫檢查點(diǎn)抑制劑有效的機(jī)制：

NHL表達(dá)PD-L1、2與cHL不同25%ofDLBCLtumorsexpressPD-1/PD-L1[Andorskyet

al.2011]primarymediastinalB-celllymphoma(PMBL)which,similartoHL，frequentlyharbors9p22amplificationleadingtooverexpressionofPD-L1/PD-L2[Shiet

al.2014].R/RcHL-納武單抗

YounesA,SantoroA,ShippM,etal:NivolumabforclassicalHodgkin’slymphomaafterfailureofbothautologousstem-celltransplantationandbrentuximabvedotin:Amulticentre,multicohort,single-armphase2trial.LancetOncol17:1283-1294,2016single-armphase2studyECOG0or1,nivolumabintravenouslyover60minat3mg/kgevery2weeksuntilprogressionAug26,2014～Feb20,2015,34hospitalsandacademiccentresacrossEuropeandNorthAmerica.primaryendpointwasobjectiveresponse,medianfollow-upof8·9months.R/RcHL-納武單抗

YounesA,SantoroA,ShippM,etal:NivolumabforclassicalHodgkin’slymphomaafterfailureofbothautologousstem-celltransplantationandbrentuximabvedotin:Amulticentre,multicohort,single-armphase2trial.LancetOncol17:1283-1294,2016lymphomawentintoremissionin53(66%)of80patientsanddisappearedentirelyinseven.NearlyallpatientswithclassicHLwhorespondedtothetreatmenthadatleasta50%reduction,andresponseslasted8months.Nivolumabwasgenerallywelltolerated.Themostcommonadverseeffectsofanygradewerefatigue,infusion-relatedreaction,andrash.R/RcHL-納武單抗

YounesA,SantoroA,ShippM,etal:NivolumabforclassicalHodgkin’slymphomaafterfailureofbothautologousstem-celltransplantationandbrentuximabvedotin:Amulticentre,multicohort,single-armphase2trial.LancetOncol17:1283-1294,2016Severeadverseeffects,suchaslowbloodcounts(neutropenia)andliverenzymeabnormalities(increasedlipase),occurredinonly5%ofpatients.Nivolumab，cHLrelapsingorprogressingafterautologousHSCTandpost-transplantationbrentuximabvedotin，F(xiàn)DA，May2016

[USFoodandDrugAdministration:Nivolumab(Opdivohtm].R/RcHL-派姆單抗

KEYNOTE-013:StudyDesignMulticenter,multicohortphaseIbtrial,open-label,December2013toSeptember2014.Primaryendpoints:safety,CRSecondaryendpoints:OR,DoR,PFS,OS,biomarkersResponsetotreatmentwasassessedatweek12andevery8weeksthereafter.cHLptswithECOGPS0/1,previousbrentuximabvedotinfailure,ASCTfailureorineligibility(N=31)

Discontinuation

permitted≥24wksPembrolizumab10mg/kgIVQ2WCRPRorSDPDTxto24mosor

PDorintolerabletoxicityDiscontinuationArmandP,etal.ASH2015.Abstract584；ArmandP,etal.JCO,34:3733-3739,2016.R/RcHL-派姆單抗

KEYNOTE-013:BaselineCharacteristicsCharacteristicPembrolizumab(N=31)Medianage,yrs(range)32(20-67)Pathology,n(%)NodularsclerosisMixedcellularity30(97)1(3)Previousradiationtherapy,n(%)10(32)Previoussystemictherapy,n(%)2-4≥514(45)17(55)Previousbrentuximabvedotinfailure,n(%)31(100)ASCT,n(%)FailureIneligibility/refusal22(71)9(29)ArmandP,etal.ASH2015.Abstract584；ArmandP,etal.JCO,34:3733-3739,2016.90%ofptshaddecreasesintargetlesionburdenincreasescirculatingnumbersofTandNKcells,upregulatesTCR/IFN-γsignalingOf20ptswithCR/PR:Stillontreatment:n=7DiscontinuedtreatmentCR:n=1PRswitchedtx:n=1AE:n=1AllogeneicSCT:n=3PD:n=7R/RcHL-派姆單抗，April2016,FDA,breakthroughtherapydesignationfortreatmentofrelapsedclassicHL.

KEYNOTE-013:EfficacyEndpoint,%Total(N=31)TransplantFailure(n=22)TransplantIneligibility/Refusal(n=9)ORRCRPR651648731459442222SD231833PD13922DoR≥24wksResponsesoccurringby12wks7180PFSat24wks69ArmandP,etal.ASH2015.Abstract584.；ArmandP,etal.JCO,34:3733-3739,2016NHL-CTLA4antibodyipilimumab

theORRtocheckpointblockadeinNHLisgenerallylowercomparedwithHLandPMBL.phaseItrialofipilimumabin18patientswithR/RNHL,anORRof11%wasobserved[Ansellet

al.2009].Notably,responses,althoughlow,werequitedurablewithanongoingCRlastingmorethan31and19monthsinoneDLBCLandoneFLpatient,respectively.NHL-nivolumab/pembrolizumabphaseI,nivolumabinvarioussubtypesofNHL(n=54)revealedthehighestrateofORRwasachievedinpatientswithFLat40%,closelyfollowedbyDLBCLat36%

[Lesokhinet

al.2016].PatientswithT-celllymphomas(n=23)werealsoincluded,butdidnotfareaswellwithvariableresponses:15%ORR(allPR)inmycosisfungoidesand40%inperipheral