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1、Disclosure of COI,Research funding,Chugai/Roche,Kirin,BMS,Kyowa,Yakult,Weyth,Novartis,Pfizer,Taiho,Jansen,Otsuka,BayerEmployment or leadership position:noneStock ownershipTakeda,Astellas,Daiichi-Sankyo,Donation,Pfizer,Kirin,Chugai/Roche,Yakult,Novartis,Jansen,Taiho,Honoraria:noneConsultant or adviso
2、rt role:noneExpert Testimony:none 000000000,Todays talk,Clinical practice of NHL,Registration system for WHO classification of NHLStandard chemotherapy in NHL and HLRCHOP in DLBCLResistance to rituximab,Live-cell confocal fluorescence microscopy,CDCADCCRelationship CDC and response to rituximab and
3、prognosisMutation of CD20 and CDC,Clinical practice of Non-Hodgkins Lymphoma(B-cell lymphoma)in CIH,Old,but an important prognostic marker sIL-2R,and CD5 in RCHOP treatment,DLBCL:treatment result by CHOPRituximab,CHOP n=83:76%,R-CHOPn=92:97%,P=0.0002 0.05,%:3-year PFS,Days from treatment,Over-all su
4、rvival rate,87 cases treated by CHOP and 141 cases treated by RCHOP Were analized in DLBCL.,RCHOP was superior to CHOP in both,RCHOP is superior to CHOP,and sIL-2R is still good marker For prognosis.,Mechanisms of action of rituximab,proliferationblock,ADCC,CDC,apoptosis,NK,M,PMN,FcR,C1q,C2-C9,CD20,
5、CD20+lymphoma,rituximab,Research methodology,Prediction of response and prognosis,Establishment of clinically applicable bio-imaging,Cancer cells from the patients,Ultra super speedySensitivity test,Live-cell bio-imaging,Confocal fluoresence,Prediction of response to rituximab by imaging,Response to
6、 rituximab in lymphoma cells from the patients,Probably ineffective,Probably effective,10min,10min,The principle of imaging-based CDC susceptibility assay,Diagnostic details of patients evaluated for CDC susceptibility,Correlation between CDC and clinical response,DLBCL,FL,chemotherapywith rituximab
7、,chemotherapyw/o rituximab,P=0.0023,P=0.00067,Reproducible ADCC assay,KHYG-1,LTR,Fcgr3a(158V),LTR,LTR,Fcgr3a(158F),LTR,IRES,IRES,ZsGreen,ZsGreen,KHYG-1/mock-ZsGreen,KHYG-1/158V-ZsGreen,KHYG-1/158F-ZsGrreen,NK leukemia cell line CD3-,CD5-,CD7+,CD16-,CD56+,TCR-,ZsGreen,rituximab,PI,ADCC assay,KHYG-1/m
8、ock,KHYG-1/158V,KHYG-1/158F,LDH release assay Target:Ramos E/T:1 Co-culture:4hr,51Cr release assay Target:Ramos E/T:1 Co-culture:4hr,Effect of serum on ADCC activity,Serum(-),Serum(+),Rituximab(-),Rituximab(+),Ramos vs KHYG-1/FcRIIIa(158V)in heat-inactivate serum,Effects of IgG on ADCC activity,Daud
9、i vs.KHYG-1/FcRIIIaRituximab:0.1g/mL Co-culture:for 4hr,Daudi vs.KHYG-1/FcRIIIaRituximab:0.1g/mL Co-culture:for 4hr IgG(12mg/mL),Effect of complement on ADCC activity,Daudi vs.KHYG-1/FcRIIIaRituximab:0-100g/mL Co-culture:for 4hr serum/heat-inactivated serum:50%(v/v),Summary,Depletion of peripheral B
10、 cells,complement,Consumption of C,Serum IgG,CDC,ADCC,C2-C9,rituximab,C1q,NK,M,PMN,CD20,FcR,Mutations of C-terminal region of CD20 molecule predict CD20 expression and time to progression after rituximab in non-Hodgkins lymphomaYasuhito Terui,Yuji Mishima,Natsuhiko Sugimura,Kiyotsugu Kojima,Takuma S
11、akurai,Yuko Mishima,Ryoko Kuniyoshi,Akiko Rokudai,Masahiro Yokoyama,Kengo Takeuchi,Chie Watanabe,Shunji Takahashi,Yoshinori Ito,and Kiyohiko Hatake Department of Medical Oncology and Hematology,Cancer Institute Hospital,Japanese Foundation for Cancer Research;Division of Clinical Chemotherapy,Cancer
12、 Chemotherapy Center,Japanese Foundation for Cancer Research;Olympus Bio-imaging Laboratory,Cancer Chemotherapy Center,Japanese Foundation for Cancer Research;Department of Pathology,Cancer Institute Hospital,Japanese Foundation for Cancer Research,Tokyo;Nutritional Science Laboratory,Morinaga Milk
13、Co.,Kanagawa,Japan.,Terui Y et al.,abstracts in ASH 2006 and ASCO 2007,MethodsSince June 2002 to November 2004,retrospective analysis was performed in CIH(evaluable 50 cases of NHL)2.We performed flow cytometry(CD20 antigen)in each fresh lymphoma cells from the patients3.Mutation analysis of CD20,St
14、ructure of CD20 mutation,CD20 negative DLBCL lymphoma transformed during R-CHOP treatment,M Raji PT K562,CD20,Flow cytometric analysis,RT-PCR,Sequence analysis,Summary of 50 cases with biopsy after PD,Histopathology treatment cases Biopsy after PDMALT R 3 1 R-CHOP like 11 R-CHOPRTx 1 R-VP-16 1 1 FL
15、R 1 R-CHOP like 5 2 R-CHOPRTx 1 DLBCL R-CHOP 21 2 RTxR-CHOP 1 1CLL R 1 1 R-CHOP like 1SLL R 1Lymphoplasmacytic R-CHOP like 1 Mantle CHOPRTR 1 1,total 50 9,CD20 mutation site region casesC-terminal deletion C-terminal cytoplasmic 4(truncation)2.Extracellular 2nd extracellular 1 TM 4th transmembrane 1
16、4.Early termination N-terminal cytoplasmic 5,CD20 mutation in 11/50 NHL,CD20 expression in mutated lymphoma cells,C-terminal deletion and its structure,K562,K562/WT,K562/TM,K562/CD-1,K562/CD-2,K562/CD-3,CD20 expression in K562 cells with C-terminal deleteion,Surface CD20,Western blot analysis using
17、N-terminal antibody for CD20 antigen,normal C-terminal deletion groupCR#(%)19(49)1(25)Non-CR#(%)21(51)3(75)計 40 4,Response to R-containing treatment in both normal and CD20 mutated cases,Progression-free survival after R-containing chemo in normal and C-terminal deletion group,n=4,n=40,ConclusionC-t
18、erminal deletion mutation is related to loss of CD20 and shortened PFS,Other MoAbs,B-cell lymphomaCD20 Rituximab、GA101、HumaxCD20 ZevalinCD22CMC-544T-cell lymphomaCD4 HumaxCD4CCR4 Anti-CCR4 Ab,B-cell：82.7,T/NK-cell：10.3,HL：7.0,B-cell lymphoma n=414,T/NK-cell lymphoma n=53,Overall survival rate,CHOP n
19、=24:58%,Other therapy n=10:57%,Overall survival rate,PTCL,Clinical aspects of T-cell lymphoam in CIH,B-cell lymphoma&T/K lymphoma,IGF1R,Receptor tyrosine kinaseq chromosomeA.A.,single polypeptidecleaved by protease and subunit and subunit makes heterodimer and expressed on the surface chain is degra
20、ded by ubiquitin/proteasomeExpressed on T cells（CDCD）Homology with IR,IGF1R expression on cell lines,Jurkat,TALL,CCRF,KMS-BM,KMS-PE,IM-9,IM-9 VR,IGF1R,IGF1R,-actin,Jurkat,K562,Raji,Daudi,KYSE,BALL-1,ARH,SKW,IGF1R expression on the cell surface,IGF1R,IGF1R,-actin,The effect of Glucose on Jurkat cell
21、proliferationWith bortezomib,Hours in culture,0.1%Glucose,2.0%Glucose,x 104 cells/ml,The effect of glucose for IGF1R expression changes on Jurkat cells,0.1%Glucose,2.0%Glucose,0 1 2 3 4,0 1 2 3 4,IGF1R,IGF1R,-actin,Day,The effect of bortezomib on Jurkat cells,Bortezomib(10nM),Hours in culture,x 104
22、cells/ml,0.1%Glucose,2.0%Glucose,IGF1R expression after addition of bortezomib on Jurkat cells,0.1%Glucose,2.0%Glucose,0 1 2 3 4,0 1 2 3 4,IGF1R,IGF1R,-actin,Bortezomib 20nM addition,Day,IGF1R molecular targeting drugs,MoAbs CP-751871 IMC-A12 Em164 MK-0646 R1507 AMG-479Low molecular weight drugs AEW
23、541 INSM18 Rinfabate,Carboplatin And Paclitaxel With Or Without CP-751,871(An IGF-1R Inhibitor)For Advanced NSCLC Of Squamous,Large Cell And Adenosquamous Carcinoma Histology2.Phase 3 Trial of CP-751,871 And Erlotinib in Refractory Lung Cancer3Phase 2 Study of CP-751,871 in Combination With Docetaxe
24、l and Prednisone in HRPCStudy Of CP-751,871 In Combination With Exemestane In Postmenopausal Women With Hormone Receptor Positive Advanced Breast Cancer5.Study Of CP-751,871 In Patients With Ewings Sarcoma Family Of Tumors6.Study Using CP-751,871 In Patients With Stage IV Colorectal Cancer That Has
25、Not Responded To Previous Anti-Cancer Treatments7.Phase 2 Trial Of CP-751,871 And Docetaxel In Advanced Breast Cancer8.Combination Study of CP-751,871 with Paclitaxel and Carboplatin in Advanced Lung Cancer9.Study of anti-IGF-IR CP-751,871 in patients with solid tumorsStudy of CP-751,871 in Combinat
26、ion With Cisplatin and Gemcitabine in Chemotherapy-naive Patients WithAdvanced Non-Small Cell Lung Cancer11.Study of CP-751,871 in combination with carboplatin and Paclitaxel in Advanced Lung Cancer12.Phase I Pilot Study of Neoadjuvant CP-751,871 in Women with operable early breast cancer 13.Phase I
27、,Pharmacokinetic and Pharmacodynamic Study of the AntiInsulinlike Growth Factor Type 1 Receptor Monoclonal Antibody CP-751,871 in Patients With Multiple Myeloma,Anti-IGF1R Ab clinical trials,Summary,Rituximab resistance of CDC can be explained by the expression of CD55,CD5,and CD20 mutation.CD20 mut
28、ated cases can be treated by ICE,or newer MoAbs for CD20 or CD22.IGFR-1 expression may be a next target.,Great thanks to:,Department of Medical Oncology and Hematology,Dr.Yasuhito TeruiDr.Yasuhiro YokoyamaDr.Yuko MishimaDr.Daisuke EnnishiDr.AsaiData manager:Ms.Suitsu,Yamazaki,Yagou,Division of Clinical Chemotherapy and Olympus Bio-Imaging Labo,Dr.Yuji MishimaDr.Satoshi Matsuzaka,
