1、免疫檢查點抑制劑 在腫瘤免疫治療中的現(xiàn)狀,傳統(tǒng)治療:,Regarding to Cancer Therapy,手術治療,化療治療,放射治療,靶向治療:,Regarding to Cancer Therapy,單克隆抗體 Mab,小分子化合物 Smart drugs,抗HER-2：Herceptin 抗EGFR：Cetuximab 抗CD20：Rituximab 抗VEGF：Bevacizumab,EGFR酪氨酸激酶抑制劑：Gefitinib Bcr-Abl酪氨酸激酶抑制劑：Imatinib VEGFR抑制劑：Endostar 多激酶抑制劑：Sorafenib,某種藥物只能對特定突變基因型腫瘤產(chǎn)

2、生作用；腫瘤基因突變產(chǎn)生藥物耐受性導致長期的治療效果下降；存在嚴重的不良反應；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,Cancer Immunotherapy,2011年諾貝爾生理學或醫(yī)學獎揭曉，三位科學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用”,Cancer Immunotherapy,SCIENCE 2013 VOL 342 1432-1433,機制： 腫瘤

3、細胞產(chǎn)生特異性抗原 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年六大值得關注的科學領域之一 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 植物基礎研究,Cancer Immunotherapy,免疫調(diào)節(jié)劑（非特異性）： 應用免疫調(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

4、（主動免疫）： 利用腫瘤細胞或腫瘤抗原物質(zhì)誘導機體的特異性免疫和體液免疫，增強機體抗腫瘤能力，預防術后擴散和復發(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,8,Introduction to T Cell Cosig

5、naling,T cell Effector cell of adaptive immune system.,Naive T cell need two distinct signals to initiate function.,9,Introduction to CD28/CTLA-4,10,Introduction to CD28/CTLA-4,11,Introduction to CD28/CTLA-4,12,Introduction to CD28/CTLA-4,Story of Anti-CTLA-4(Ipilimumab),Breaking tolerance :basic co

6、ncept of cancer immunotherapy,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

7、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 repor

8、t in CCR of ipilimumab treatment for metastatic melanoma.,James P. Allison,YERVOY(iplimumab) by Bristol-Myers Squibb,Fully humanized antibody Binding to CTLA-4 Blocking B7/CTLA-4 interaction,Story 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，其疾病已進展正

9、在接受對轉(zhuǎn)移疾病治療， 接受Ipilimumab加gp100(403例患者) 單獨ipilimumab(137例) 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)。,Story of Anti-CTLA-4(Ipilimumab),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)

10、,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),Story of Anti-CTLA-4(Ipilimumab),Story of Anti-CTLA-4(Ipilimumab),

11、Clinical trials: Non-small-cell lung cancer Prostage cancer Extensive-disease-small-cell lung cancer . . . .,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

12、 T 384(9948):1109-17.,Story of B7-H1/PD-1,Lancet.2014 Sep 20;384(9948):1109-17.,Story of B7-H1/PD-1,Lancet.2014 Sep 20;384(9948):1109-17.,Story of B7-H1/PD-1,與Ipilimumab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 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）。,Story of B7

13、-H1/PD-1,N 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-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

14、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,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