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 2014 6 19 (James P. Allison) (Tasuku Honjo) (MD Anderson Cancer Center) 1995 T -4(cytotoxic T lymphocyte antigen-4, CTLA-4) 1992-1(programmed cell death protein-1, PD- 1) CTLA-4 PD-1 20 100 (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 2012 12 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) 2014 6 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
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-4 1987 Brunet Nature CTLA-4 CTLA-4 1995 CTLA-4 knockout CTLA-4(-/-) 1 CTLA-4 CTLA-4 (6) 2 priming phase T T T B7 CD28 T T CTLA-4 CTLA-4 18 2014, Vol.57, No.9
440 CD28 B7 CTLA-4 CD28 T T (7) CTLA-4 CTLA-4 ipilimumab tremelimumab T (immune-related adverse effects, iraes) 2 ipilimumab Hodi 2010 676 ipilimumab ipilimumab 100 (gp100 vaccine) 100 3 3 10.0 10.1 6.4 ipilimumab ipilimumab (p<0.001) (8) 18% ipilimumab 2 5% 100 2 4 ipilimumab 3 (reeducate) Robert 2011 502 ipilimumab dacarbazine dacarbazine dacarbazine ipilimumab 11.2 9.1 47.3% 36.3% (p<0.001) (9) FDA 2011 3 ipilimumab ipilimumab 10-15% (complete response, CR) 1-2% (tyrosine kinase inhibitor, TKI) 6 (10) 60% (Grade 3-4) 15-25% ipilimumab 2.PD-1 1992 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
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-1 296 107 28% 24 17 61% 43% 27% 22 18% 9.6 (15) nivolumab PD-1 CTLA-4 nivolumab (biomarker) PD-L1 42 17 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 20 2014, Vol.57, No.9
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: 841-847. 2. Dunn GP, Bruce AT, Ikeda H, et al.: Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002; 3: 991-998. 3. Starr TK, Jameson SC, Hogquist KA: Positive and negative selection of T cells. Annu Rev Immunol 2003; 21: 139-176. 4. 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: 5300-5309. 5. Zou W, Chen L: Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 2008; 8: 467-477. 6. Leach DR, Krummel MF, Allison JP: Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996; 2014, Vol.57, No.9 21
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