《美罗华在淋巴瘤治疗中的应用》由会员分享，可在线阅读，更多相关《美罗华在淋巴瘤治疗中的应用（54页珍藏版）》请在金锄头文库上搜索。
1、Lymphoma: A Decade of Rituximab and the Next ChapterWenru Song, MD, PhDPfizer Global Research & Development-Oncology&Baylor Institute for Immunology ResearchOutlineHistorical perspective & reflections in Rituximabs developmentImpact of Rituximab-Lymphoma-Rheumatoidarthristis,lupus,andotherautoimmune
2、diseases-OthersolidtumorsNew emerging therapies in lymphomaMonoclonal Antibodies from Hybridoma TechnologyAntigenCells Fuse into a HybridomaCancerousPlasma CellAntibody-producingPlasma Cell Monoclonal AntibodiesGeorges Kohler and Cesar Milstein (1975) in Nature.Monoclonal antibodies are artificially
3、 produced against a specific antigen.Production of monoclonal antibodies (mAbs) with hybridoma technique.With this technique a group of lymphocytes producing all the same antibody protein is obtained. revolutionizing diagnostic medicine. Mabs against cancer, infections, and other diseases.History of
4、 Monoclonal Antibody (Mab) TherapyMurine Mab*Ibritomomab*tositumomabHumanized*trastuzumab*bevacizumab*TheraCIMChimeric*Cetuximab*rituximab *131I -Ch-TNT Human*panitumumab CH1CH3CH2VHCLVLCDR1975:First murine Mab from hybridoma(KohlerandMilstein,Nature)1980s-90s:Humanization of murine Mabs (chimeric M
5、ab)1997:1st Mab for cancer immunotherapy: Rituximab1998:Fully human Mab:-XenoMouse (Abgenix), HuMab-mouse (Medarex) or Phage scFv library1997- 2007: 11 Mabs approvedforuseincancerbyUSFDAFDAApprovedMonoclonalAntibodiesYEARProductTargetIndication1986OrthocloneCD3Transplant Rejection1994ReoProGPIIa/III
6、bAngioplasty1997RituxanCD20B Cell Lymphoma1998ZenapaxIL2RTransplant Rejection1998SimulectIL2RTransplant Rejection1998RemicadeTNFCrohns, RA1998HerceptinHer2Breast Cancer2000MylotargCD33AML2001CampathCD52CLL2002ZevalinCD20B Cell Lymphoma2003BexxarCD20B Cell Lymphoma2003RaptivaCD11aPsoriasis2004Avastin
7、VEGFColon Cancer20042004200620062007ErbituxTysabriLucentisVectibixSolirisEGFRa a4b b1 integrinVEGF-AEGFRC5Colon CancerMultiple sclerosisMacular degenerationColon CancerPNHThe “Ups & Downs” of Monoclonal Antibody (mAb) Development “Hey, these are magic bullets”“mAbs should be even in soup”“I heard th
8、ere are some problems”“Id apply them only to my enemies”“mAbs work in some cases!”19751982198619941997First mAb producedSuccess in lymphomaOKT3 approvedLilly purchase Hybritech ($350m)Wellcome drops CampathPanorex & ReoPro app.RituximabGenetic engineeringJesus Gomez-Navarro 5th most common cancer in
9、 both men and women in US Hodgkins lymphoma and Non-Hodgkins Lymphoma (NHL) Incidence increases 3-4% annually (doubled in last 2 decades), one of only two cancers with continued increase Many sub-types of NHL, majority with B-cell origin-Diffuse large B cell lymphoma (DLBCL): most common NHL (30%) -
10、Follicular lymphoma (FL): 2nd most common NHL (20%)-Mantle cell lymphoma (MCL): poorest prognosis (6-10%) Leading the oncology field in disease biology, diagnosis, and therapy (radiation, chemo, immunotherapy, chemo-immunotherapy) Lymphoma Rituximab (Rituxan, MabThera) Targeted therapy -CD20 on lymp
11、homa -direct tumor killing by Rituximab Immunotherapy-host immune system-indirect tumor killing by host immune cellsNatural Killler Cells MonocytesFcR2) Complement-mediated Killing1) Apoptosis, Anti-proliferation3) Antibody-dependent Cellular Cytotoxicity (ADCC)Tumor CellFcRDendritic Cells4) Antigen
12、 Presentation and Cross-primingRituximab Anti-tumor Effect: Proposed Mechanisms CD20 or other tumor AgsT CellsVaccine-like effect after Rituximab Treatment * In vivo: longer duration of remission after re-treatment with Rituxan than the initial Rituxan treatment *In vitro: enhanced cross-priming of
13、cytoxic T cells by Rituxan-induced apopotic tumor cellsFcRDendritic CellsT CellsTumor 1st FDA-approved therapeutic antibody to treat cancer (11/1997) 1st fully integrated into chemo-immunotherapy (R-chemo) 1st and only biologic therapy in combination with chemo (R-CVP, etc) that improved progress-fr
14、ee survival (PFS) in pts with 1st line follicular lymphoma, with emerging trend to improve overall survival for the 1st time 1st treatment of any kind (with CHOP or anthracycline-based chemo) to have improved overall survival (OS) in 1st line DLBCL in more than 25 yrsRituximab (Rituxan, MabThera): A
15、 history of firsts Chimeric mab to CD20, IgG1 Weekly x 4 (375mg/m2): Rapid CD20+B cell depletion in blood (100%-few days), BM (90%-1wk), and LN (80%- a few wks), return normal level in 9-12 months Onset and maximal clinical response: 1mt and 3-4 mts Initial Rx in relapsed FL: 50% ORR (6%CR; 44%PR);
16、mDR 11mt; Re-Rx: ORR 40% (10%CR/30%PR); mDR 15mt Maintenance Rx: Qwk X4 every 6 mt or Q3mt for 2 yrs No change of serum Ig and incidence of infection, and the T cell response from vaccination is still OKRituximab (Rituxan, MabThera): FactsAnti-idiotype (Id) antibodyLymphomaB cellTwolinesofMonoclonal
17、AntibodyTherapyDevelopmentForLymphomaRituximabCD20Tumor Idiotype (Id)14 New England Journal of Medicine, 306:517. 1982 Treatment of B Cell Lymphoma with Monoclonal Anti-Idiotype AntibodyRichard A Miller, David G. Maloney, Roger Warnke, and Ronald LevyCancer Res. 1980;40:3147Serotherapy of a patient
18、with a monoclonal antibody(murine anti-human CD20 Mab) directed against a human lymphoma-associated antigenLee Nadler, et al Antibodies: a slow breakthrough of a new technology2006 Panitumumab (Vectibix)19751984198619901994Technologiestoreduceimmunogenicityofmonoclonalantibodies:technologicalevoluti
19、ontowardshumanization,humanantibodiesinnovationbiographyofdrugsChristian Zeller1976 1978, 1985, 1986 12/1992 03/1993 1995 03/96 11/97, 06/98 2006 IND from IDEC1st ptIn P1Levy last pt In P3 FDA EMEA1st line;R-chemo;maintenanceTimeline of Rituximab DevelopmentIDEC & Genentech/RocheCo-developHybritechI
20、DECBiotherapy SystemLevy/MillerGenentechBoyer/CohenCD20 geneIn 1980NadlerIDECDevelopment of IDECs Stock PricesChristian ZellerPhase I trial doneIDEC & GenentechCo-developFDA approvalPhaseI:1993-94-singledose:10,50,100,250,500mg/m2,NoMTD-15pts:2PR(100,500mg/m2)-MaloneyDG,Blood84:2457,1994PhaseI:1994-
21、95-multipledose(weeklyx4):125,250,375mg/m2,NoMTD-20pts:6PRs(1/3in125,2/6in250,3/9in375),ORR=33%-MaloneyDG,JClinOnc15:3266,1997PhaseII:1995-96-Fixeddose(375mg/m2),weeklyx4(determinedbytheavailableMab)-37pts:3CR/14PR(ORR=46%),mTTP10.2months-MaloneyDG,Blood90:2188,1997PhaseII/IIIPivotaltrial:1995-96Ear
22、ly clinical development of RituximabRituximabPivotalPhaseII/IIITrial:ClinicalResponseinRelapsedIndolentorFollicularLymphomaMcLaughlin et al. J Clin Oncol. 1998.OutlineHistoricalperspectiveinRituximabsdevelopmentImpact of Rituximab-Lymphoma-Rheumatoid arthritis, lupus, and other autoimmune diseases-O
23、ther solid tumorsNewemergingtherapiesinlymphomaRandomized Trials of Chemotherapy plus Rituximab versus Chemotherapy Alone in B-Cell LymphomaCheson B, Leonard J. N Engl J Med 2008; 359:613Randomized Trials of Maintenance Treatment with Rituximab versus ObservationRandomized Trials of Maintenance Trea
24、tment with Rituximab versus ObservationCheson B, Leonard J. N Engl J Med 2008;359:613-626Extended Uses of Rituximab: Integration into Lymphoma Standard of CareSalvagetherapyforchemo-refractoryorrelapsed:lowgradeUp-fronttherapyDelayoravoidchemotherapylowgradeCombinationtherapyWithchemotherapyWithothe
25、rbiologicals-enhanceADCCWithothermonoclonalsMaintenancetherapyMortality Rates of Non-Hodgkins Lymphoma25Rituximab PublicationsNumber of publicationsYearPublications1st clinical trial160180200200801001201400204060Jan/91929394959697989900FDAapprovalPivotaltrial results-1 million pts worldwide being tr
26、eated4378 in 2008Rituxan / MabThera: a blockbusterChristian ZellerTop 5 Best Selling Oncology Drugs in 2007Top 5 Best Selling Oncology Drugs in 2007RankOncology ProductCompany2007 WW Revenue ($M)Oncology Indications1RituxanGenentech/Biogen-IDEC$3,820NHL2HerceptinGenentech$3,356BC3AvastinGenentech$2,
27、880NSCLC, CRC, BC4GleevecNovartis$2,737CML, GIST, ALL5EloxatinSanofi Aventis$2,456CRCPfizer-OncologyApproved MAbs for Cancer TherapyTargetNameTumorYear FormatHer-2Trastuzumab(Herceptin)Breast1998Humanized IgG1VEGFBevacizumab(Avastin)Colon,NSCLC,Breast2004Humanized IgG1EGFRCetuximab(Erbitux)Colon,H/N
28、2004chimeric IgG1Panitumumab(Vectibix)Colon2006Fully human IgG2Nimotuzumab* (Thera CMI)Nasopharyngel2005 Humanized IgG1DAN-associated131I -Ch-TNT*Lung2003Chemiric, 131ICD20RituximabNHL1997Chimeric IgG1CD52Alemtuzumab (Campath-1H)CLL2001Humanized IgG1CD33Gemtuzumab(Myelotarg)AML2000Humanized IgM-cali
29、chamycinCD20Ibritumomab(Zevalin)NHL2002Murine 90Y-IgG1CD20Tositumomab(Bexxar)NHL2003Murine131I-IgG1*First approved in ChinaOutlineHistoricalperspectiveinRituximabsdevelopmentImpactofRituximab-Lymphoma-Rheumatoid arthristis, lupus, and other autoimmune diseases-Other solid tumorsNewemergingtherapiesi
30、nlymphoma(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)Cheson B, Leonard J. N Engl J Med 2008;359:613-626Unconjugated Monoclon
31、al Antibodies for B-Cell Cancers Drug/Sponsor DesignPhase Line of TherapyGaliximab (CD80) (Biogen)Galiximab +Rituxan (R)vs Rituxan (R)IIIRelapsed or refractory FLVelcade(Millennium/JJ)Velcade + Rituxan vs Rituxan IIIRelpased or refractory FLSGN-40 (CD40)(SG/Genentech)SGN-40 (CD40)+ RituxanI Relapsed
32、 FL and maginal zone NHLSGN-40(SG/Genentech)SGN-40+ R-chemo vs R-chemoIIRelapsed DLBCLRevlimid(Celgene)Revlimid + RituxanIIRelapsed or refractory FLOfatumumab (2nd generation RituxanGSK/GeneMab)Ofatumumab vs RituxanIIIRelapsed or refractory FLEpratuzumab (CD22)(Immunomedics/CALGB)Epratuzumab + Ritux
33、anII1st line FLInvestigational Combination BioRx for B-Cell CancersMostpotent“antigen-presentingcells”Resideintissuestocollectantigen-traveltolymphnodesCo-culturewithantigens-cellularvaccineDendritic CellsIn situ Vaccination with DCChemo+DC 15/15DCChemo + Chemo 0/8DC 0/7No Rx 0/9Mean Tumor SizeDaysp
34、osttumorimplantationSong & LevyCan Res 2005Dendritic CellsChemotherapyOr Radiotherapy Leukapheresis Intratumoral DC Vaccination + Conventional TherapyIntratumorInjection213US FDA approvd three Investigational New Drug (INDs) Applications:-Colon cancer with hepatic metasteses (phase I; Stanford) -Loc
35、ally advanced pancreatic cancer (phase I/II; Stanford)-Lymphoma and other solid tumors (phase I/II; Baylor)Intratumoral DC Vaccination + Conventional Therapy: From Lab to ClinicCpG bridges innate and adaptive immunityBacterial DNA ACGTTGAGTTCGTACGCATACGAVertebrate DNA AGCTTGAGTCmCGGATGGGTAAGAImmune
36、system recognizes CpG through TLR-9 and induces activation of DC, B & T cells Dendritic CellTumor-specific T CellsCpGCpGTLR-9TLR-9B Cell TumorCpG Only Works Intra-TumorallyLiJ,SongW,etal.,JImmunol.2007,179:2493RadiationInsituVaccinationwithCpGCpGPre-treatmentWeek1263 yo male with recurrent follicula
37、r lymphoma: partial responseASCO2008US Oncology Growth Market ProjectionsAcknowledgement Stanford University Medical Center -RonaldLevy-EdgarEngleman Baylor Institute for Immunology Research & Baylor Sammons Cancer Center-JacquesBanchereau,StevePaulson-MaryleneLeogier,JingtaoChen,LicunWu,ZhiqingWang
38、 $ Baylor University Healthcare System Foundation $ US National Cancer Institute/NIH Pfizer Oncology: JesusGomez-NavarroQuestions?Function:antibodyB cellTwo Arms of the Immune SystemB cells (Humoral)T cells (Cellular) Make antibodiesKill abnormal cellsforeignsubstance(antigen)T cellAbnormalcellAntib
39、ody StructureThe Immune System is a mixture of ClonesEach B cell can make only one antibodyEach T cell can make only one T cell receptor FcgR IIIA 158 V/F polymorphism V/V V/F F/F F Carriers 8/10 12/28 9/23 21/51 (80%) (43%) (39%) (41%) p=0.037 Weng and Levy J Clin Onc 2003 Rituximab Clinical Respon
40、se Determined by Host Genetics 7-Year Results of GELA Study (LNH-98.5)Primary end point: EFSSecondary end points: PFS, OS, DFS, and RRASSESSUntreated elderly patients with DLBCL stratified by risk factors(0-1 vs 2-3)(N=399)RANDOMIZER-CHOPq3w 8 (n=202)CHOPq3w 8 (n=197)Coiffier et al. ASCO 2007. Abstr
41、act 8009.Coiffier et al. ASCO 2007. Abstract 8009.0.00.20.40.60.81.0012345678P0.0001YearsSurvivalProbabilityR-CHOP52CHOP29 PFS (%)7-Year Results of GELA Study (LNH-98.5)0.00.20.40.60.81.0012345678P=0.0004SurvivalProbabilityYearsR-CHOP53CHOP36OS (%).TumorBiopsy+VaccineProductionTumorIdiotype(Id)Prote
42、inImmunizationKLHcarrierproteinAdjuvant(SAF)Id123MyelomacellA Therapeutic Vaccine for Lymphoma“Rescuehybridization” 0204060801000246810PROBABILITY (%)TIME (YEARS)Responders (n=14)non-Responders (n=18)p0.0001Freedom From ProgressionFollicular Lymphoma first remissionHsu et al Blood 1997BioVest Phase
43、III TrialTreatmentScheduleEnrollmentMonthlyVaccinesx7Immunization: 28 weeksRecovery26weekschemoFollowforTimetoProgressionRandomize2/13phaseIIItrials(NCI/BioVest,Favirille,Genitope)Selected studies of single-agent rituximab in low-grade or follicular NHLaAbbreviations: NHL, non-Hodgkins lymphoma; CR,
44、 complete response; OR, overall response, PFS, progression-free survival; TTP, time to progression; DR duration of response.PatientsResponse (%)ReferencesPopulationRituximab treatment(n)CRORTime-to-event outcomeNewly diagnosed32, 33follicularNHL,375mg/m2weekly4494980medianPFS=18monthslowtumorburden5
45、-yearRFS=28%34follicularNHL,375mg/m2weekly4363672medianTTP=26monthsGrade1Relapsed/refractory26, 27low-gradeor375mg/m2weekly4166648medianDR=11.2monthsfollicularNHL28follicularNHL375mg/m2weekly470346medianDR=11months29follicularNHL,375mg/m2weekly4301747medianDR=5.8monthsadvancedstage30low-gradeor375mg/m2weekly431339medianDR=5.9monthsfollicularNHL,bulkydisease31low-gradeor375mg/m2weekly8371443medianDR=13.4+monthsfollicularNHL
