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1、肺癌免疫治疗进展,Future Outlook,Update of checkpoint Inhibitors in lung cancer therapy,Cancer Immunotherapy,1,2,3,Outline,2,Confidential 2/21/2013,Future Outlook,Update of checkpoint Inhibitors in lung cancer therapy,Cancer Immunotherapy,1,2,3,Outline,3,Confidential 2/21/2013,肿瘤免疫治疗攻克肿瘤的新希望,人类抗击肿瘤的历史 肿瘤免疫治疗
2、具有特异性和靶向性，一直为临床医师高度关注，近年进 步显著，使得免疫治疗成为更具期待的领域,进入21世纪，分子靶向 治疗如火如荼,4,Confidential 2/21/2013,e,Key events in the history of cancer immunotherapy,1890s 1st CA vaccine developed (coley),1973 discovery of the dendritic cell(steinman),1976 1st study with BCG in bladder CA,1978 Discovery of tumor specific m
3、ABs,1985 1st study with adoptive T-ce ll transfer in CA,1986 IFN(cytokine) approved for CA,1990s Discovery of role of checkpoints in CA,1992 Il-2(Cytokine) approved for CA,1997 1st mAB approved for CA,2010 1st cellular immunotherapy approved for CA,2011 1st checkpoint inhibitor approved for CA,2014
4、2nd checkpoint inhibitor approved for CA,Enthusiasm phase 1976-1985,Skepticism phase 1986-1992,Renaissance phase 1997-,5,美国Science杂志: 2013年六大值得关注的科学领域 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 基础植物研究,6,Breakthrough of year 2013,Science. 2013 Dec 20;342(6165):1432-3,7,Confidential 2/21/2013,Immunit
5、y. 39(1)25 July 2013, Pages 110,Stimulatory and Inhibitory Factors in the Cancer-Immunity Cycle,8,CTLA-4 and PD-1/PD-L1 checkpoint blockade for cancer treatment,9,CTLA-4 and PD-1/PD-L1 Checkpoint Blockade for Cancer Treatment,Immune checkpoint blockade includes agents targeting the negative regulato
6、rs CTLA-4 and PD-1 CTLA-4 attenuates the early activation of naive and memory T cells in the lymph nodes Agents targeting CTLA-4 include ipilimumab and tremelimumab In contrast, PD-1 modulates the effector phase of T cell activity in peripheral tissues via interaction with PD-L1 and PD-L2 Agents tar
7、geting PD-1 include nivolumab and MK-3475 Agents targeting PD-L1 include MPDL3280A and MEDI4736,Kyi C, et al. FEBS Lett. 2014;588:368-376,10,Confidential 2/21/2013,Comparing CTLA-4 and PD-1,Crit Rev Oncol Hematol. 2014;89:140-165.,CTLA-4 and PD-1 have separate but complimentary roles in immune respo
8、nses,11,Confidential 2/21/2013,Future Outlook,Update of checkpoint Inhibitors in lung cancer therapy,Cancer Immunotherapy,1,2,3,Outline,12,Confidential 2/21/2013,CTLA-4 Checkpoint Inhibitor,13,Confidential 2/21/2013,Anti-CTLA-4 antibodies can induce clinical response in a broad variety of cancer,Ada
9、pted form Lebbe et al. ESMO 2008,Presented By Lawrence Fong at 2014 ASCO Annual Meeting,Bladder Renal Esophageal CNS Colorectal Glioblastoma Leukemia Soft Tissue Sarcoma,14,Confidential 2/21/2013,J Clin Oncol. 2012 Jun 10;30(17):2046-54,Ann Oncol. 2013 Jan;24(1):75-83,15,Confidential 2/21/2013,J Cli
10、n Oncol. 2012 Jun 10;30(17):2046-54,Ipilimumab in combination with PC as first-line therapy in stage IIIB/IV NSCLC,16,Confidential 2/21/2013,KaplanMeier plots for OS,J Clin Oncol. 2012 Jun 10;30(17):2046-54,Deaths/patients 51/66 51/68 Median (95% CI), months 8.28 (6.80 to 12.39) 12.22 (9.26 to 14.39
11、) HR (95% CI) 0.87 (0.59 to 1.28) Log-rank P 0 .23,Control,Phased Ipi,Deaths/patients 51/66 51/70 Median (95% CI), months 8.28 (6.80 to 12.39) 9.69 (7.59 to 12.48) HR (95% CI) 0.99 (0.67 to 1.46) Log-rank P 0.48,Concurrent lpi,Control,17,Confidential 2/21/2013,Events/patients 61/66 58/70 Median (95%
12、 CI), mo 4.21(2.76 to 5.32) 4.11 (2.76 to 5.32) HR (95% CI) 0.88 (0.61 to 1.27) Log-rank P .25,J Clin Oncol. 2012 Jun 10;30(17):2046-54,KaplanMeier plots for PFS per immune-related (ir) response criteria (irPFS) and modified WHO criteria (mWHO-PFS).,Events/patients 56/66 54/68 Median (95% CI), 4.63m
13、(4.14 to 5.52) 5.68 (4.76 to 7.79) HR (95% CI) 0.72 (0.50 to 1.06) Log-rank P .05,Control,Phased Ipi,Events/patients 56/66 55/70 Median (95% CI), 4.63m (4.14 to 5.52) 5.52 (4.17 to 6.74) HR (95% CI) 0.81 (0.55 to 1.17) Log-rank P .13,Control,Concurrent lpi,Events/patients 61/66 56/68 Median (95% CI)
14、,mo 4.21 (2.76 to 5.32) 5.13 (4.17 to 5.72) HR (95% CI) 0.69 (0.48 to 1.00) Log-rank P .02,Control,Phased Ipi,Control,Concurrent lpi,18,Confidential 2/21/2013,Adverse Events,J Clin Oncol. 2012 Jun 10;30(17):2046-54,19,Confidential 2/21/2013,Follow-UP Every 12 wks For survival,SCREENING,INDUCTION,MAI
15、NTENANCE,FOLLOW-UP,CA184-104: phase III trial comparing the the efficacy of ipilimumab (Ipi) with PC versus placebo with PC in patients (pts) with stage IV/recurrent NSCLC of squamous histology,Tumor assessment Every 12 wks,J Clin Oncol 31, 2013 (suppl; abstr TPS8117),primary endpoint OS secondary endpoints OS among pts who receive blinded therapy PFS best overall response rate,Tumor assessment Wks 7, 13, 19, 25,Exclusion Criteria: Brain Metastases Autoimmune diseases,PC Paclitaxel (175 mg/m2 , IV) +Carboplatin (AUC=6, IV),20,Confid
