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多发性骨髓瘤的转化医学研究VCAM-1FibronectinICAM-1LFA-1MUC-1VLA-4CytokinesIL-6,VEGFIGF-1,SDF-1BAFF,APRILBSF-3TNF

TGFVEGFNF-BNF-BBMSCadhesionmoleculesNF-BSmad,ERKJAK/STAT3MEK/ERKPI3-KGSK-3FKHRCaspase-9NF-BmTORBadPKCBcl-xLMcl-1

MEK/ERKp27Kip1NF-BBcl-xLIAPCyclin-DMMSurvivalAnti-apoptosisCellcycleSurvivalAnti-apoptosisCellcycleproliferationSurvivalAnti-apoptosisAktmigrat

ionProliferationAnti-apoptosiscytokinesRafAdhesion骨髓微环境与骨髓瘤细胞的生长、生存和耐药HideshimaTandAndersonKC、NatRevCancer2007,SCCD40BA

FF-RCellsurfacetargetsVEGFR196219831986199619992000+二膦酸盐口服马法兰+泼尼松VAD大剂量地塞米松自体干细胞支持下的大剂量化疗蛋白酶体抑制剂新一代免疫调节剂多发性骨髓瘤治

疗的发展史大剂量马法兰1984沙利度胺ABMT硼替佐米:从实验室到临床的快速转化2000I期临床试验2000靶向于骨髓瘤细胞和骨髓微环境,能克服体内外耐药2001针对难治复发骨髓瘤开展了II期临床试验2003获FDA批准:CR率35

%,中位反应持续时间12个月2004III期临床试验:与地塞米松比较,治疗复发骨髓瘤2005FDA批准其用于难治性骨髓瘤:硼替佐米延长TTP和OS2006新的蛋白酶体抑制剂和联合用药方案2006作为一线治疗,有特别

高的总反应率和CR率2008FDA批准硼替佐米为MM一线治疗用药2010研究发现硼替佐米在MM巩固和维持治疗中有效BortezomibJNK;Caspases&PARPcleavage;ROS;∆mCyto-c&Smacrelease;IA

Ps;mitochondrialCa+2influx;Bidcleavage,Fas&FasL,BH-3onlyproteins:Bim,Bik,&NOXA凋亡Migration,VEGF,ProangiogenicMMP-9,&Caveol

in-1;OsteoclastogenesisviaMIP1,BAFFOsteoblastformation抗新生血管形成&抑制破骨细胞活性Caspase-12cleavage;phospo-PERK;

GADD-153,ATF4,GRP78,&XBP-1splicing诱导内质网应激Cdkinhibitors:P21&p27,p53Cyclins:D1,E1,A,B.细胞周期MM-BMSC’sinteraction;ICAM,VCAM,V3IGF-1,IL-6,BAFF,R

ANKL微环境NF-B,MAPK,JAK/STATIGF-1/IL-6.PI3K-Akt生长&生存HeatShockProteins-27,-70,90;DNA-PK热休克蛋白&DNA损伤修复Chymotrypsin-andCa

spase-likeproteasomeactivities;Mono-ubiquitination;26SProteasomesubunits作用于蛋白酶体硼替佐米的抗骨髓瘤作用机制•1998-2000:Len作用于骨髓瘤细胞(通过casp

ase-8促进凋亡)及骨髓微环境•2001:I期临床试验,最大耐受剂量为25mg,毒副作用不大,79%的患者≥SD•2002:三个II期试验肯定了其疗效和耐受性;Dex能提高Len的ORR•2006:针对复发MM的III期临

床试验表明,Len+Dex优于安慰剂+Dex(OR,CR,TTP,OS),获FDA批准•2009:针对复发和新诊断的MM的13项II-III期临床试验表明,Len+Bort+Dex联用获得较好的ORR•2012:III期临床试验,Len能延长自体移植患者的PFS和OS•2013:I

II期临床试验,用Len+Dex直至PD能延长PFS和OS来那度胺:从实验研究到临床应用来那度胺治疗骨髓瘤的作用机制MMcellsBoneMarrowStromalCellsDendriticCellsIL-6TNF

IL-1AIL-2IFNCD8+TCellsCEBoneMarrowVesselsICAM-1VEGFbFGFDBNKCellsNK-TCellsHideshimaetal、Blood96:2943,2000Daviesetal、Blood98:210,2001Gup

taetal、Leukemia15:1950,2001Mitsiadesetal、Blood99:4525,2002LentzschetalCancerRes62:2300,2002LeBlancRetal、Blood1

03:1787,2004HayashiTetal、BritJHematol128:192,2005PKCNFATPI3KIL-2CD28新发现的免疫调节剂作用机制Kronkeetal,Science,2014Luetal,Science,2014StewartAK,R

ichardsonPG,SanMiguelJFBlood2009联合用药方案应用于骨髓瘤一线治疗20S20S19S19S5,5i1,1i2,2iATPases/Cdc48PotentialTherapeuticTargets26SPROTEASOMEA

TPADPUBenzymesE1,E2andE3-UB-LigasesUbUbUbPoly-ubiquitinatedproteins(proteasomesubstrates)Freeforre-cyclingSixProteaseactivitiesDegr

adedproteinUbImmunoproteasome针对蛋白酶体的新药DeubiquitylatingEnzymes(DUBs)Bortezomib,Carfilzomib,CEP-18770ONYX-0912MLN2238

NPI-0052:5,1,25PR-924TargetingUSP-7USP14/UCHL15蛋白酶体抑制剂的作用机制是调节NF-kB？•多种肿瘤NF-kB活性升高,为何MM效果特别好？•为何NF-kB

抑制剂对骨髓瘤细胞的抑制不如万珂？骨髓瘤细胞的软肋•骨髓瘤患者血清M蛋白能够超过100g/l(AFP是以μg/l为单位的)•骨髓瘤细胞每分钟能够分泌10000至80000个M蛋白分子•其中1/4至1/3估计发生错误折叠•未折叠

或错误折叠的蛋白能够导致细胞凋亡Proteinproteinaggregates(toxic)UbUbUbUb26SproteasomeUbUbUbUbUbAggresomePanibinostat,Vorinostat,ACY1215dyneinUbUbdynei

nMicrotubuleAutophagyBortezomib,Carfilzomib,NPI0052,MLN9708,ONX0912UbUbUbLysosomeHDAC6HDAC6HDAC6UbUb研究合理的联合治

疗方案(联合HDAC)Hideshimaetal、ClinCancerRes、2005;11:8530、Catleyetal、Blood、2006;108:3441-9、Vorinostat治疗复发难治MM•VANTAGE088:国际多中心随机双盲研究,比较

Vorinostat或安慰剂联合硼替佐米,治疗复发难治MM•Vorinostat+硼替佐米组对复发难治患者有效–显著提高治疗反应率:ORR54%vs41%(P<0、0001);CBR71%vs53%(P<0、0001)–联合用药组的PFS、TTP比安慰剂+硼替佐米组更

长–PFS风险比(hazardratio)下降了23%(P=0、01)–两组的PFS分别为7、63月(6、9–8、4)、6、83月(5、7–7、7)–最常见的3-4级不良事件为(vorinostat组vs安慰剂组):血小板

减少(45%vs24%),中性粒细胞减少(28%vs25%),贫血(17%vs13%DimopoulosetalLancetOncol2013;14:1129-40、Panobinostat治疗复发难治MM•PANOR

AMA1–随机双盲II期临床试验,比较Panobinostat或安慰剂+硼替佐米、地塞米松治疗复发难治MM–中位PFS延长4月,ORR、OS无显著差异,nCR/CR率增加2倍(28%vs16%)–以下毒副作用发生率在PAN-BTZ-Dex组较高:3、4级腹泻(

25、5%vs8%),疲乏(23、0%vs11、9%),血小板减少(67、4%vs31、4%),白细胞减少(34、5%vs11、4%),因急性事件导致治疗中断的发生率(33、6%vs17、3%)、•PAN

ORAMA2–PAN-BTZ-Dex方案对既往反复治疗过的、对硼替佐米耐药的MM患者的疗效:ORR34、5%;CBR52、7%;中位PFS:5、4月;中位OS:17、5月1,2•有必要接着寻找毒性小但选择性更高的HDACi1.RichardsonPG,etal

、Blood、2013;122:2331-23372.RichardsonPGetal、Blood2013;122:Abstract1970EARLYLATE%MutEarly,PRAMEF12,25.4%%MutEarly,FOXD3,26.2%%MutEarly,COL24A1,0.0%%

MutEarly,NRAS,0.0%%MutEarly,ADAMTS4,0.0%%MutEarly,TMEM183B,0.0%%MutEarly,USH2A,11.9%%MutEarly,OBSCN,4.5%%MutEarly,TFB2M,6.5%%Mut

Early,ASXL2,47.4%%MutEarly,SLC3A1,12.6%%MutEarly,ZNF638,50.0%%MutEarly,NCKAP5,0.0%%MutEarly,KCNH8,0.0

%%MutEarly,ATRIP,14.8%%MutEarly,PLS1,0.0%%MutEarly,KDR,34.9%%MutEarly,PRDM9,0.0%%MutEarly,ACOT12,0.0%%MutEarly,PCDHA9,27.8%%MutEar

ly,PCDHA13,33.6%%MutEarly,PCDHB6,0.0%%MutEarly,KIAA1191,0.0%%MutEarly,GPRIN1,0.0%%MutEarly,CDKAL1,23.1%%MutEarly,TCTE

1,0.0%%MutEarly,DEFB110,10.0%%MutEarly,COL9A1,38.9%%MutEarly,ROS1,28.0%%MutEarly,PTPRK,42.3%%MutEarly,TIAM2,0.0%%MutEarl

y,MYOM2,0.0%%MutEarly,DCAF4L2,21.1%%MutEarly,LRRC69,0.0%%MutEarly,ASAP1,16.2%%MutEarly,C9orf144,12.7%%MutEarly,TRPM3,9.9%%MutLate,PRAMEF12,0.0%%MutLa

te,FOXD3,0.0%%MutLate,COL24A1,45.1%%MutLate,NRAS,42.5%%MutLate,ADAMTS4,46.6%%MutLate,TMEM183B,15.7%%MutLate,USH2A,0.0%%MutLate,OBSC

N,0.0%%MutLate,TFB2M,0.0%%MutLate,ASXL2,56.7%%MutLate,SLC3A1,0.0%%MutLate,ZNF638,28.7%%MutLate,NCKAP5,59.2%%MutL

ate,KCNH8,40.7%%MutLate,ATRIP,0.0%%MutLate,PLS1,45.7%%MutLate,KDR,44.9%%MutLate,PRDM9,32.4%%MutLate,ACOT12

,26.2%%MutLate,PCDHA9,36.7%%MutLate,PCDHA13,37.1%%MutLate,PCDHB6,37.7%%MutLate,KIAA1191,32.0%%MutLate,GPRIN1,

35.2%%MutLate,CDKAL1,0.0%%MutLate,TCTE1,61.6%%MutLate,DEFB110,0.0%%MutLate,COL9A1,26.5%%MutLate,ROS1,48.5%%MutLate,PTPRK,34.9%%MutLat

e,TIAM2,30.9%%MutLate,MYOM2,47.7%%MutLate,DCAF4L2,0.0%%MutLate,LRRC69,42.6%%MutLate,ASAP1,0.0%%MutLate,C9orf144,0.0%00.20.40.60.811.2PRAMEF12COL24A1A

DAMTS4USH2ATFB2MSLC3A1NCKAP5ATRIPKDRACOT12PCDHA13KIAA1191CDKAL1DEFB110ROS1TIAM2DCAF4L2ASAP1TRPM3PD4301%MutEarly%MutLateEarlymu

tationnotinlatesampleNewmutationsinlatesampleEarlyTumorLateTumor全基因组测序发现MM进展过程中获得新的分子生物学异常EarlyTumorLateTumorBollietal,Naturem

2014骨髓瘤基因组演化及克隆演变NoChangeDifferentialClonalResponseLinearEvolutionBranchingEvolutionBollietal,Naturem,2014正在研究中的靶向治疗药物➢BTKinhibitors➢KSPinhib

itors(Array520)➢AKTinhibitor➢Nucleartransportinhibitors(KPT)➢CDKinhibitors➢Bromodomaininhibitors抗体介导的细胞依赖的细胞毒作用(ADCC)ADCCEffectorcells

:MMFcR补体依赖的细胞毒作用(CDC)CDCMMC1qC1q通过靶向信号通路来诱导凋亡和阻滞骨髓瘤生长MM➢LucatumumaborDacetuzumab(CD40)➢Elotuzumab(CS1)➢Daratumumab(CD3

8)➢XmAb5592(HM1、24)➢huN901-DM1(CD56)➢nBT062-maytansinoid(CD138)➢1339(IL-6)➢BHQ880(DKK1)➢RAP-011(activinA)➢Daratumumab(C

D38)➢Daratumumab,SAR(CD38)以单抗为基础的骨髓瘤靶向治疗Tai&AndersonBoneMarrowResearch2011•在基因和蛋白水平,骨髓瘤细胞均高表达CS1•Elotuzumab(Elo)是以CS1为靶点的人源化单抗•用Elo治疗MM的临床试验中,治疗反

应为SD•临床前研究表明,来那度胺能够增强Elo抗骨髓瘤的ADCC作用(Taietal,Blood2008)•I/II期临床试验:Len+Dex+Elo治疗复发MM的反应率为80-90%,PFS>33月•一项III期临床试验(比较Len+Dex+Elo与Len+D

ex治疗复发MM的疗效)正在进行中ElotuzumabLenDexDaratumumabAnti-CD38MoAbDeWeersetal,JImmunol2011;186:1840Laubachetal2014;23:445

、I期临床试验:29例患者中,18例获益(5PR,4MR,9SD)16mg/kg:inthe4of7responderswhohad>=5%BMPCsatstudyentry,theBMPCswerec

learedfollowingtreatment、16mg/kg:inthe4of7responderswhohad>=5%BMPCsatstudyentry,theBMPCswereclearedfollowingtreatment、35%(16mg/kg)

vs10%(8mg/kg)responseLokhosrtetalASCO2014Daratumumab治疗后M蛋白水平变化CohortA8mg/kgCohortB8mg/kgCohortC8mg/kgCohortD16mg/kgIMWGCriteria(forme

asurablediseaseatbaseline)S-Serum,U–Urine,F-FLCUSSSSSSSSSSSSSUSSFSSSSSSUSFSSSUUSSUFSUSUFUUUUUU-100-80-60-40-20020406080

100Daratumumab/Len/Dex治疗复发MM•良好的安全性•未发现最大耐受剂量(MTD);通过药动学/药效学研究决定了其RP2D;已完成安全性和疗效评价、•ORR75%(15/20),3CR,6VGPR、•3例曾对来那度胺耐药的患者:2PR,1VGPRPlesneretalASCO20

14针对骨髓瘤抗原特异肽的疫苗•使用具有免疫原性的HLA-A2特异的HSP、XBP1,CD138,CS1肽段,以诱导针对MM抗原的、MM细胞特异的、HLA限制性的CTL反应LiR,HouJ,etal、BrJHaematol

、2014;166:690-701•多功能的反应:IFN-γ,细胞毒性,增殖,对骨髓瘤细胞系和原代细胞的CD107a脱颗粒反应•肽特异抗体的治疗反应:特异性具有个体差异,联合治疗更有效•临床试验:对疫苗的免疫反应;来那度胺和疫苗联合的队列研究正在招募患者Baeet

al,Leukemia2011;25:1610-9、Baeetal,BritJHematol2011;155:349-61、Baeetal,BritJHematol2012;157:687-701、Ba

eetal,ClinCanRes2012;17:4850-60、DC/MM融合疫苗治疗难治复发MM的I期临床试验•耐受良好,无自体免疫反应•在大多数患者体内能诱导出特异的淋巴细胞•诱导针对新抗原的体液免疫应答(SEREX分析)•7

0%的患者治疗后病情稳定Vasiretal、BritJHematol2005;129:687-700RosenblattetalBlood2011;117:393-402、◼DC/MM融合疫苗能诱导体外抗MM免疫,并抑制移植

瘤动物模型体内MM细胞的生长骨髓瘤自体移植后行MM/DC融合疫苗治疗29%54%38%25%33%13%0%10%20%30%40%50%60%70%80%90%100%100DayPost-TransplantPo

st100Day(BestResponse)%ParticipantsCR/nCRVGPRPRRosenblattetal,CCR2013;19:3640-8、CTN今年将开始实施一项RCT试验,以比较自体移植后行来那度胺±疫苗治疗的疗效差异Aviganeta

lPD-1/PD-L1能降低抗肿瘤免疫应答StromalPD-L1modulationofTcellsImmunecellmodulationofTcellsPD-L1/PD-1-mediatedInhibitionoftumorcellkillingIFN-med

iatedup-regulationoftumorPD-L1PrimingandActivationofTcellsPD-L2mediatedinhibitionofTH-2TcellsreceptorChenDS,IrvingBA,HodiFS、ClinCancerRe

s、2012;18:6580、肿瘤微环境PD-L1表达能抑制抗肿瘤T细胞活性:1.肿瘤灶内免疫细胞表达PD-L12.肿瘤细胞亦表达PD-L1cancercellPD-L1lymphocyte肿瘤内T细胞估计

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