1、,XXXXXXXXXXXXX,成都市第三人民医院 肿瘤科周从明2018-1-8,免疫治疗疗效预测,1,近年来，以CTLA-4、PD-1/PD-L1抑制剂为代表的免疫疗法正在颠覆着整个癌症治疗领域，目前已经在黑色素瘤、非小细胞肺癌、头颈癌、肾细胞癌、霍奇金淋巴瘤、膀胱癌、结直肠癌、胃癌等众多癌症类型中取得了非常好的治疗效果。但遗憾的是，只有约25%的患者能够从这类免疫疗法中获益。,影响免疫治疗疗效的因素,12、化疗,CM 012：ORR与PD-L1表达有关,Lancet Oncology 2017,4,PD-L1表达与5年生存率,5,6,的定义是全基因组中计入胚系 变体后体细胞突变数目，具体是指
2、肿瘤组织内所评估基因的外显子编码区每兆碱基中发生置换、插入、缺失突变的总数。,PD-L150% + 高TMB,7,PD-L1阴性肺腺癌患者一次PD-1治疗肿瘤消失,8,Iwata T ,et al., Complete Response Achieved 1 Year after a Single Administration of Nivolumab in a Patient with Lung Adenocarcinoma with Negative Expression of PD-L1. J Thorac Oncol. 2017 Dec;12(12):e205-e207.,存在EGFR
3、突变者效果差,9,KRAS突变,10,病理类型,11,12,MSI,13,14,D.T. Le, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015,TMB与MSI,15,Zachary R. Chalmers, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Medicine 2017,放疗,16,Shaverdian,
4、N., et al., Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol, 2017,在第一次使用PD-1抗体治疗前，一半以上的患者是在9.5个月之前接受的放疗，最短的是1个月，最长的是106个月。A、C图是接受任一形式放疗的患者，B、D图是接受颅外放疗的患者。
5、,OS：10.7月 vs 5.3月,PFS：4.4月 vs 2.1月,放疗,17,Yuan Z, Fromm A, Ahmed K A, et al. Radiotherapy rescue of a nivolumab-refractory immune response in a patient with PD-L1 negative metastatic squamous cell carcinoma of the lungJ. Journal of Thoracic Oncology, 2017.,放疗,18,Yuan Z, Fromm A, Ahmed K A, et al. Rad
6、iotherapy rescue of a nivolumab-refractory immune response in a patient with PD-L1 negative metastatic squamous cell carcinoma of the lungJ. Journal of Thoracic Oncology, 2017.,化疗,19,Langer CJ et al.Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lu
7、ng cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study.Lancet Oncol. (2016),Keytruda联合化疗的有效率是55%，单独化疗的有效率是29%，联合治疗的有效率更高。,Keytruda联合化疗的中位无进展生存期是13个月，单独化疗组的PFS是8.9个月，联合治疗能降低47%的疾病进展风险。,化疗,20,Langer CJ et al.Carboplatin and pemetrexed with or without pembrolizumab for advanced, no
8、n-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study.Lancet Oncol. (2016),Keytruda联合化疗的有效率是55%，单独化疗的有效率是29%，联合治疗的有效率更高。Keytruda联合化疗的中位无进展生存期是13个月，单独化疗组的PFS是8.9个月，联合治疗能降低47%的疾病进展风险。,K药联合化疗的有效率是55%，单独化疗的有效率是29%，联合治疗的有效率更高。K药联合化疗的中位无进展生存期是13个月，单独化疗组的PF
9、S是8.9个月，联合治疗能降低47%的疾病进展风险。,21,22,患者大便中Akkermansia muciniphila影响PD-1抑制剂治疗疗效,Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Bertrand Routy. science. 2 November 2017.,Science,肠道菌群,23,对PD-1疗法有反应的30名患者与没有反应的13名患者的肠道菌群明显不同。,Gut microbiome influences efficacy of P
10、D-1-based immunotherapy against epithelial tumors. Bertrand Routy. science. 2 November 2017.,Science,研究人员以112例接受过抗PD-1免疫疗法的致命性皮肤癌-晚期黑色素瘤患者为研究对象，通过16S RNA与全基因组测序，统计了患者粪便中微生物的多样性。结果发现对PD-1疗法有反应的30名患者与没有反应的13名患者的肠道菌群明显不同。,V.Gopalakrishnan et al. Gut microbiome modulates response to anti-PD-1 immunother
11、apy in melanoma patients. Science.2 November 2017,Science,25,Commensal Bifidobacterium promotes antitumor immunity and facilitates antiPD-L1 efficacy. Sivan A.Science. 2015 Nov 27;350(6264):1084-9,黑色素瘤老鼠移植后给与PD-L1治疗,Science,TP53- NSCLC+pembrolizumab,Potential Predictive Value of TP53 and KRAS Mutati
12、on Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma. Dong ZY et al., Clin Cancer Res. 2017Jun 15;23(12):3012-3024.,27,RET：黑色素瘤；ATB：广谱抗菌素(氨苄青霉素+链霉素+多粘菌素) MCA-205：肉瘤 动物实验,Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.Bertrand Routy. s
13、cience. 2 November 2017.,Science,使用抗菌素,28,NSCLC 非小细胞肺癌；ATB (-内酰胺类+/-抑制剂、氟喹诺酮类、大环内酯类)；RCC 肾癌；UC 尿路上皮癌,临床研究 PD-1/PD-L1抗体,Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Bertrand Routy. science. 2 November 2017.,Science,29,30,Responses of Gut Microbiota and Glu
14、cose and Lipid Metabolism to Prebiotics in Genetic Obese and Diet-Induced Leptin-Resistant Mice. Amandine Everard,et al. DIABETES, VOL. 60, NOVEMBER 2011 2775,GLP-1：胰高血糖素样肽-1,31,比利时的研究人员于2013年研究发现Akkermansia细菌，能够帮助减肥、改善肥胖，同时还能够降低血糖、改善糖尿病，是非常重要的一种益生菌。它的工作方式是：调节肠道内黏液厚度和维持肠道屏障完整性，减少糖分吸收。,减肥细菌,目前已经知道艾克曼
15、菌跟很多健康问题有反向关系。也就是艾克曼细菌越少的个体，越容易发胖、出现炎症和2型糖尿病。 反过来，如果肠道内的艾克曼细菌越多，那么动物就有越少的肥胖、炎症和2型糖尿病。,32,研究人员给比正常老鼠的脂肪多两至三倍的老鼠喂了一种被称为Akkermansia muciniphila的细菌，在不改变其饮食的情况下，它们的多余体重减少了近一半，且胰岛素抗体水平也降低了。并且发现在患有遗传性肥胖的小鼠的肠道中Akk菌的含量相较于瘦小鼠而言极少，还有，长期高热量饮食的肥胖小鼠，肠道内Akk菌含量也非常低。 研究发现，人类同样如此，身材好的人，肠道中Akk菌含量较为丰富（达到3-5%甚至更多），而肥胖人群
16、的肠道中Akk菌相较于身材好的人来说含量则很低，两类人群差异巨大。,33,The Akkermansia-muciniphila is a gut microbiota signature in psoriasis. LiRong Tan. Exp Dermatol. 2017 Nov 11,银屑病患者肠道内菌群与正常人间的差异,预防银屑病？,34,Ht: H.typhlonius Am: A.muciniphila,肠道同时存在H.typhlonius和A.muciniphila的小鼠比只有H.typhlonius而没有A.muciniphila的小鼠肠道肿瘤的发生率低50%(11.7个 V
17、S 23.4个)。,Akkermansia muciniphila and Helicobacter typhlonius modulate intestinal tumor development in mice. Celia Dingemanse,et al. Carcinogenesis, 2015, Vol. 36, No. 11, 13881396,23.4个,11.7个,预防肿瘤？,35,Responses of Gut Microbiota and Glucose and Lipid Metabolism to Prebiotics in Genetic Obese and Di
18、et-Induced Leptin-Resistant Mice. Amandine Everard,et al. DIABETES, VOL. 60, NOVEMBER 2011 2775,口服益生元显著增加小鼠肠道中的A. muciniphila数量,36,纳武单抗（Nivolumab，Opdivo）的免疫相关不良事件与疗效具有正相关,Koichi Sato, et al., Correlation between immune-related adverse events and efficacy in non- small cell lung cancer treated with nivolumab，Lung Cancer 115 (2018) 7174,PD-1单抗的不良事件与疗效,Thanks !,
