439 (major histocompatibility complex, MHC) (peptide) T T (T cell receptor, TCR) T T (ligand) T 1 (4) B 7 (B7 family) (tumor necrosis factor family) B

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1 438 從第一屆唐獎生技醫藥獎談癌症免疫治療的展望文圖 / 張景明張金堅 * 澄清醫院中港院區血液腫瘤科外科 * 前言 (James P. Allison) (Tasuku Honjo) (MD Anderson Cancer Center) 1995 T -4(cytotoxic T lymphocyte antigen-4, CTLA-4) (programmed cell death protein-1, PD- 1) CTLA-4 PD (William Coley) 1957 Thomas Burnet (immune surveillance) (1) 2002 Schreiber (immunoediting) (elimination) (equilibrium) (escape) 3 E (2) CTLA-4 PD-1 唐獎成立之背景圖 1 T 細胞的活化或抑制, 需要兩個訊號的傳遞, 第一個訊號是 MHC 與 TCR 的結合來產生, 第二個訊號則由許許多多抗原呈現細胞上的配體與 T 細胞上的接受器結合所產生 (4) T 細胞抗原呈現細胞與腫瘤細胞間的關係 T (antigen presenting cells, APC) T T T T clonal selection T (3) T 2014, Vol.57, No.9 17

2 439 (major histocompatibility complex, MHC) (peptide) T T (T cell receptor, TCR) T T (ligand) T 1 (4) B 7 (B7 family) (tumor necrosis factor family) B7-1 CD80 B7-2 CD86 PD- L1(PD-1 ligand) PD-L2(PD-2 ligand) B7 (5) B7-1 T CD28 T B7-1 T CTLA-4 T T T T B7-1 CD28 T CTLA-4 T (self tolerance) (immune checkpoints) 嶄新的癌症免疫治療免疫檢查站的臨床應用 T 1 CTLA-4 PD-1 CTLA-4 PD-1 圖 2 ( 圖左 ) 代表早期的免疫反應, 於淋巴結中發生, 藉由 MHC 與 TCR 結合產生第一個訊號,B7 與 CD28 結合產生第二個訊號, 造成 T 細胞的活化, 而活化後 CTLA-4 後表現增加, 會與 CD28 競爭結合 B7, 因而產生抑制 T 細胞的訊號, 而抗 CTLA-4 抗體便可以將這抑制性的訊號阻斷 ( 圖右 ) 免疫作用期發生在周邊組織或是腫瘤細胞中,T 細胞在接觸抗原後便會表現 PD-1, 當與腫瘤細胞上的 PD-L1 結合, 便會傳遞抑制 T 細胞的訊息, 若有抗 PD-1 抗體抗 PD-L1 抗體, 便能將此抑制性的訊號阻斷,T 細胞便可活化毒殺腫瘤細胞 (7) 1.CTLA-4 CTLA Brunet Nature CTLA-4 CTLA CTLA-4 knockout CTLA-4(-/-) 1 CTLA-4 CTLA-4 (6) 2 priming phase T T T B7 CD28 T T CTLA-4 CTLA , Vol.57, No.9

3 440 CD28 B7 CTLA-4 CD28 T T (7) CTLA-4 CTLA-4 ipilimumab tremelimumab T (immune-related adverse effects, iraes) 2 ipilimumab Hodi ipilimumab ipilimumab 100 (gp100 vaccine) ipilimumab ipilimumab (p<0.001) (8) 18% ipilimumab 2 5% ipilimumab 3 (reeducate) Robert ipilimumab dacarbazine dacarbazine dacarbazine ipilimumab % 36.3% (p<0.001) (9) FDA ipilimumab ipilimumab 10-15% (complete response, CR) 1-2% (tyrosine kinase inhibitor, TKI) 6 (10) 60% (Grade 3-4) 15-25% ipilimumab 2.PD PD-1 (11) T T (antigen-experienced memory T cells, Tm) PD-1 PD-L1 PD-L2 T T 2 (7) (tumor microenvironment) (tumor-infiltrating lymphocytes, TIL) PD-1 PD-1 CTLA-4 B (NK cell) T (Treg) PD-1 (12) PD-1 T B T PD-L1 PD-L2 (13) PD-L1 (innate immune resistance) (oncogenic signalling) PD-L1 T 2014, Vol.57, No.9 19

4 441 (adaptive immune resistance) T (IFN- ) PD-L1 T 3 (14) PD-1 PD-L1 PD-L2 PD-1 PD-L1 PD-L2 T PD-1 PD-L1 PD-L2 T PD-1 CTLA-4 nivolumab PD % % 43% 27% 22 18% 9.6 (15) nivolumab PD-1 CTLA-4 nivolumab (biomarker) PD-L PD-L1 25 PD-L1 9 (36%) (p=0.006) 圖 3 兩種有關腫瘤的免疫逃脫機制 (a) 先天性免疫抗性, 腫瘤細胞內的致癌訊息傳導路徑會使得腫瘤細胞表面的 PD-L1 表現增加, 因而使得 T 細胞受到抑制而無法毒殺腫瘤 (b) 後天性免疫抗性, 發炎反應產生的伽瑪干擾素會誘發腫瘤細胞產生更多的 PD-L1, 最後造成 T 細胞的抑制 (14) PD-1 PD-L1 PD-L2 癌症免疫治療的挑戰 1. 免疫治療之反應與傳統化學治療之反應不同 (RECIST criteria) Wolchok (immunerelated response criteria, irrc) 4 (16) 2. 生物標記的研究 , Vol.57, No.9

5 442 PD-L1 (absolute lymphocyte count) (17) 3. 癌症免疫治療與其他藥物的合併治療 Wolchok ipilimumab(anti-ctla-4) nivolumab(anti-pd-1) 88 40% 53% (grade 3/4) 53% (18) ipilimumab (granulocyte-macrophage colony stimulating factor, GM-CSF) (19) ipilimumab 結語 20 (science) (Breakthrough of the year) CTLA-4 PD-1 ICOS(inducible T cell co-stimulator) LAG3(lymphocyte activation gene 3) TIM3(T cell immunoglobulin mucin 3) 參考文獻 1. Burnet M: Cancer: A biological approach. III. Viruses associated with neoplastic conditions. IV. Practical applications. Br Med J 1957; 1: Dunn GP, Bruce AT, Ikeda H, et al.: Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002; 3: Starr TK, Jameson SC, Hogquist KA: Positive and negative selection of T cells. Annu Rev Immunol 2003; 21: Ott PA, Hodi FS, Robert C: CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res 2013; 19: Zou W, Chen L: Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 2008; 8: Leach DR, Krummel MF, Allison JP: Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996; 2014, Vol.57, No.9 21

6 : Kyi C, Postow MA: Checkpoint blocking antibodies in cancer immunotherapy. FEBS Lett 2014; 588: Hodi FS, O'Day SJ, McDermott DF, et al.: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: Robert C, Thomas L, Bondarenko I, et al.: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364: Prieto PA, Yang JC, Sherry RM, et al.: CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res 2012; 18: Ishida Y, Agata Y, Shibahara K, et al.: Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992; 11: Francisco LM, Salinas VH, Brown KE, et al.: PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 2009; 206: Ramsay AG: Immune checkpoint blockade immunotherapy to activate anti-tumour T-cell immunity. Br J Haematol 2013; 162: Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nature reviews Cancer 2012; 12: Topalian SL, Hodi FS, Brahmer JR, et al.: Safety, activity, and immune correlates of anti-pd-1 antibody in cancer. N Engl J Med 2012; 366: Wolchok JD, Hoos A, O'Day S, et al.: Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15: Luke JJ, Callahan MK, Postow MA, et al.: Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan- Kettering Cancer Center, and University Hospital of Lausanne experience. Cancer 2013; 119: Wolchok JD, Kluger H, Callahan MK, et al.: Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369: van Elsas A, Hurwitz AA, Allison JP: Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med 1999; 190: , Vol.57, No.9

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) (interacti

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) (interacti 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