恶性黑色素瘤药物发展.pptxVIP

恶性黑色素瘤药物发展第1页/共79页 黑色素瘤治疗靶点全身治疗化疗细胞因子抗体型疫苗 新的分子靶向药物促凋亡剂 抗BRAF抗VEGFR2EGFR, MEK, ERK抗整合素抗血管生成制剂第2页/共79页 转移潜能无限增值血管生成自主生长信号肿瘤抑制缺失阻断凋亡(Hanahan Weinberg, 2000)已知肿瘤细胞特征第3页/共79页 IV期黑色素瘤的III期临床试验(1)第4页/共79页 EggermontIV期黑色素瘤含干扰素的III期临床试验 (2) 第5页/共79页 IV期黑色素瘤的III期临床试验(1)化疗+ IL-2 + IFN第6页/共79页 黑色素瘤生物化疗的纪念(从今开始)一线治疗的研究药物第7页/共79页 CTLA4 阻断第8页/共79页 抗CTLA-4 单克隆抗体IL-2B7MHCTCRCD28. . . . . . . . . . . . . . . ~AntigenAPCT-cellCTLA-4B7MHCTCRCD28~AntigenB7MHCTCRCD28CTLA-4. . . . . . . . . . . . . . . Antigen抗CTLA-4 单克隆抗体MHCIL-2~第9页/共79页 T细胞受体: MHC抗原CD28: B7 CTLA-4: B7疫苗? CTLA-4: T细胞激活的“刹车”第10页/共79页 Copyright ?2003 by the National Academy of Sciences断层扫描示治疗前病变(左侧)，治疗后达到完全缓解：病例13（A与B）及病例11（C-F）Ipilimumab联合多肽类疫苗治疗进展期黑色素瘤(NCI)Phan GQ, et al. Proc. Natl. Acad. Sci. 2003;100:8372-8377.第11页/共79页 一例进展期黑色素瘤患者Ipilimumab相关性皮疹Ipilimumab 刺激黑色素细胞免疫识别 (A) 网状红斑样皮疹 (B) 血管周围淋巴细胞浸润突破表皮(C) CD4+ T细胞临近死亡的黑色素细胞(D) CD8+ T细胞临近死亡的黑色素细胞1. Hodi SF, et al. Proc Natl Acad Sci. 2003;100:4712-4717. 第12页/共79页 1. Attia P, et al. J Clin Oncol. 2005;23:6043-6053.2. Beck K, et al. J Clin Oncol. 2006;24:2283-2289.Overview of Gastrointestinal (GI) irAEsDiarrhea is a frequent irAEs1,2 Most cases are mild or moderateWatery to frank bloodBiopsy usually demonstrates inflammatory colitisManagement algorithm establishedMost cases respond to either symptomatic treatment or steroidsCan rarely lead to GI perforation (1%) requiring surgery2第13页/共79页 1. Robinson et al. J Immunother. 2004;27:478.2. Phan et al. Proc Natl Acad Sci USA. 2003;100:8372.Ipilimumab-Induced Colitis Resembles IBD and Usually Resolves Without Sequela With Appropriate Therapy第14页/共79页 Blansfield et al. J Immunother. 2005;28:593-598.Overview of irAEs in Endocrine OrgansHypophysitis Symptoms at presentation: memory loss, fatigue, impotence, headacheManagement Discontinue ipilimumabTemporary corticosteroid administrationHormonal replacementPatients are asymptomatic Slow return of some endocrine function第15页/共79页 6/30/04 Baseline(4.5 mm)12/3/04 Headache/Fat