綜 Commentary Interleukin-2) (tumor vaccine) T CTLA-4 PD-1 (ligand) T CTLA Brunet JF Nature 3 CTLA-4 (the immunoglobulin superfamily) (interacti

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1 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 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 Jun 藥學雜誌 127 7

(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)

2 綜 Commentary Interleukin-2) (tumor vaccine) T CTLA-4 PD-1 (ligand) T CTLA Brunet JF Nature 3 CTLA-4 (the immunoglobulin superfamily) (interaction) 1995 CTLA-4 T T CTLA 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 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

(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 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 ipilimumab glycoprotein 100 (gp 100) ipilimumab gp 100 (median overall survival) ipilimumab dacarbazine dacarbazine % 36.3% % 17.9% % 12.2% 二 PD-1 blocking antibodies Nivolumab IgG4 kappa 146KDa FDA nivolumab nivolumab nivolumab ipilimumab ipilimumab (median progression-free survival) 綜 32 2 Jun 藥學雜誌 127 9

(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.

4 綜 Commentary nivolumab docetaxel % 24% grade 3 4 7% 55% nivolumab docetaxel % 39% grade % 54% 10 (sunitinib pazopanib axitinib ) (clear-cell renal cell carcinoma) 821 nivolumab mtor everolimus (objective response rate) 25% 5% grade % 37% Pembrolizumab IgG4 kappa 149KDa ipilimumab BRAF KEYNOTE pembrolizumab pembrolizumab ipilimumab % 68.4% 58.2% grade % 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

6 (objective response rate) 25% 5% 4.6 4.

5 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 Jun 藥學雜誌

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

6 綜 Commentary 參考資料 : 1. Ira Mellman, George Coukos and Glenn Danoff: Cancer immunotherapy comes of age. Nature 2011;480: Drew M. Pardoll: The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews cancer 2012;12: Chrisann Kyi, Michael A. Postow: Checkpoint blocking antibodies in cancer immunotherapy. FEBS Letters 2014;588: : 2014;57(No.9): Taku Okazaki and Tasuku Honjo: PD-1 and PD-1 ligands: from discovery to clinical application. International Immunology 2007; 19(No.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: 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: 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: R. J. Motzer, B. Escudier, D. F. McDermott, et al: Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015; 373: Caroline Robert, Jacob Schachter, Georgina V. Long, et al: Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 2015; 372: (Superbugs) 專有名詞介紹 (superbugs) Review on Antimicrobial Resistance , / / 12 THE JOURNAL OF TAIWAN PHARMACY Vol.32 No.2 Jun

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.

( ) 4+2 4+1 一藥師考試人數統計 ( 表一 ) 表一最近十年 (90 年至 99 年 ) 藥師國考報名到考及格人數統計表 ( 表一 ) 2 2001 2002 2003-1 2003-2 2004-1 2004-2 2005-1

( ) 4+2 4+1 一藥師考試人數統計 ( 表一 ) 表一最近十年 (90 年至 99 年 ) 藥師國考報名到考及格人數統計表 ( 表一 ) 2 2001 2002 2003-1 2003-2 2004-1 2004-2 2005-1 綜合評論 Commentary 臺灣藥學教育與藥師考試之改造林藥師藥局藥師林振順 ( 整理 ) 考試委員胡幼圃 ( 口述 ) 壹前言 2003 pharm.d. 2006 2008 2003 2005 2011 8 ( ) PGY 貳藥師考試 640 ( 15 ) 4+1+1 ( ) ( ) 8 THE JOURNAL