免疫檢查點(diǎn)抑制劑在腫瘤免疫治療中的現(xiàn)狀

1、免疫檢查點(diǎn)抑制劑免疫檢查點(diǎn)抑制劑在腫瘤免疫治療中的現(xiàn)狀在腫瘤免疫治療中的現(xiàn)狀傳統(tǒng)治療傳統(tǒng)治療:Regarding to Cancer Therapy手術(shù)治療手術(shù)治療化療治療化療治療放射治療放射治療靶向治療靶向治療:Regarding to Cancer Therapy單克隆抗體單克隆抗體 Mab小分子化合物小分子化合物 Smart drugs某種藥物只能對特定突變基因型腫瘤產(chǎn)生作用；腫瘤基因突變產(chǎn)生藥物耐受性導(dǎo)致長期的治療效果下降；存在嚴(yán)重的不良反應(yīng)；部分腫瘤不能通過靶向藥物得到有效治療。Cancer Immunotherapy最新的腫瘤免疫治療是通過調(diào)動機(jī)體的免疫系統(tǒng)，增強(qiáng)腫瘤微環(huán)境抗腫瘤免

2、疫力，從而控制和殺傷腫瘤細(xì)胞Cancer Immunotherapy2011年諾貝爾生理學(xué)或醫(yī)學(xué)獎(jiǎng)揭曉，三位科學(xué)家因在免疫治療獲獎(jiǎng).布魯斯博伊特勒 朱爾斯霍夫曼 拉爾夫.斯坦曼受體和先天性免疫激活方面的發(fā)展發(fā)現(xiàn)樹突狀細(xì)胞及其在獲得性免疫中的應(yīng)用” Cancer ImmunotherapySCIENCE 2013 VOL 342 1432-1433機(jī)制： 腫瘤細(xì)胞產(chǎn)生特異性抗原 樹突細(xì)胞吞噬凋亡腫瘤，將腫瘤抗原呈遞給T細(xì)胞 未受抑制并且激活的T細(xì)胞通過腫瘤特異性抗原識別并殺死腫瘤。 其中免疫調(diào)節(jié)T細(xì)胞（TReg cell）通過抑制T細(xì)胞或解除抑制來調(diào)節(jié)T細(xì)胞活性，避免T細(xì)胞對體內(nèi)正常細(xì)胞產(chǎn)生殺傷

3、作用。2013年六大值得關(guān)注的科學(xué)領(lǐng)域之一單細(xì)胞測序“普朗克”探測微波背景輻射人類連接組計(jì)劃探索南極冰下世界癌癥免疫療法植物基礎(chǔ)研究Cancer Immunotherapy免疫調(diào)節(jié)劑（非特異性）：應(yīng)用免疫調(diào)節(jié)劑增強(qiáng)機(jī)體免疫功能，激活機(jī)體的抗腫瘤免疫應(yīng)答，治療腫瘤。干擾素，白介素-2，胸腺肽，胸腺肽；香菇多糖，豬苓多糖，酵母多糖；腫瘤疫苗（主動免疫）：利用腫瘤細(xì)胞或腫瘤抗原物質(zhì)誘導(dǎo)機(jī)體的特異性免疫和體液免疫，增強(qiáng)機(jī)體抗腫瘤能力，預(yù)防術(shù)后擴(kuò)散和復(fù)發(fā)，治療腫瘤。腫瘤疫苗：多肽疫苗，核酸疫苗，重組病毒疫苗，細(xì)菌疫苗，DC疫苗等過繼性免疫治療（被動免疫）：是將活化的具有殺傷性的免疫細(xì)胞轉(zhuǎn)輸給腫瘤病人，提

4、高機(jī)體的抗腫瘤能力，殺傷患者體內(nèi)腫瘤細(xì)胞的一種療法。目前可供轉(zhuǎn)輸?shù)募?xì)胞有CIK 細(xì)胞，LAK細(xì)胞，CTL細(xì)胞，TIL細(xì)胞等。免疫結(jié)合點(diǎn)阻斷治療：針對T淋巴細(xì)胞抗原4（CTLA-4）的抗體（Ipilimumab）；針對T細(xì)胞的程序性死亡因子PD1/PD-L1的抗體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陽性有不可切除的III或IV期黑色素瘤患者，其疾病已進(jìn)展正在接受對轉(zhuǎn)移疾病治療，l接受Ipilimumab加gp100(403例患者)l單獨(dú)ipilimumab(137例)l或單獨(dú)gp100(136例)N Engl J Med 2010;363:711-23.Ipilimumab劑量3 mg/kg體重，每3周1次直至四次治療(誘導(dǎo))。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! 美國前總統(tǒng)卡特腦部癌細(xì)胞消失，讓世界再次聚焦美國前總統(tǒng)卡特腦部癌細(xì)胞消失，讓世界再次聚焦PD-1/PD-L1重磅炸彈！重磅

15、炸彈！2015年12月6日，美國第39屆總統(tǒng)吉米卡特于6日發(fā)表聲明說，醫(yī)生在給他做完最近一次腦部MRI后，沒有發(fā)現(xiàn)此前在他大腦中出現(xiàn)的黑色素瘤轉(zhuǎn)移灶或新的癌細(xì)胞。Story of B7-H1/PD-1Clinical trials have been conducted in following cancer:Colorectal cancerMelanoma Prostate cancerNSCLCRenal cell carcinom百時(shí)美施貴寶的PD-1抑制劑Opdivo（nivolumab）2014年7月在日本獲得批準(zhǔn)，成為全球批準(zhǔn)的首個(gè)PD-1抑制劑；默沙東的Keytruda于201

16、4年9月初獲FDA批準(zhǔn)，是美國批準(zhǔn)的首個(gè)PD-1抑制劑。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治療的客觀反應(yīng)率：10mg/kg Q2W：患者57人；客觀反應(yīng)率56%；95%可信區(qū)間為42-69%10mg/kg Q3W：患者56人；客觀反應(yīng)率27%；95%可信區(qū)間為16-40%2mg/kg Q3W：患者22人；客觀反

19、應(yīng)率14%；95%可信區(qū)間為3-35%【患者總?cè)藬?shù)135；客觀反應(yīng)率37%；95%可信區(qū)間為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與與Ipilimumab相比，相比，Keytruda可以提高晚期黑色素瘤的整體生存率和無進(jìn)展生存率可以提高晚期黑色素瘤的整體生存率和無進(jìn)展生存率研究納入了來自16個(gè)國家的834名患者，隨機(jī)分為三組。中位隨訪時(shí)間是7.9個(gè)月，平均暴露時(shí)間是164天（兩周組）、151天（三周組）和50天（Ipilimumab組）。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