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 mABs,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 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,Immunity. 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 regulators 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 targeting 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 responses,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,Adapted 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 Clin 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) 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% 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(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),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,MAINTENANCE,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