治 癌 新 策 略 免 疫 檢 查 點 抑 制 劑 綜 苑 裡 李 綜 醫 院 藥 劑 科 藥 師 莊 峻 毅 苑 裡 李 綜 醫 院 檢 驗 科 醫 事 檢 驗 師 林 君 萍 苑 裡 李 綜 醫 院 放 射 科 醫 事 放 射 師 張 凱 光 苑 裡 李 綜 醫 院 護 理 部 護 理 師 吳 衿 寧 衛 生 福 利 部 苗 栗 醫 院 藥 劑 科 藥 師 吳 求 珍 摘 要 T (T lymphocytes T cells) (ligand) (co-stimulatory receptors) CD28 (cluster of differentiation 28 28) OX40 (TNF receptor superfamily member 4; TNFRSF4 CD134) 4-1BB (TNF receptor superfamily 9) (co-inhibitory receptors) CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) PD-1 (programmed cell death 1) LAG-3 (lymphocyte activation gene 3 CD223) T (immune checkpoint) T (self tolerance) (immune homeostasis) 1-4 CTLA-4 PD-1 2014 CTLA-4 PD-1 (James P. Allison) (Tasuku Honjo) immune checkpoint immune checkpoint inhibitors 壹 前 言 (cancer immunotherapy) 1891 (William Coley) 1 (interferon) 2 (IL-2 32 2 Jun. 30 2016 藥 學 雜 誌 127 7
綜 Commentary Interleukin-2) (tumor vaccine) T CTLA-4 PD-1 (ligand) T CTLA-4 1987 Brunet JF Nature 3 CTLA-4 (the immunoglobulin superfamily) (interaction) 1995 CTLA-4 T T CTLA-4 2011 FDA CTLA-4 ipilimumab 1992 T PD-1 PD-1 PD-1 PD-1 5 PD-1 PD-L1 PD-L2 PD-L1 T PD-1 FDA 2014 2015 PD-1 pembrolizumab nivolumab 貳 免 疫 檢 查 點 的 免 疫 調 節 ( ) T T 6 ( ) 1 (priming phase) T (antigen presenting cell, APC) (dendritic cell) (antigen processing) (maturation) (major histocompatibility complex, MHC) T (T cell receptor TCR) T B7-1(CD80) B7-2(CD86) T CD28 T T (proliferation) (differentiation) T CTLA-4 T ( ) 3 T (tumor microenvironment) (immune surveillance) T TCR MHC T (cytotoxic T cell) (perforin) (granzyme) (granulysin) T (helper T cell) (IFN- ) (cytokines) 6 PD- L1 (PD-1 ) PD-1 2 PD-1 PD-L1 8 THE JOURNAL OF TAIWAN PHARMACY Vol.32 No.2 Jun. 30 2016
PD-1 PD-L1 ( ) 3 T (anergy) 1 圖 一 免 疫 系 統 對 抗 癌 細 胞 機 轉 示 意 圖 圖 二 初 期 的 免 疫 反 應 T 細 胞 活 化 及 抗 CTLA-4 3 抗 體 之 作 用 圖 三 T 細 胞 被 腫 瘤 細 胞 抑 制 活 性 及 抗 PD-1 抗 3 體 之 作 用 參 抑 制 性 的 免 疫 檢 查 點 抑 制 劑 一 CTLA4 blocking antibody Ipilimumab IgG1 kappa 148KDa ipilimumab 4 676 ipilimumab glycoprotein 100 (gp 100) ipilimumab gp 100 (median overall survival) 10.0 10.1 6.4 502 ipilimumab dacarbazine dacarbazine 11.2 9.1 1 47.3% 36.3% 2 28.5% 17.9% 3 20.8% 12.2% 二 PD-1 blocking antibodies Nivolumab IgG4 kappa 146KDa FDA nivolumab 7 945 nivolumab nivolumab ipilimumab ipilimumab (median progression-free survival) 6.9 11.5 2.9 綜 32 2 Jun. 30 2016 藥 學 雜 誌 127 9
綜 Commentary 8 272 nivolumab docetaxel 9.2 6.0 1 42% 24% grade 3 4 7% 55% 9 582 nivolumab docetaxel 12.2 9.4 1 51% 39% grade 3 4 10% 54% 10 (sunitinib pazopanib axitinib ) (clear-cell renal cell carcinoma) 821 nivolumab mtor everolimus 25.0 19.6 (objective response rate) 25% 5% 4.6 4.4 grade 3 4 19% 37% Pembrolizumab IgG4 kappa 149KDa ipilimumab BRAF KEYNOTE-6 11 834 pembrolizumab pembrolizumab ipilimumab 12 74.1% 68.4% 58.2% 5.5 4.1 2.8 grade 3 5 13.3% 10.1% 19.9% 肆 未 來 展 望 與 結 CTLA-4 PD-1 ( ) 1 1 圖 四 免 疫 檢 查 點 免 疫 調 控 蛋 白 10 THE JOURNAL OF TAIWAN PHARMACY Vol.32 No.2 Jun. 30 2016
Immune Checkpoint Inhibitors, The New Strategy Against Cancer 綜 Chun-Yi Chuang 1, Chun-Ping Lin 2, Kai-Kuang Chang 3, Chin-Ning Wu 4, Chiu-Jen Wu 5 Department of Pharmacy, Yuanli Lee s General Hospital, Lee s Medical Corporation 1 Department of Medical laboratory, Yuanli Lee s General Hospital, Lee s Medical Corporation 2 Department of Radiology, Yuanli Lee s General Hospital, Lee s Medical Corporation 3 Department of Nursing, Yuanli Lee s General Hospital, Lee s Medical Corporation 4 Department of Pharmacy, Miao-Li General Hospital, Department of Health 5 Abstract There are a number of known receptors that exist in surface of T cells. Depending on immune responses of the interactions among the receptors and ligands, these receptors are divide into two groups. One group provides positive signals to activate immune system so called co-stimulatory receptors, including CD28, OX40 and 4-1BB. The other group provides negative signals to inhibit immune system so called co-stimulatory receptors, including CTLA-4, PD-1 and LAG-3. These co-stimulatory and inhibitory signals provided by interaction of receptors and ligands are called immune checkpoints. Immune checkpoints are crucial for the maintenance of self-tolerance and also to protect tissues from damage during the immune system responding to pathogenic infection. Finally immune checkpoints can regulate immune system to maintain self tolerance to avoid autoimmune damage and to keep immune homeostasis. CTLA-4 and PD-1 inhibitors have been well used in cancer therapy. The 2014 Tang Prize in Biopharmaceutical Science is awarded to James P. Allison and Tasuku Honjo for their outstanding research of CTLA-4 and PD-1 as immune inhibitory molecules to lead the applications in cancer immunotherapy. 32 2 Jun. 30 2016 藥 學 雜 誌 127 11
綜 Commentary 參 考 資 料 : 1. Ira Mellman, George Coukos and Glenn Danoff: Cancer immunotherapy comes of age. Nature 2011;480:480-489. 2. Drew M. Pardoll: The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews cancer 2012;12:252-264. 3. Chrisann Kyi, Michael A. Postow: Checkpoint blocking antibodies in cancer immunotherapy. FEBS Letters 2014;588:368-376. 4. : 2014;57(No.9):17-22. 5. Taku Okazaki and Tasuku Honjo: PD-1 and PD-1 ligands: from discovery to clinical application. International Immunology 2007; 19(No.7): 813-824. 6. 2005 630-642 7. J. Larkin, V. Chiarion-Sileni, R. Gonzalez, et al: Conbined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015; 373:23-34. 8. Julie Brahmer,Karen L. Reckamp, Paul Bass, et al: Nivolumab versus Docetaxel in Advanced Squamous- Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015; 373:123-35. 9. Hossein Borghaei, Luis Paz-Ares, Leora Horn, et al: Nivolumab versus Docetaxel in Advanced Nonsquamous- Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015; 373:1627-39. 10. R. J. Motzer, B. Escudier, D. F. McDermott, et al: Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015; 373:1803-13. 11. Caroline Robert, Jacob Schachter, Georgina V. Long, et al: Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 2015; 372:2521-32. (Superbugs) 專 有 名 詞 介 紹 (superbugs) Review on Antimicrobial Resistance 2050 1,000 3 2016 5 19 / / 12 THE JOURNAL OF TAIWAN PHARMACY Vol.32 No.2 Jun. 30 2016