免疫檢查點抑制劑在腫瘤免疫治療中的現(xiàn)狀精品課件

1、2021/4/26精品 PPT 模板1免疫檢查點抑制劑免疫檢查點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2021/4/26精品 PPT 模板2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2021/4/26精品 PPT 模板3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；存在嚴重的不良反應(yīng)；部分腫瘤不能通過靶向藥物得到有

2、效治療。2021/4/26精品 PPT 模板4Cancer Immunotherapy最新的腫瘤免疫治療是通過調(diào)動機體的免疫系統(tǒng)，增強腫瘤微環(huán)境抗腫瘤免疫力，從而控制和殺傷腫瘤細胞2021/4/26精品 PPT 模板5Cancer Immunotherapy2011年諾貝爾生理學(xué)或醫(yī)學(xué)獎揭曉，三位科學(xué)家因在免疫治療獲獎.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)樹突狀細胞及其在獲得性免疫中的應(yīng)用” 2021/4/26精品 PPT 模板6Cancer ImmunotherapySCIENCE 2013 VOL 342 1432-1433機制： 腫瘤細胞產(chǎn)生特異

3、性抗原 樹突細胞吞噬凋亡腫瘤，將腫瘤抗原呈遞給T細胞 未受抑制并且激活的T細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細胞（TReg cell）通過抑制T細胞或解除抑制來調(diào)節(jié)T細胞活性，避免T細胞對體內(nèi)正常細胞產(chǎn)生殺傷作用。2013年六大值得關(guān)注的科學(xué)領(lǐng)域之一單細胞測序“普朗克”探測微波背景輻射人類連接組計劃探索南極冰下世界癌癥免疫療法植物基礎(chǔ)研究2021/4/26精品 PPT 模板7Cancer Immunotherapy免疫調(diào)節(jié)劑（非特異性）：應(yīng)用免疫調(diào)節(jié)劑增強機體免疫功能，激活機體的抗腫瘤免疫應(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

4、疫苗（主動免疫）：利用腫瘤細胞或腫瘤抗原物質(zhì)誘導(dǎo)機體的特異性免疫和體液免疫，增強機體抗腫瘤能力，預(yù)防術(shù)后擴散和復(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胞轉(zhuǎn)輸給腫瘤病人，提高機體的抗腫瘤能力，殺傷患者體內(nèi)腫瘤細胞的一種療法。目前可供轉(zhuǎn)輸?shù)募毎蠧IK 細胞，LAK細胞，CTL細胞，TIL細胞等。免疫結(jié)合點阻斷治療：針對T淋巴細胞抗原4（CTLA-4）的抗體（Ipilimumab）；針對T細胞的程序性死亡因子PD1/PD-L1的抗體2021/4/26精品 PPT 模板8Introduction to T

5、 Cell CosignalingT cell Effector cell of adaptive immune system.Naive T cell need two distinct signals to initiate function.2021/4/26精品 PPT 模板9Introduction to CD28/CTLA-42021/4/26精品 PPT 模板10Introduction to CD28/CTLA-49、 人的價值，在招收誘惑的一瞬間被決定。2022-2-262022-2-26Saturday, February 26, 202210、低頭要有勇氣，抬頭要有低氣。

6、2022-2-262022-2-262022-2-262/26/2022 8:25:28 PM11、人總是珍惜為得到。2022-2-262022-2-262022-2-26Feb-2226-Feb-2212、人亂于心，不寬余請。2022-2-262022-2-262022-2-26Saturday, February 26, 202213、生氣是拿別人做錯的事來懲罰自己。2022-2-262022-2-262022-2-262022-2-262/26/202214、抱最大的希望，作最大的努力。2022年2月26日星期六2022-2-262022-2-262022-2-2615、一個人炫耀什么，

7、說明他內(nèi)心缺少什么。2022年2月2022-2-262022-2-262022-2-262/26/202216、業(yè)余生活要有意義，不要越軌。2022-2-262022-2-26February 26, 202217、一個人即使已登上頂峰，也仍要自強不息。2022-2-262022-2-262022-2-262022-2-262021/4/26精品 PPT 模板12Introduction to CD28/CTLA-42021/4/26精品 PPT 模板13Introduction to CD28/CTLA-42021/4/26精品 PPT 模板142021/4/26精品 PPT 模板15Sto

8、ry of Anti-CTLA-4(Ipilimumab)Breaking tolerance :basic concept of cancer immunotherapy2021/4/26精品 PPT 模板16Story of Anti-CTLA-4(Ipilimumab)Time table of the long adventure1987，Discover of CTLA-4. Nature1987328,267-2701996，James Allison published a paper in Science showing that CTLA-4 antibodies erase

9、d 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

10、. 2012，Steve A. Rosenberg group published a long term follow up report in CCR of ipilimumab treatment for metastatic melanoma.James P. Allison2021/4/26精品 PPT 模板17YERVOY(iplimumab) by Bristol-MyersSquibbFully humanized antibodyBinding to CTLA-4Blocking B7/CTLA-4 interactionStory of Anti-CTLA-4(Ipilim

11、umab)2021/4/26精品 PPT 模板18Story 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ipilimumab(137例)l或單獨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))。2021/4/26精品 PPT 模板19Story of Anti-CTLA-4(Ipilimumab)N Engl J

12、Med 2010;363:711-23.2021/4/26精品 PPT 模板20Story of Anti-CTLA-4(Ipilimumab)N Engl J Med 2010;363:711-23.2021/4/26精品 PPT 模板21Story 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 cutaneo

13、us melanoma with adequate resection of lymph nodes ipilimumab (n=475) or placebo (n=476)2021/4/26精品 PPT 模板22Story of Anti-CTLA-4(Ipilimumab)2021/4/26精品 PPT 模板23Story of Anti-CTLA-4(Ipilimumab)Clinical trials:Non-small-cell lung cancerProstage cancerExtensive-disease-small-cell lung cancer . . . .202

14、1/4/26精品 PPT 模板24PD-1 (CD279)Member of Ig superfamily Inducible expression on T or B cellDeliver 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 2021/4/26精品 PPT 模板25Story of B7-H1/PD-1FACTSB7

15、-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 10:5094CONCLUSIONTumor cells take B7-H1 as a weapo

16、n to disable tumor sensitive T cell in that way tumor cells can suppress immune cell function and escape from immune attack.SOLUTIONBlocking B7-H1/PD-1 interaction to protect tumor infiltrating T cell in order to enhance cell immune against tumor.2021/4/26精品 PPT 模板26Beginning of the story1992，Discov

17、er 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 WilliamB.ColeyAwardjointly for distinguished research in tumor immunologyStory of B7-H1/PD-1Chen Lieping Tasu

18、ku HonjoGorden J. Freeman Arlene H. Sharpe 2021/4/26精品 PPT 模板27Story of B7-H1/PD-1重磅重磅! 美國前總統(tǒng)卡特腦部癌細胞消失，讓世界再次聚焦美國前總統(tǒng)卡特腦部癌細胞消失，讓世界再次聚焦PD-1/PD-L1重磅炸彈！重磅炸彈！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)移灶或新的癌細胞。2021/4/26精品 PPT 模板28Story of B7-H1/PD-1Clinical trials have been condu

19、cted in following cancer:Colorectal cancerMelanoma Prostate cancerNSCLCRenal cell carcinom百時美施貴寶的PD-1抑制劑Opdivo（nivolumab）2014年7月在日本獲得批準，成為全球批準的首個PD-1抑制劑；默沙東的Keytruda于2014年9月初獲FDA批準，是美國批準的首個PD-1抑制劑。2021/4/26精品 PPT 模板29Story of B7-H1/PD-1Bid For FutureBMS: BMS936558(Nivolumab, MDX-1106) , humanized ma

20、b, 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(Genentec

21、h): MPDL3280A, anti B7H1 mab,in phase I trial.MedImmune/AstraZeneca: MEDI-4736, anti B7H1 mab,in phase I trial.2021/4/26精品 PPT 模板30Story of B7-H1/PD-1Clinical efficacy and safety of lambrolizumab (MK-3475, Anti-PD-1 monoclonal antibody) in patients with advanced melanoma.Journal of Clinical Oncology

22、, 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%】2021/4/26精品 PPT 模板31Story of B7-H1/PD-

23、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):1109-17.2021/4/26精品 PPT 模板32Story of B7-H1/PD-1Lancet. 2014 Sep 20;384(9948):1109-17.2021/4/26精品 PPT 模板33Sto

24、ry of B7-H1/PD-1Lancet. 2014 Sep 20;384(9948):1109-17.2021/4/26精品 PPT 模板34Story 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展生存率可以提高晚期黑色素瘤的整體生存率和無進展生存率研究納入了來自16個國家的834名患者，隨機分為三組。中位隨訪時間是7.9個月，平均暴露時間是164天（兩周組）、151天（三周組）和50天（Ipilimumab組）。Keytruda10mg/kg/2 wKeytruda10mg/kg/3 wIpilimumab3mg

25、/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%2021/4/26精品 PPT 模板35Story 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.2021/4/26精品 PPT 模板36Story of B7-H1/PD-1N Engl J Med. 20

26、15 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 allthe 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 untre

27、ated patients2021/4/26精品 PPT 模板37Story 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.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 pat

28、ients, and 16.2 months (95% CI, 16.2 to not reached) for previously untreated patients2021/4/26精品 PPT 模板38Cancer Immuno TherapyOne book has closed,and a new one has opened.2021/4/26精品 PPT 模板399、 人的價值，在招收誘惑的一瞬間被決定。22.2.2622.2.26Saturday, February 26, 202210、低頭要有勇氣，抬頭要有低氣。*2/26/2022 8:25:30 PM11、人總是珍惜為得到。22.2.26*Feb-2226-Feb-2212、人亂于心，不寬余請。*Saturday, February 26, 202213、生氣是拿別人做錯的事來懲罰自己。22.2.2622.2.26*February 26, 202214、抱最大的希望，作最大的努力。2022年2月26日星期六*22.2.2615、一個人炫耀什么，說明他內(nèi)心缺少什么。2022年2月*22.2.26*February 26, 202216、業(yè)余生活要有意義，不要越軌。*2/26/202217、一個人即使已登上頂峰，也仍要自強不息。*22