美羅華在淋巴瘤治療中的應(yīng)用

1、Lymphoma: A Decade of Rituximab and the Next Chapter,,Wenru Song, MD, PhDPfizer Global Research & Development-Oncology&Baylor Institute for Immunology Research,Outline,,Historical perspective & reflection

2、s in Rituximab’s developmentImpact of Rituximab-Lymphoma-Rheumatoid arthristis, lupus, and other autoimmune diseases-Other solid tumorsNew emerging therapies in lymphoma,Monoclonal Antibodies from Hybridoma Te

3、chnology,Georges Kohler and Cesar Milstein (1975) in Nature.Monoclonal antibodies are artificially produced against a specific antigen.Production of monoclonal antibodies (mAbs) with hybridoma technique.With this tech

4、nique a group of lymphocytes producing all the same antibody protein is obtained.? revolutionizing diagnostic medicine.? Mabs against cancer, infections, and other diseases.,,History of Monoclonal Antibody (Mab) Therap

5、y,Murine Mab*Ibritomomab*tositumomab,Humanized*trastuzumab*bevacizumab*TheraCIM,Chimeric*Cetuximab*rituximab *131I -Ch-TNT,Human*panitumumab,1975: First murine Mab from hybridoma (Kohler and Milstein, Nature)

6、1980’s-90’s: Humanization of murine Mabs (chimeric Mab) 2019:1st Mab for cancer immunotherapy: Rituximab2019: Fully human Mab: -XenoMouse (Abgenix), HuMab-mouse (Medarex) or Phage scFv library,,2019- 2019:

7、11 Mabs approved for use in cancer by US FDA,,FDA Approved Monoclonal Antibodies,,,The “Ups & Downs” of Monoclonal Antibody (mAb) Development,,“Hey, these are magic bullets”,“mAbs should be even in soup”,“I heard t

8、here are some problems”,“I’d apply them only to my enemies”,“mAbs work in some cases!”,,1975,1982,1986,1994,2019,First mAb produced,Success in lymphoma,OKT3 approved,Lilly purchase Hybritech ($350m),Wellcome drops Campat

9、h,Panorex & ReoPro app.,Rituximab,Genetic engineering,,,Jesus Gomez-Navarro,5th most common cancer in both men and women in US Hodgkin’s lymphoma and Non-Hodgkin’s Lymphoma (NHL) Incidence increases 3-4% annual

10、ly (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%) -Follicular lymphoma (

11、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),Lympho

12、ma,Rituximab (Rituxan, MabThera) Targeted therapy -CD20 on lymphoma -direct tumor killing by Rituximab Immunotherapy-host immune system-indirect tumor killing by host immune cells,,,,,,,,,,,,Natural Killle

13、r Cells Monocytes,FcR,,,,,,,2) Complement-mediated Killing,1) Apoptosis, Anti-proliferation,3) Antibody-dependent Cellular Cytotoxicity (ADCC),Tumor Cell,,,FcR,Dendritic Cells,4) Antigen Presentation and Cro

14、ss-priming,,,,,,,Rituximab Anti-tumor Effect: Proposed Mechanisms,CD20 or other tumor Ags,,T Cells,,,,Vaccine-like effect after Rituximab Treatment,* In vivo: longer duration of remission after re-treatment with Rituxan

15、 than the initial Rituxan treatment *In vitro: enhanced cross-priming of cytoxic T cells by Rituxan-induced apopotic tumor cells,,,,,FcR,Dendritic Cells,,T Cells,Tumor,,1st FDA-approved therapeutic antibody to treat

16、cancer (11/2019) 1st fully integrated into chemo-immunotherapy (R-chemo) 1st and only biologic therapy in combination with chemo (R-CVP, etc) that improved progress-free survival (PFS) in pts with 1st line follicula

17、r 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 y

18、rs,Rituximab (Rituxan, MabThera): A 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 i

19、n 9-12 months Onset and maximal clinical response: 1mt and 3-4 mts Initial Rx in relapsed FL: 50% ORR (6%CR; 44%PR); mDR 11mt; Re-Rx: ORR 40% (10%CR/30%PR); mDR 15mt Maintenance Rx: Qwk X4 every 6 mt or Q3mt for

20、 2 yrs No change of serum Ig and incidence of infection, and the T cell response from vaccination is still OK,Rituximab (Rituxan, MabThera): Facts,,Anti-idiotype (Id) antibody,,LymphomaB cell,Two lines of Monoclonal A

21、ntibody Therapy Development For Lymphoma,Rituximab,,CD20,Tumor Idiotype (Id),,,,New England Journal of Medicine, 306:517. 1982 Treatment of B Cell Lymphoma with Monoclonal Anti-Idiotype AntibodyRichard A Miller

22、, David G. Maloney, Roger Warnke, and Ronald Levy,Cancer Res. 1980;40:3147Serotherapy of a patient with a monoclonal antibody(murine anti-human CD20 Mab) directed against a human lymphoma-associated antigenLee Nadl

23、er, et al,Antibodies: a slow breakthrough of a new technology,Technologies to reduce immunogenicity of monoclonal antibodies:technological evolution towards humanization, human antibodies innovation biography o

24、f drugs,Christian Zeller,,,1976 1978, 1985, 1986 12/1992 03/1993 2019 03/96 11/97, 06/98 2019,,IND from IDEC,,1st ptIn P1Levy,,last pt In P3,,FDA,,EMEA,,1st line;R-chemo;maintenance,Ti

25、meline of Rituximab Development,IDEC & Genentech/RocheCo-develop,,Hybritech,IDEC,,Biotherapy SystemLevy/Miller,,GenentechBoyer/Cohen,CD20 geneIn 1980Nadler,IDEC,Development of IDEC’s Stock Prices,Christian Zell

26、er,Phase I trial doneIDEC & GenentechCo-develop,FDA approval,Phase I: 1993-94-single dose: 10, 50, 100, 250, 500 mg/m2, No MTD -15 pts: 2 PR (100, 500 mg/m2)-Maloney DG, Blood 84:2457, 1994Phase I: 1994-9

27、5-multiple dose (weekly x 4): 125, 250, 375 mg/m2, No MTD-20 pts: 6 PRs (1/3 in 125, 2/6 in 250, 3/9 in 375), ORR=33%-Maloney DG, J Clin Onc 15:3266, 2019Phase II: 2019-96 -Fixed dose (375 mg/m2), weekly x4 (de

28、termined by the available Mab)-37 pts: 3 CR/14PR (ORR=46%), mTTP 10.2 months-Maloney DG, Blood 90:2188, 2019Phase II/III Pivotal trial: 2019-96,Early clinical development of Rituximab,Rituximab Pivotal Phase II/III

29、Trial: Clinical Response in Relapsed Indolent or Follicular Lymphoma,McLaughlin et al. J Clin Oncol. 2019.,,,,,,,,,,,Outline,,Historical perspective in Rituximab’s developmentImpact of Rituximab-Lymphoma-Rheumatoi

30、d arthritis, lupus, and other autoimmune diseases-Other solid tumorsNew emerging therapies in lymphoma,Randomized Trials of Chemotherapy plus Rituximab versus Chemotherapy Alone in B-Cell Lymphoma,Cheson B, Leonard

31、J. N Engl J Med 2019; 359:613,Randomized Trials of Maintenance Treatment with Rituximab versus Observation,Randomized Trials of Maintenance Treatment with Rituximab versus Observation,Cheson B, Leonard J. N Engl J Med 2

32、019;359:613-626,Extended Uses of Rituximab: Integration into Lymphoma Standard of Care,,Salvage therapy for chemo-refractory or relapsed: low gradeUp-front therapyDelay or avoid chemotherapy—low gradeCombination the

33、rapyWith chemotherapyWith other biologicals- enhance ADCCWith other monoclonalsMaintenance therapy,Mortality Rates of Non-Hodgkin’s Lymphoma,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Rituximab Publications,,Number of publication

34、s,Year,,Publications,,1st clinical trial,,,,,160,180,200,80,100,120,140,0,20,40,60,Jan/91,92,93,94,95,96,97,98,99,00,FDAapproval,Pivotaltrial results,,,,,,,,,,,1 million pts worldwide being treated,4378 in 2019,Rituxan

35、 / MabThera: a blockbuster,Christian Zeller,Top 5 Best Selling Oncology Drugs in 2019,Pfizer-Oncology,Approved MAbs for Cancer Therapy,,*First approved in China,Outline,,Historical perspective in Rituximab’s development

36、Impact of Rituximab-Lymphoma-Rheumatoid arthristis, lupus, and other autoimmune diseases-Other solid tumorsNew emerging therapies in lymphoma (phase I-III trials)-human or humanized anti-CD20: enhanced ADCC, C

37、DC-Other new targets: CD22, CD40, CD80, mTOR, HDAC, Revlimid, Avastin, Velcade, PKC-b, TRAIL, Bcl-2, CTLA-4-Rituxan-based combinational Bio-Rx-In situ vaccines (dendritic cells, CpG),Cheson B, Leonard J. N Engl J M

38、ed 2019;359:613-626,Unconjugated Monoclonal Antibodies for B-Cell Cancers,Investigational Combination BioRx for B-Cell Cancers,Most potent “antigen-presenting cells” Reside in tissues to collect antigen -> travel to

39、lymph nodes Co-culture with antigens -> cellular vaccine,Dendritic Cells,,In situ Vaccination with DC,,,Chemo+DC 15/15,,,,,,,,,,,,,,,,,,,,,,,,DC,Chemo +,Chemo 0/8,DC 0/7,No Rx 0/9,Mean Tumor Size,Days post

40、 tumor implantation,Song & LevyCan Res 2019,,,Dendritic Cells,ChemotherapyOr Radiotherapy,,,,,,Leukapheresis,Intratumoral DC Vaccination + Conventional Therapy,,,,IntratumorInjection,,,,,2,1,3,,,,,,,,,US FDA appr

41、ovd three Investigational New Drug (INDs) Applications:-Colon cancer with hepatic metasteses (phase I; Stanford) -Locally advanced pancreatic cancer (phase I/II; Stanford)-Lymphoma and other solid tumors (phase I/II;

42、Baylor),Intratumoral DC Vaccination + Conventional Therapy: From Lab to Clinic,CpG bridges innate and adaptive immunity,Bacterial DNA ACGTTGAGTTCGTACGCATACGAVertebrate DNA AGCTTGAGTCmCGGATGGGTAAGAImmune system rec

43、ognizes CpG through TLR-9 and induces activation of DC, B & T cells,Dendritic Cell,,Tumor-specific T Cells,,CpG,TLR-9,TLR-9,B Cell Tumor,CpG Only Works Intra-Tumorally,Li J, Song W, et al., J Immunol. 2019,179:2493,,

44、,Radiation,In situ Vaccination with CpG,,CpG,,Pre-treatment,Week 12,,,,,,63 yo male with recurrent follicular lymphoma: partial response,ASCO 2019,US Oncology Growth Market Projections,,,,,,Acknowledgement,Stanford Unive

45、rsity Medical Center Ronald LevyEdgar Engleman Baylor Institute for Immunology Research & Baylor Sammons Cancer Center-Jacques Banchereau, Steve Paulson-Marylene Leogier, Jingtao Chen, Licun Wu, Zhiqing Wan

46、g $ Baylor University Healthcare System Foundation $ US National Cancer Institute/NIH Pfizer Oncology: Jesus Gomez-Navarro,Questions??,Function:,antibody,Two Arms of the Immune System,B cells (Humoral),T cells (Cel

47、lular),Make antibodies,Kill abnormal cells,,,,,foreignsubstance(antigen),Abnormalcell,,,Antibody Structure,,,,,The Immune System is a mixture of Clones,Each B cell can make only one antibodyEach T cell can make only

48、 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%)

49、 (39%) (41%) p=0.037 Weng and Levy J Clin Onc 2019,Rituximab Clinical Response Det

50、ermined by Host Genetics,7-Year Results of GELA Study (LNH-98.5),Primary end point: EFSSecondary end points: PFS, OS, DFS, and RR,ASSESS,,,,,Untreated elderly patients with DLBCL stratified by risk factors(0-1 vs 2-3

51、)(N=399),RANDOMIZE,R-CHOPq3w × 8 (n=202),CHOPq3w × 8 (n=197),,Coiffier et al. ASCO 2019. Abstract 8009.,,Coiffier et al. ASCO 2019. Abstract 8009.,7-Year Results of GELA Study (LNH-98.5),,.,Tumor Bi

52、opsy,,,+,Vaccine Production,,,Tumor Idiotype (Id) Protein,Immunization,,,,KLHcarrier protein,Adjuvant (SAF),Id,,,,,,,,,,,,,,,,,,1,2,3,,,,,,,,,,Myeloma cell,,A Therapeutic Vaccine for Lymphoma,,“Rescue hybridization”,Fr

53、eedom From ProgressionFollicular Lymphoma first remission,Hsu et al Blood 2019,,BioVest Phase III Trial,Treatment Schedule,Enrollment,Monthly Vaccines x7,,,,Immunization: 28 weeks,Recovery26 weeks,,chemo,Follow for T

54、ime to Progression,Randomize 2/1,3 phase III trials(NCI/BioVest, Favirille, Genitope),Selected studies of single-agent rituximab in low-grade or follicular NHL,aAbbreviations: NHL, non-Hodgkin's lymphoma; CR, comple