免疫检查点抑制剂在肿瘤免疫治疗中的现状

免疫检查点抑制剂在肿瘤免疫治疗中的现状传统治疗:RegardingtoCancerTherapy手术治疗化疗治疗放射治疗靶向治疗:RegardingtoCancerTherapy单克隆抗体Mab小分子化合物Smartdrugs某种药物只能对特定突变基因型肿瘤产生作用；肿瘤基因突变产生药物耐受性导致长期的治疗效果下降；存在严重的不良反应；部分肿瘤不能通过靶向药物得到有效治疗。CancerImmunotherapy最新的肿瘤免疫治疗是通过调动机体的免疫系统，增强肿瘤微环境抗肿瘤免疫力，从而控制和杀伤肿瘤细胞CancerImmunotherapy2011年诺贝尔生理学或医学奖揭晓，三位科学家因在免疫治疗获奖.布鲁斯．博伊特勒朱尔斯．霍夫曼拉尔夫.斯坦曼受体和先天性免疫激活方面的发展发现树突状细胞及其在获得性免疫中的应用”CancerImmunotherapySCIENCE2013VOL3421432-1433机制：肿瘤细胞产生特异性抗原树突细胞吞噬凋亡肿瘤，将肿瘤抗原呈递给T细胞未受抑制并且激活的T细胞通过肿瘤特异性抗原识别并杀死肿瘤。其中免疫调节T细胞（TRegcell）通过抑制T细胞或解除抑制来调节T细胞活性，避免T细胞对体内正常细胞产生杀伤作用。CancerImmunotherapy免疫调节剂（非特异性）：应用免疫调节剂增强机体免疫功能，激活机体的抗肿瘤免疫应答，治疗肿瘤。干扰素，白介素-2，胸腺肽，胸腺肽α；香菇多糖，猪苓多糖，酵母多糖；肿瘤疫苗（主动免疫）：利用肿瘤细胞或肿瘤抗原物质诱导机体的特异性免疫和体液免疫，增强机体抗肿瘤能力，预防术后扩散和复发，治疗肿瘤。肿瘤疫苗：多肽疫苗，核酸疫苗，重组病毒疫苗，细菌疫苗，DC疫苗等过继性免疫治疗（被动免疫）：是将活化的具有杀伤性的免疫细胞转输给肿瘤病人，提高机体的抗肿瘤能力，杀伤患者体内肿瘤细胞的一种疗法。目前可供转输的细胞有CIK细胞，LAK细胞，CTL细胞，TIL细胞等。8IntroductiontoTCellCosignalingTcell——Effectorcellofadaptiveimmunesystem.NaiveTcellneedtwodistinctsignalstoinitiatefunction.9IntroductiontoCD28/CTLA-410IntroductiontoCD28/CTLA-411IntroductiontoCD28/CTLA-412IntroductiontoCD28/CTLA-4StoryofAnti-CTLA-4(Ipilimumab)Breakingtolerance:basicconceptofcancerimmunotherapyStoryofAnti-CTLA-4(Ipilimumab)Timetableofthelongadventure——1987，DiscoverofCTLA-4.Nature1987328,267-270——1996，JamesAllisonpublishedapaperinScienceshowingthatCTLA-4antibodieserasedtumorsinmice.——1999，Medarexacquiredrightstotheantibody,takingtheleapfrombiologytodrug.——2010，BMSpublishedareportinNEJMofantiCTLA-4antibodyipilimumabtreatmentformetastaticmelanoma.——2011,theU.S.FDAapprovedBristol-MyersSquibb’santi–CTLA-4treatmentformetastaticmelanoma.——2012，SteveA.RosenberggrouppublishedalongtermfollowupreportinCCRofipilimumabtreatmentformetastaticmelanoma.JamesP.AllisonYERVOY(iplimumab)byBristol-MyersSquibbFullyhumanizedantibodyBindingtoCTLA-4BlockingB7/CTLA-4interactionStoryofAnti-CTLA-4(Ipilimumab)StoryofAnti-CTLA-4(Ipilimumab)676例HLA-A*0201–阳性有不可切除的III或IV期黑色素瘤患者，其疾病已进展正在接受对转移疾病治疗，接受Ipilimumab加gp100(403例患者)单独ipilimumab(137例)或单独gp100(136例)NEnglJMed2010;363:711-23.Ipilimumab剂量3mg/kg体重，每3周1次直至四次治疗(诱导)。StoryofAnti-CTLA-4(Ipilimumab)NEnglJMed2010;363:711-23.StoryofAnti-CTLA-4(Ipilimumab)NEnglJMed2010;363:711-23.StoryofAnti-CTLA-4(Ipilimumab)intravenousinfusionsof10mg/kgipilimumaborplaceboevery3weeksforfourdoses,thenevery3monthsforupto3years.951stageIIIcutaneousmelanomawithadequateresectionoflymphnodesipilimumab(n=475)orplacebo(n=476)StoryofAnti-CTLA-4(Ipilimumab)StoryofAnti-CTLA-4(Ipilimumab)Clinicaltrials:Non-small-celllungcancerProstagecancerExtensive-disease-small-celllungcancer....PD-1(CD279)•MemberofIgsuperfamily•InducibleexpressiononTorBcell•DeliverinhibitionsignalStoryofB7-H1/PD-1PD-L1(B7-H1,CD274)•MemberofIgsuperfamily•ConstitutiveexpressiononT&APCetc•ConditionallydelivernegativesignalStoryofB7-H1/PD-1FACTS•B7-H1isfrequentlyup-regulatedondifferenttypesoftumorcells,whereitinhibitslocalantitumorTcellresponses.•PD-1isexpressedonthemajorityoftumorinfiltratinglymphocytes.J.Konishi,K.Yamazaki,M.Azuma,etal.ClinCancerRes200410:5094CONCLUSIONTumorcellstakeB7-H1asaweapontodisabletumorsensitiveTcellinthatwaytumorcellscansuppressimmunecellfunctionandescapefromimmuneattack.SOLUTIONBlockingB7-H1/PD-1interactiontoprotecttumorinfiltratingTcellinordertoenhancecellimmuneagainsttumor.Beginningofthestory——1992，DiscoverofPD-1byTasukuHonjo.——1999，ChenLiepinggroupfoundB7H1,whichwaslateridentifiedligandofPD-1.——2000，GordenJ.FreemanreportedPDL1,whichwasfoundidenticaltoB7H1.——2014，ReceiveWilliamB.ColeyAwardjointlyfordistinguishedresearchintumorimmunologyStoryofB7-H1/PD-1ChenLiepingTasukuHonjoGordenJ.FreemanArleneH.SharpeStoryofB7-H1/PD-1重磅!美国前总统卡特脑部癌细胞消失，让世界再次聚焦PD-1/PD-L1重磅炸弹！2015年12月6日，美国第39届总统吉米·卡特于6日发表声明说，医生在给他做完最近一次脑部MRI后，没有发现此前在他大脑中出现的黑色素瘤转移灶或新的癌细胞。StoryofB7-H1/PD-1Clinicaltrialshavebeenconductedinfollowingcancer:•Colorectalcancer•Melanoma•Prostatecancer•NSCLC•Renalcellcarcinom百时美施贵宝的PD-1抑制剂Opdivo（nivolumab）2014年7月在日本获得批准，成为全球批准的首个PD-1抑制剂；默沙东的Keytruda于2014年9月初获FDA批准，是美国批准的首个PD-1抑制剂。StoryofB7-H1/PD-1BidForFutureBMS:BMS936558(Nivolumab,MDX-1106),humanizedmab,inphaseIIItrial.MERCK:pembrolizumabMK-3475,humanizedmab,inphaseIIItrial.ONO:OPDIVO®(Nivolumab)approvedforthetreatmentofunresectablemelanoma.CURETECH:Pidilizumab(CT-011),humanizedmab,inphaseIItrial.GSK:AMP-224,aFc-B7DCfusionprotein,inphaseItrial.ROCHE(Genentech):MPDL3280A,antiB7H1mab,inphaseItrial.MedImmune/AstraZeneca:MEDI-4736,antiB7H1mab,inphaseItrial.StoryofB7-H1/PD-1Clinicalefficacyandsafetyoflambrolizumab(MK-3475,Anti-PD-1monoclonalantibody)inpatientswithadvancedmelanoma.JournalofClinicalOncology,2013ASCOAnnualMeetingAbstracts.Vol31,No15_suppl(May20Supplement)晚期黑色素瘤患者lambrolizumab治疗的客观反应率：10mg/kgQ2W：患者57人；客观反应率56%；95%可信区间为42-69%10mg/kgQ3W：患者56人；客观反应率27%；95%可信区间为16-40%2mg/kgQ3W：患者22人；客观反应率14%；95%可信区间为3-35%【患者总人数135；客观反应率37%；95%可信区间为29-45%】StoryofB7-H1/PD-1Anti-programmed-death-receptor-1treatmentwithpembrolizumabinipilimumab-refractoryadvancedmelanoma:arandomiseddose-comparisoncohortofaphase1trial.Lancet.2014Sep20;384(9948):1109-17.StoryofB7-H1/PD-