免疫检查点抑制剂在肿瘤免疫治疗中的现状
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Breaking tolerance :basic concept of cancer immunotherapy
Story of Anti-CTLA-4(Ipilimumab)
Time table of the long adventure
——1987，Discover of CTLA-4. Nature 1987 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 Squibb’s anti–CTLA4 treatment for metastatic melanoma. ——2012，Steve A. Rosenberg group published a long term follow up report in CCR of ipilimumab treatment for metastatic melanoma.
Story of B7-H1/PD-1
PD-1 (CD279) •Member of Ig superfamily •Inducible expression on T or B cell •Deliver inhibition signal PD-L1 (B7-H1,CD274) •Member of Ig superfamily •Constitutive expression on T & APC etc •Conditionally deliver negative signal
8
Introduction to CD28/CTLA-4
9
Introduction to CD28/CTLA-4
10
Introduction to CD28/CTLA-4
11
Introduction to CD28/CTLA-4
12
Story of Anti-CTLA-4(Ipilimumab)
N Engl J Med 2010;363:711-23.
Story of Anti-CTLA-4(Ipilimumab)
951 stage III cutaneous melanoma with adequate resection of lymph nodes ipilimumab (n=475) or placebo (n=476) intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years.
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.
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.
免疫检查点抑制剂 在肿瘤免疫治疗中的现状
Regarding to Cancer Therapy
传统治疗:
手术治疗
化疗治疗
放射治疗
Regarding to Cancer Therapy
靶向治疗: 单克隆抗体 Mab 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。
Story of B7-H1/PD-1
Clinical efficacy and safety of lambrolizumab (MK-3475, Anti-PD-1 monoclonal antibody) in patients with advanced melanoma.
SCIENCE 2013 VOL 342 1432-1433
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α；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
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)
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。
Introduction to T Cell Cosignaling
T cell ——Effector cell of adaptive immune system. Naive T cell need two distinct signals to initiate function.
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.
Ipilimumab剂量3 mg/kg体重，每3周1次直至四次治疗(诱导)。 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)
James P. Allison
Story of Anti-CTLA-4(Ipilimumab)
YERVOY(iplimumab) by Bristol-Myers Squibb
Fully hபைடு நூலகம்manized antibody Binding to CTLA-4 Blocking B7/CTLA-4 interaction
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。
Story of B7-H1/PD-1
SOLUTION
Blocking B7-H1/PD-1 interaction to protect tumor infiltrating T cell in order to enhance cell immune against tumor.
J. Konishi, K. Yamazaki, M. Azuma, et al. Clin Cancer Res 2004 10:5094
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。
发现树突状细胞及其 在获得性免疫中的应 用”
Cancer Immunotherapy
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。
Story of B7-H1/PD-1
Beginning of the story
Tasuku Honjo
Chen Lieping
Gorden J. Freeman
Arlene H. Sharpe
——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
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
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
Story of Anti-CTLA-4(Ipilimumab)
Story of Anti-CTLA-4(Ipilimumab)
Clinical trials:
Non-small-cell lung cancer
Prostage cancer
Extensive-disease-small-cell lung cancer . . . .
Story of Anti-CTLA-4(Ipilimumab)
Time table of the long adventure
——1987，Discover of CTLA-4. Nature 1987 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 Squibb’s anti–CTLA4 treatment for metastatic melanoma. ——2012，Steve A. Rosenberg group published a long term follow up report in CCR of ipilimumab treatment for metastatic melanoma.
Story of B7-H1/PD-1
PD-1 (CD279) •Member of Ig superfamily •Inducible expression on T or B cell •Deliver inhibition signal PD-L1 (B7-H1,CD274) •Member of Ig superfamily •Constitutive expression on T & APC etc •Conditionally deliver negative signal
8
Introduction to CD28/CTLA-4
9
Introduction to CD28/CTLA-4
10
Introduction to CD28/CTLA-4
11
Introduction to CD28/CTLA-4
12
Story of Anti-CTLA-4(Ipilimumab)
N Engl J Med 2010;363:711-23.
Story of Anti-CTLA-4(Ipilimumab)
951 stage III cutaneous melanoma with adequate resection of lymph nodes ipilimumab (n=475) or placebo (n=476) intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years.
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.
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.
免疫检查点抑制剂 在肿瘤免疫治疗中的现状
Regarding to Cancer Therapy
传统治疗:
手术治疗
化疗治疗
放射治疗
Regarding to Cancer Therapy
靶向治疗: 单克隆抗体 Mab 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。
Story of B7-H1/PD-1
Clinical efficacy and safety of lambrolizumab (MK-3475, Anti-PD-1 monoclonal antibody) in patients with advanced melanoma.
SCIENCE 2013 VOL 342 1432-1433
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α；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
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)
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。
Introduction to T Cell Cosignaling
T cell ——Effector cell of adaptive immune system. Naive T cell need two distinct signals to initiate function.
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.
Ipilimumab剂量3 mg/kg体重，每3周1次直至四次治疗(诱导)。 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)
James P. Allison
Story of Anti-CTLA-4(Ipilimumab)
YERVOY(iplimumab) by Bristol-Myers Squibb
Fully hபைடு நூலகம்manized antibody Binding to CTLA-4 Blocking B7/CTLA-4 interaction
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。
Story of B7-H1/PD-1
SOLUTION
Blocking B7-H1/PD-1 interaction to protect tumor infiltrating T cell in order to enhance cell immune against tumor.
J. Konishi, K. Yamazaki, M. Azuma, et al. Clin Cancer Res 2004 10:5094
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。
发现树突状细胞及其 在获得性免疫中的应 用”
Cancer Immunotherapy
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。
Story of B7-H1/PD-1
Beginning of the story
Tasuku Honjo
Chen Lieping
Gorden J. Freeman
Arlene H. Sharpe
——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
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
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
Story of Anti-CTLA-4(Ipilimumab)
Story of Anti-CTLA-4(Ipilimumab)
Clinical trials:
Non-small-cell lung cancer
Prostage cancer
Extensive-disease-small-cell lung cancer . . . .