免疫检查点抑制剂在肿瘤免疫治疗中的现状ppt参考课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,2020/3/5,*,免疫检查点抑制剂,在肿瘤免疫治疗中的现状,1,2024/10/15,传统治疗,:,Regarding to Cancer Therapy,手术治疗,化疗治疗,放射治疗,2,2024/10/15,靶向治疗,:,Regarding to Cancer Therapy,单克隆抗体,Mab,小分子化合物,Smart drugs,抗,HER-2,：,Herceptin,抗,EGFR,：,Cetuximab,抗,CD20,：,Rituximab,抗,VEGF,：,Bevacizumab,EGFR,酪氨酸激酶抑制剂：,Gefitinib,Bcr-Abl,酪氨酸激酶抑制剂：,Imatinib,VEGFR,抑制剂：,Endostar,多激酶抑制剂：,Sorafenib,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。,3,2024/10/15,Cancer Immunotherapy,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,4,2024/10/15,Cancer Immunotherapy,2011,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”,5,2024/10/15,Cancer Immunotherapy,SCIENCE 2013 VOL 342 1432-1433,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（,TReg,cell,）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。,2013,年六大值得关注的科学领域之一,单细胞测序,“普朗克”探测微波背景辐射,人类连接组计划,探索南极冰下世界,癌症免疫疗法,植物基础研究,6,2024/10/15,Cancer Immunotherapy,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,；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。,免疫结合点阻断治疗：,针对,T,淋巴细胞抗原,4,（,CTLA-4,）的抗体（,Ipilimumab,）；针对,T,细胞的程序性死亡因子,PD1/PD-L1,的抗体,7,2024/10/15,Introduction to T Cell Cosignaling,T cell Effector cell of adaptive immune system.,Naive T cell need two distinct signals to initiate function.,8,2024/10/15,Introduction to CD28/CTLA-4,9,2024/10/15,Introduction to CD28/CTLA-4,10,2024/10/15,Introduction to CD28/CTLA-4,11,2024/10/15,Introduction to CD28/CTLA-4,12,2024/10/15,13,2024/10/15,Story of Anti-CTLA-4(Ipilimumab),Breaking tolerance :basic concept of cancer immunotherapy,14,2024/10/15,Story of Anti-CTLA-4(Ipilimumab),Time table of the long adventure,1987,，,Discover of CTLA-4.,Nature1987 328, 267-270,1996,，,James Allison,published a paper in,Science,showing that CTLA-4 antibodies erased tumors in mice.,1999,，,Medarex,acquired rights to the antibody, taking the leap from biology to drug.,2010,，,BMS,published a report in,NEJM,of anti CTLA-4 antibody ipilimumab treatment for metastatic melanoma.,2011, the U.S. FDA approved Bristol-Myers Squibbs antiCTLA-4 treatment for metastatic melanoma.,2012,，,Steve A. Rosenberg group,published a long term follow up report in,CCR,of ipilimumab treatment for metastatic melanoma.,James P. Allison,15,2024/10/15,YERVOY(iplimumab),by,Bristol-Myers Squibb,Fully humanized antibody,Binding to CTLA-4,Blocking B7/CTLA-4 interaction,Story of Anti-CTLA-4(Ipilimumab),16,2024/10/15,Story of Anti-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,),N Engl J Med 2010;363:711-23.,Ipilimumab,剂量,3 mg/kg,体重，每,3,周,1,次直至四次治疗,(,诱导,),。,17,2024/10/15,Story of Anti-CTLA-4(Ipilimumab),N Engl J Med 2010;363:711-23.,18,2024/10/15,Story of Anti-CTLA-4(Ipilimumab),N Engl J Med 2010;363:711-23.,19,2024/10/15,Story of Anti-CTLA-4(Ipilimumab),intravenous infusions of 10 mg/kgipilimumabor placebo every 3 weeks for four doses, then every 3 months for up to 3 years.,951 stage III cutaneous melanoma with adequate resection of lymph nodes,ipilimumab (n=475) or placebo (n=476),20,2024/10/15,Story of Anti-CTLA-4(Ipilimumab),21,2024/10/15,Story of Anti-CTLA-4(Ipilimumab),Clinical trials:,Non-small-cell lung cancer,Prostage cancer,Extensive-disease-small-cell lung cancer,.,.,.,.,22,2024/10/15,PD-1 (CD279),Member of Ig superfamily,Inducible expression on T or B cell,Deliver inhibition signal,Story of B7-H1/PD-1,PD-L1 (B7-H1,CD274),Member of Ig superfamily,Constitutive expression on T & APC etc,Conditionally deliver negative signal,23,2024/10/15,Story of B7-H1/PD-1,FACTS,B7-H1 is frequently up-regulated on different types of tumor cells, where it inhibits local antitumor T cell responses.,PD-1 is expressed on the majority of tumor infiltrating lymphocytes,.,J. Konishi, K. Yamazaki, M. Azuma, et al. Clin Cancer Res 2004 10:5094,CONCLUSION,Tumor cells take B7-H1 as a weapon to disable tumor sensitive T cell in that way tumor cells can suppress immune cell function and escape from immune attack.,SOLUTION,Blocking B7-H1/PD-1 interaction to protect tumor infiltrating T cell in order to enhance cell immune against tumor.,24,2024/10/15,Beginning of the story,1992,，,Discover of PD-1 by,Tasuku Honjo,.,1999,，,Chen Lieping,group,found B7H1, which was later identified ligand of PD-1.,2000,，,Gorden J. Freeman,reported PDL1, which was found identical to B7H1.,2014,，,Receive,William B. Coley Award,jointly for distinguished research in tumor,immunology,Story of B7-H1/PD-1,Chen Lieping,Tasuku Honjo,Gorden J. Freeman,Arlene H. Sharpe,25,2024/10/15,Story of B7-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。,26,2024/10/15,Story of B7-H1/PD-1,Clinical trials have been conducted in following cancer:,Colorectal cancer,Melanoma,Prostate cancer,NSCLC,Renal cell carcinom,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。,27,2024/10/15,Story of B7-H1/PD-1,Bid For Future,BMS,:,BMS936558(Nivolumab, MDX-1106), humanized mab, in phase III trial.,MERCK,: pembrolizumab,MK-3475, humanized mab, in phase III trial.,ONO,:,OPDIVO(Nivolumab),approved,for the treatment of unresectable melanoma.,CURETECH,:,Pidilizumab (CT-011),humanized mab, in phase II trial.,GSK,:,AMP-224, a Fc-B7DC fusion protein,in phase I trial.,ROCHE(Genentech),:,MPDL3280A, anti B7H1 mab,in phase I trial.,MedImmune/AstraZeneca,:,MEDI-4736,anti B7H1 mab,in phase I trial.,28,2024/10/15,Story of B7-H1/PD-1,Clinical efficacy and safety of lambrolizumab (MK-3475, Anti-PD-1 monoclonal antibody) in patients with advanced melanoma.,Journal of Clinical Oncology, 2013 ASCO Annual Meeting Abstracts. Vol 31, No 15_suppl (May 20 Supplement),晚期黑色素瘤患者,lambrolizumab,治疗的客观反应率：,10mg/kg Q2W,：患者,57,人；客观反应率,56%,；,95%,可信区间为,42-69%,10mg/kg Q3W,：患者,56,人；客观反应率,27%,；,95%,可信区间为,16-40%,2mg/kg Q3W,：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%】,29,2024/10/15,Story of B7-H1/PD-1,Anti-programmed-death-receptor-1treatmentwithpembrolizumabin ipilimumab-refractoryadvancedmelanoma: a randomised dose-comparison cohort of a phase 1 trial.,Lancet.,2014 Sep 20;384(9948):1109-17.,30,2024/10/15,Story of B7-H1/PD-1,Lancet.,2014 Sep 20;384(9948):1109-17.,31,2024/10/15,Story of B7-H1/PD-1,Lancet.,2014 Sep 20;384(9948):1109-17.,32,2024/10/15,Story of B7-H1/PD-1,与,Ipilimumab,相比，,Keytruda,可以提高晚期黑色素瘤的整体生存率和无进展生存率,研究纳入了来自,16,个国家的,834,名患者，随机分为三组。中位随访时间是,7.9,个月，平均暴露时间是,164,天（两周组）、,151,天（三周组）和,50,天（,Ipilimumab,组）。,Keytruda,10mg/kg/2,w,Keytruda,10mg/kg/3,w,Ipilimumab,3mg/kg/3w,6 month PFS%,47.3%,46.4%,26.5%,12-month survival rates,74.1%,68.4%,58.2%,response rate,33.7%,32.9%,11.9%,33,2024/10/15,Story of B7-H1/PD-1,N Engl J Med.,2015 May 21;372(21):2018-28.,Pembrolizumab for the treatment of non-small-cell lung cancer.,34,2024/10/15,Story of B7-H1/PD-1,N Engl J Med.,2015 May 21;372(21):2018-28.,Pembrolizumab for the treatment of non-small-cell lung cancer.,Median progression-free survival was 3.7 months (95% CI, 2.9 to 4.1) for all,the patients, 3.0 months (95% CI, 2.2 to 4.0) for previously treated patients, and 6.0 months (95% CI, 4.1 to 8.6) for previously untreated patients,35,2024/10/15,Story of B7-H1/PD-1,N Engl J Med.,2015 May 21;372(21):2018-28.,Pembrolizumab for the treatment of non-small-cell lung cancer.,Median overall survival was 12.0 months (95% CI, 9.3 to 14.7) for all the patients, 9.3 months (95% CI, 8.4 to 12.4) for previously treated patients, and 16.2 months (95% CI, 16.2 to not reached) for previously untreated patients,36,2024/10/15,Cancer Immuno Therapy,One book has closed,and a new one has opened.,37,2024/10/15,