免疫检查点抑制剂在肿瘤免疫治疗中的现状

1、免疫检查点抑制剂免疫检查点抑制剂在肿瘤免疫治疗中的现状在肿瘤免疫治疗中的现状传统治疗传统治疗:Regarding to Cancer Therapy手术治疗手术治疗化疗治疗化疗治疗放射治疗放射治疗靶向治疗靶向治疗:Regarding to Cancer Therapy单克隆抗体单克隆抗体 Mab小分子化合物小分子化合物 Smart drugs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。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

2、疫力，从而控制和杀伤肿瘤细胞Cancer Immunotherapy2011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” Cancer ImmunotherapySCIENCE 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

3、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

4、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8Introduction to T Cell CosignalingT cell Effector cell of adaptive immune system.Naive T cell need two distinct signals to initiate function.9Introduction to CD28/CTLA-

5、410Introduction to CD28/CTLA-411Introduction to CD28/CTLA-412Introduction to CD28/CTLA-4Story of Anti-CTLA-4(Ipilimumab)Breaking tolerance :basic concept of cancer immunotherapyStory of Anti-CTLA-4(Ipilimumab)Time table of the long adventure1987，Discover of CTLA-4. Nature1987328,267-2701996，James Al

6、lison 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 appr

7、oved 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. AllisonYERVOY(iplimumab) by Bristol-MyersSquibbFully humanized antibodyBinding to CTLA-4Blocki

8、ng B7/CTLA-4 interactionStory of Anti-CTLA-4(Ipilimumab)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，l接受Ipilimumab加gp100(403例患者)l单独ipilimumab(137例)l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)。Story of Anti-CTLA-4(Ipilimuma

9、b)N Engl J Med 2010;363:711-23.Story of Anti-CTLA-4(Ipilimumab)N Engl J Med 2010;363:711-23.Story of Anti-CTLA-4(Ipilimumab) intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. 951 stage III cutaneous melanoma with adequate res

10、ection of lymph nodes ipilimumab (n=475) or placebo (n=476)Story of Anti-CTLA-4(Ipilimumab)Story of Anti-CTLA-4(Ipilimumab)Clinical trials:Non-small-cell lung cancerProstage cancerExtensive-disease-small-cell lung cancer . . . .PD-1 (CD279)Member of Ig superfamily Inducible expression on T or B cell

11、Deliver inhibition signal Story of B7-H1/PD-1PD-L1 (B7-H1,CD274)Member of Ig superfamily Constitutive expression on T & APC etcConditionally deliver negative signal Story of B7-H1/PD-1FACTSB7-H1 is frequently up-regulated on different types of tumor cells, where it inhibits local antitumor T cell re

12、sponses. PD-1 is expressed on the majority of tumor infiltrating lymphocytes. J. Konishi, K. Yamazaki, M. Azuma, et al. Clin Cancer Res 2004 10:5094CONCLUSIONTumor 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

13、 immune attack.SOLUTIONBlocking B7-H1/PD-1 interaction to protect tumor infiltrating T cell in order to enhance cell immune against tumor.Beginning of the story1992，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

14、reported PDL1, which was found identical to B7H1.2014，Receive WilliamB.ColeyAwardjointly for distinguished research in tumor immunologyStory of B7-H1/PD-1Chen Lieping Tasuku HonjoGorden J. Freeman Arlene H. Sharpe Story of B7-H1/PD-1重磅重磅! 美国前总统卡特脑部癌细胞消失，让世界再次聚焦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！重磅

15、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。Story of B7-H1/PD-1Clinical trials have been conducted in following cancer:Colorectal cancerMelanoma Prostate cancerNSCLCRenal 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201

16、4年9月初获FDA批准，是美国批准的首个PD-1抑制剂。Story of B7-H1/PD-1Bid For FutureBMS: 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 (C

17、T-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.Story of B7-H1/PD-1Clinical efficacy and safety of lambrolizumab (MK-3475, Ant

18、i-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

19、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%】Story of B7-H1/PD-1Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial.Lancet. 2014 Sep 20;384(9948):1109-17.Story of B7-H1/PD-1Lancet. 20

20、14 Sep 20;384(9948):1109-17.Story of B7-H1/PD-1Lancet. 2014 Sep 20;384(9948):1109-17.Story of B7-H1/PD-1与与Ipilimumab相比，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）。Keytruda10mg/kg/2 wKeytruda10mg/kg/3 wIp

21、ilimumab3mg/kg/3w6 month PFS%47.3%46.4%26.5%12-month survival rates 74.1%68.4%58.2% response rate33.7%32.9%11.9%Story of B7-H1/PD-1N Engl J Med. 2015 May 21;372(21):2018-28. Pembrolizumab for the treatment of non-small-cell lung cancer.Story of B7-H1/PD-1N Engl J Med. 2015 May 21;372(21):2018-28. Pembr