美罗华在淋巴瘤治疗中的应用

Lymphoma:ADecadeofRituximabandtheNextChapterWenruSong,MD,PhDPfizerGlobalResearch&Development-Oncology&BaylorInstituteforImmunologyResearch5/9/20241美罗华在淋巴瘤治疗中的应用OutlineHistoricalperspective&reflectionsinRituximab’sdevelopmentImpactofRituximab -Lymphoma -Rheumatoidarthristis,lupus,andotherautoimmunediseases -Othersolidtumors

Newemergingtherapiesinlymphoma5/9/20242美罗华在淋巴瘤治疗中的应用MonoclonalAntibodiesfromHybridomaTechnologyAntigenCellsFuseintoaHybridomaCancerousPlasmaCellAntibody-producingPlasmaCellMonoclonalAntibodiesGeorgesKohlerandCesarMilstein(1975)inNature.Monoclonalantibodiesareartificiallyproducedagainstaspecificantigen.Productionofmonoclonalantibodies(mAbs)withhybridomatechnique.Withthistechniqueagroupoflymphocytesproducingallthesameantibodyproteinisobtained.

revolutionizingdiagnosticmedicine.

Mabsagainstcancer,infections,andotherdiseases.5/9/20243美罗华在淋巴瘤治疗中的应用HistoryofMonoclonalAntibody(Mab)TherapyMurineMab*Ibritomomab*tositumomabHumanized*trastuzumab*bevacizumab*TheraCIMChimeric*Cetuximab*rituximab

*131I-Ch-TNT

Human*panitumumab

CH1CH3CH2VHCLVLCDR1975:

Firstmurine

Mabfromhybridoma

(KohlerandMilstein,Nature)1980’s-90’s:

Humanizationofmurine

Mabs(chimeric

Mab)

2019: 1st

Mabforcancerimmunotherapy:Rituximab2019:

FullyhumanMab:-XenoMouse(Abgenix),HuMab-mouse(Medarex) orPhagescFvlibrary2019-2019:

11MabsapprovedforuseincancerbyUSFDA5/9/20244美罗华在淋巴瘤治疗中的应用FDAApprovedMonoclonalAntibodiesYEARProductTargetIndication1986OrthocloneCD3TransplantRejection1994ReoProGPIIa/IIIbAngioplasty2019RituxanCD20BCellLymphoma2019ZenapaxIL2RTransplantRejection2019SimulectIL2RTransplantRejection2019RemicadeTNFCrohn’s,RA2019HerceptinHer2BreastCancer2000MylotargCD33AML2019CampathCD52CLL2019ZevalinCD20BCellLymphoma2019BexxarCD20BCellLymphoma2019RaptivaCD11aPsoriasis2019AvastinVEGFColonCancer20192019201920192019ErbituxTysabriLucentisVectibixSolirisEGFRa4b1integrinVEGF-AEGFRC5ColonCancerMultiplesclerosisMaculardegenerationColonCancerPNH5/9/20245美罗华在淋巴瘤治疗中的应用The“Ups&Downs”ofMonoclonalAntibody(mAb)Development

“Hey,theseare

magicbullets”“mAbsshouldbeeveninsoup”“Iheardtherearesomeproblems”“I’dapplythemonlytomyenemies”“mAbsworkinsomecases!”19751982198619942019FirstmAbproducedSuccessinlymphomaOKT3approvedLillypurchaseHybritech($350m)WellcomedropsCampathPanorex&

ReoProapp.RituximabGeneticengineeringJesusGomez-Navarro5/9/20246美罗华在淋巴瘤治疗中的应用

5thmostcommoncancerinbothmenandwomeninUSHodgkin’slymphomaandNon-Hodgkin’sLymphoma(NHL)Incidenceincreases3-4%annually(doubledinlast2decades),oneofonlytwocancerswithcontinuedincreaseManysub-typesofNHL,majoritywithB-cellorigin -DiffuselargeBcelllymphoma(DLBCL):mostcommonNHL(30%) -Follicularlymphoma(FL):2ndmostcommonNHL(20%) -Mantlecelllymphoma(MCL):poorestprognosis(6-10%)Leadingtheoncologyfieldindiseasebiology,diagnosis,andtherapy(radiation,chemo,immunotherapy,chemo-immunotherapy)

Lymphoma5/9/20247美罗华在淋巴瘤治疗中的应用

Rituximab(Rituxan,MabThera)

Targetedtherapy

-CD20onlymphoma

-directtumorkillingbyRituximab

Immunotherapy

-hostimmunesystem

-indirecttumorkillingby

hostimmunecells5/9/20248美罗华在淋巴瘤治疗中的应用NaturalKilllerCellsMonocytesFcR2)Complement-mediatedKilling1)Apoptosis,Anti-proliferation3)Antibody-dependentCellularCytotoxicity(ADCC)TumorCellFcRDendriticCells4)AntigenPresentationandCross-primingRituximabAnti-tumorEffect:ProposedMechanismsCD20orothertumorAgsTCells5/9/20249美罗华在淋巴瘤治疗中的应用Vaccine-likeeffectafterRituximabTreatment*Invivo:longerdurationofremissionafterre-treatmentwithRituxanthantheinitialRituxantreatment*Invitro:enhancedcross-primingofcytoxicTcellsbyRituxan-inducedapopotictumorcellsFcRDendriticCellsTCellsTumor5/9/202410美罗华在淋巴瘤治疗中的应用1stFDA-approvedtherapeuticantibodytotreatcancer(11/2019)1stfullyintegratedintochemo-immunotherapy(R-chemo)1standonlybiologictherapyincombinationwithchemo(R-CVP,etc)thatimprovedprogress-freesurvival(PFS)inptswith1stlinefollicularlymphoma,withemergingtrendtoimproveoverallsurvivalforthe1sttime1sttreatmentofanykind(withCHOPoranthracycline-basedchemo)tohaveimprovedoverallsurvival(OS)in1stlineDLBCLinmorethan25yrsRituximab(Rituxan,MabThera):Ahistoryoffirsts5/9/202411美罗华在淋巴瘤治疗中的应用

Chimeric

mabtoCD20,IgG1Weeklyx4(375mg/m2):RapidCD20+Bcelldepletioninblood(100%-fewdays),BM(90%-1wk),andLN(80%-afewwks),returnnormallevelin9-12monthsOnsetandmaximalclinicalresponse:1mtand3-4mtsInitialRxinrelapsedFL:50%ORR(6%CR;44%PR);mDR11mt;Re-Rx:ORR40%(10%CR/30%PR);mDR15mtMaintenanceRx:QwkX4every6mtorQ3mtfor2yrsNochangeofserumIgandincidenceofinfection,andtheTcellresponsefromvaccinationisstillOKRituximab(Rituxan,MabThera):Facts5/9/202412美罗华在淋巴瘤治疗中的应用Anti-idiotype(Id)antibodyLymphomaBcellTwolinesofMonoclonalAntibodyTherapyDevelopmentForLymphomaRituximabCD20TumorIdiotype(Id)5/9/202413美罗华在淋巴瘤治疗中的应用

NewEnglandJournalofMedicine,306:517.1982TreatmentofBCellLymphomawithMonoclonalAnti-IdiotypeAntibodyRichardAMiller,

DavidG.Maloney,RogerWarnke,andRonaldLevyCancerRes.1980;40:3147Serotherapyofapatientwithamonoclonalantibody(murineanti-humanCD20Mab)

directedagainstahumanlymphoma-associatedantigenLeeNadler,etal

5/9/202414美罗华在淋巴瘤治疗中的应用Antibodies:aslowbreakthroughofanewtechnology2019Panitumumab(Vectibix)19751984198619901994Technologiestoreduceimmunogenicityofmonoclonalantibodies: technological evolutiontowards humanization, humanantibodiesinnovation biographyofdrugsChristianZeller5/9/202415美罗华在淋巴瘤治疗中的应用19761978,1985,198612/199203/1993201903/9611/97,06/982019

INDfromIDEC1stptInP1Levy

lastptInP3

FDA

EMEA1stline;R-chemo;maintenanceTimelineofRituximabDevelopmentIDEC&Genentech/RocheCo-developHybritechIDECBiotherapySystemLevy/MillerGenentechBoyer/CohenCD20geneIn1980NadlerIDEC5/9/202416美罗华在淋巴瘤治疗中的应用DevelopmentofIDEC’sStockPricesChristianZellerPhaseItrialdoneIDEC&GenentechCo-developFDAapproval5/9/202417美罗华在淋巴瘤治疗中的应用PhaseI:1993-94 -singledose:10,50,100,250,500mg/m2,NoMTD -15pts:2PR(100,500mg/m2) -MaloneyDG,Blood84:2457,1994

PhaseI:1994-95 -multipledose(weeklyx4):125,250,375mg/m2,NoMTD -20pts:6PRs(1/3in125,2/6in250,3/9in375),ORR=33% -MaloneyDG,JClinOnc15:3266,2019PhaseII:2019-96 -Fixeddose(375mg/m2),weeklyx4(determinedbytheavailableMab) -37pts:3CR/14PR(ORR=46%),mTTP10.2months -MaloneyDG,Blood90:2188,2019PhaseII/IIIPivotaltrial:2019-96EarlyclinicaldevelopmentofRituximab5/9/202418美罗华在淋巴瘤治疗中的应用RituximabPivotalPhaseII/IIITrial:

ClinicalResponseinRelapsedIndolentorFollicularLymphomaMcLaughlinetal.JClinOncol.2019.5/9/202419美罗华在淋巴瘤治疗中的应用OutlineHistoricalperspectiveinRituximab’sdevelopmentImpactofRituximab -Lymphoma

-Rheumatoidarthritis,lupus,andotherautoimmunediseases -Othersolidtumors

Newemergingtherapiesinlymphoma5/9/202420美罗华在淋巴瘤治疗中的应用RandomizedTrialsofChemotherapyplusRituximabversusChemotherapyAloneinB-CellLymphomaChesonB,LeonardJ.NEnglJMed2019;359:6135/9/202421美罗华在淋巴瘤治疗中的应用RandomizedTrialsofMaintenanceTreatmentwithRituximabversusObservationRandomizedTrialsofMaintenanceTreatmentwithRituximabversusObservationChesonB,LeonardJ.NEnglJMed2019;359:613-6265/9/202422美罗华在淋巴瘤治疗中的应用ExtendedUsesofRituximab:IntegrationintoLymphomaStandardofCareSalvagetherapyforchemo-refractoryorrelapsed:lowgradeUp-fronttherapyDelayoravoidchemotherapy—lowgradeCombinationtherapyWithchemotherapyWithotherbiologicals-enhanceADCCWithothermonoclonalsMaintenancetherapy5/9/202423美罗华在淋巴瘤治疗中的应用MortalityRatesofNon-Hodgkin’sLymphoma5/9/202424美罗华在淋巴瘤治疗中的应用RituximabPublicationsNumberofpublicationsYearPublications1stclinicaltrial160180200801001201400204060Jan/91929394959697989900FDAapprovalPivotaltrialresults1millionptsworldwidebeingtreated4378in20195/9/202425美罗华在淋巴瘤治疗中的应用Rituxan/MabThera:ablockbusterChristianZeller5/9/202426美罗华在淋巴瘤治疗中的应用Top5BestSellingOncologyDrugsin2019RankOncologyProductCompany2019WWRevenue($M)OncologyIndications1RituxanGenentech/Biogen-IDEC$3,820NHL2HerceptinGenentech$3,356BC3AvastinGenentech$2,880NSCLC,CRC,BC4GleevecNovartis$2,737CML,GIST,ALL5EloxatinSanofiAventis$2,456CRCPfizer-Oncology5/9/202427美罗华在淋巴瘤治疗中的应用ApprovedMAbsforCancerTherapyTargetNameTumorYearFormatHer-2Trastuzumab(Herceptin)Breast2019HumanizedIgG1VEGFBevacizumab(Avastin)Colon,NSCLC,Breast2019HumanizedIgG1EGFRCetuximab(Erbitux)Colon,H/N2019chimericIgG1Panitumumab(Vectibix)Colon2019FullyhumanIgG2Nimotuzumab*(TheraCMI)Nasopharyngel2019HumanizedIgG1DAN-associated131I-Ch-TNT*Lung2019Chemiric,131ICD20RituximabNHL2019ChimericIgG1CD52Alemtuzumab

(Campath-1H)CLL2019HumanizedIgG1CD33Gemtuzumab(Myelotarg)AML2000HumanizedIgM-calichamycinCD20Ibritumomab(Zevalin)NHL2019Murine90Y-IgG1CD20Tositumomab(Bexxar)NHL2019Murine131I-IgG1*FirstapprovedinChina5/9/202428美罗华在淋巴瘤治疗中的应用OutlineHistoricalperspectiveinRituximab’sdevelopmentImpactofRituximab -Lymphoma -Rheumatoidarthristis,lupus,andotherautoimmunediseases -OthersolidtumorsNewemergingtherapiesinlymphoma(phaseI-IIItrials)

-humanorhumanizedanti-CD20:

enhancedADCC,CDC -Othernewtargets:

CD22,CD40,CD80,mTOR,HDAC,Revlimid,Avastin,Velcade,PKC-b,TRAIL,Bcl-2,CTLA-4 -Rituxan-basedcombinationalBio-Rx -Insituvaccines(dendriticcells,CpG)5/9/202429美罗华在淋巴瘤治疗中的应用ChesonB,LeonardJ.NEnglJMed2019;359:613-626UnconjugatedMonoclonalAntibodiesforB-CellCancers5/9/202430美罗华在淋巴瘤治疗中的应用

Drug/SponsorDesignPhaseLineofTherapyGaliximab(CD80)(Biogen)Galiximab+Rituxan(R)vsRituxan(R)IIIRelapsedorrefractoryFLVelcade(Millennium/JJ)Velcade+RituxanvsRituxanIIIRelpasedorrefractoryFLSGN-40(CD40)(SG/Genentech)SGN-40(CD40)+RituxanIRelapsedFLandmaginalzoneNHLSGN-40(SG/Genentech)SGN-40+R-chemovsR-chemoIIRelapsedDLBCLRevlimid(Celgene)Revlimid+RituxanIIRelapsedorrefractoryFLOfatumumab(2ndgenerationRituxanGSK/GeneMab)OfatumumabvsRituxanIIIRelapsedorrefractoryFLEpratuzumab(CD22)(Immunomedics/CALGB)Epratuzumab+RituxanII1stlineFLInvestigationalCombinationBioRxforB-CellCancers5/9/202431美罗华在淋巴瘤治疗中的应用Mostpotent“antigen-presentingcells”Resideintissuestocollectantigen->traveltolymphnodesCo-culturewithantigens->cellularvaccineDendriticCells5/9/202432美罗华在淋巴瘤治疗中的应用InsituVaccinationwithDCChemo+DC15/15DCChemo

+Chemo0/8DC0/7NoRx0/9MeanTumorSizeDaysposttumorimplantationSong&LevyCanRes20195/9/202433美罗华在淋巴瘤治疗中的应用DendriticCellsChemotherapyOrRadiotherapyLeukapheresisIntratumoralDCVaccination+ConventionalTherapyIntratumorInjection2135/9/202434美罗华在淋巴瘤治疗中的应用USFDAapprovdthreeInvestigationalNewDrug(INDs)Applications:-Coloncancerwithhepaticmetasteses(phaseI;Stanford)-Locallyadvancedpancreaticcancer(phaseI/II;Stanford)-Lymphomaandothersolidtumors(phaseI/II;Baylor)IntratumoralDCVaccination+ConventionalTherapy:FromLabtoClinic5/9/202435美罗华在淋巴瘤治疗中的应用CpGbridgesinnateandadaptiveimmunityBacterialDNA

ACGTTGAGTTCGTACGCATACGAVertebrateDNA

AGCTTGAGTCmCGGATGGGTAAGAImmunesystemrecognizesCpGthroughTLR-9andinducesactivationofDC,B&TcellsDendriticCellTumor-specificTCellsCpGTLR-9TLR-9BCellTumor5/9/202436美罗华在淋巴瘤治疗中的应用CpGOnlyWorksIntra-TumorallyLiJ,SongW,etal.,JImmunol.2019,179:24935/9/202437美罗华在淋巴瘤治疗中的应用RadiationInsituVaccinationwithCpGCpG5/9/202438美罗华在淋巴瘤治疗中的应用Pre-treatmentWeek1263yomalewithrecurrentfollicularlymphoma:partialresponseASCO20195/9/202439美罗华在淋巴瘤治疗中的应用USOncologyGrowthMarketProjections5/9/202440美罗华在淋巴瘤治疗中的应用5/9/202441美罗华在淋巴瘤治疗中的应用AcknowledgementStanfordUniversityMedicalCenter

RonaldLevyEdgarEngleman

BaylorInstituteforImmunologyResearch&BaylorSammonsCancerCenter-JacquesBanchereau,StevePaulson-MaryleneLeogier,JingtaoChen,LicunWu,ZhiqingWang$BaylorUniversityHealthcareSystemFoundation$USNationalCancerInstitute/NIHPfizerOncology:JesusGomez-Navarro5/9/202442美罗华在淋巴瘤治疗中的应用Questions??5/9/202443美罗华在淋巴瘤治疗中的应用5/9/202444美罗华在淋巴瘤治疗中的应用Function:antibodyBcellTwoArmsoftheImmuneSystemBcells(Humoral)

Tcells(Cellular)MakeantibodiesKillabnormalcellsforeignsubstance(antigen)TcellAbnormalcell5/9/202445美罗华在淋巴瘤治疗中的应用AntibodyStructure5/9/202446美罗华在淋巴瘤治疗中的应用TheImmuneSystemisamixtureofClonesEachBcellcanmakeonlyoneantibodyEachTcellcanmakeonlyoneTcellreceptor5/9/202447美罗华在淋巴瘤治疗中的应用

FcgRIIIA158V/FpolymorphismV/VV/FF/FFCarriers 8/1012/289/2321/51(80%)(43%)(39%)(41%)p=0.037

WengandLevyJClinOnc2019

Rituximab

ClinicalResponseDeterminedbyHostGenetics

5/9/202448美罗华在淋巴瘤治疗中的应用7-YearResultsofGELAStudy(LNH-98.5)Primaryendpoint:EFSSecondaryendpoints:PFS,OS,DFS,andRRASSESSUntreatedelderlypatientswithDLBCLstratifiedbyriskfactors(0-1vs2-3)(N=399)RANDOMIZER-CHOP

q3w×8(n=202)CHOP

q3w×8(n=197)Coiffieretal.ASCO2019.Abstract8009.5/9/202449美罗华在淋巴瘤治疗中的应用Coiffieretal.ASCO2019.Abstract8009.0.00.20.40.60.81.0012345678P<0.0001YearsSurvivalProbabilityR-CHOP52CHOP29PFS(%)7-YearResultsofGELAStudy(LNH-98.5)0.00.20.40.60.81.0012345678P=0.0004SurvivalProbabilityYearsR-CHOP53CHOP36

OS(%)5/9/202450美罗华在淋巴瘤治疗中的应用.TumorBiopsy+VaccineProductionTumorIdiotype(Id)ProteinImmunizationKLHcarrierproteinAdjuvant(SAF)Id123MyelomacellATher