李汉忠;张玉石;郑国洋;
LI Han-zhong;ZHANG Yu-shi;ZHENG Guo-yang;Department of Urology,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences &Peking Union Medical College;

• 1:中国医学科学院北京协和医学院北京协和医院泌尿外科

摘要(Abstract)：

随着肿瘤免疫学的迅速发展,免疫治疗逐渐引起肿瘤治疗领域专家的重视,相关研究为晚期肿瘤患者提供了新的治疗机会。以程序性死亡受体1及其配体、细胞毒性T淋巴细胞相关抗原4为代表的免疫检查点抑制剂是目前晚期肿瘤临床治疗的研究热点,已有多种免疫检查点抑制剂获得美国食品药品监督管理局批准用于晚期肿瘤免疫治疗,其不仅安全性高,且在晚期黑色素瘤、非小细胞肺癌、肾癌、尿路上皮癌、非霍奇金淋巴瘤中展现出令人振奋的治疗效果,有效延长了患者生存期。嵌合抗原受体T细胞疗法也是目前免疫治疗领域的明星产品之一,对急性白血病、非霍奇金淋巴瘤等血液系统恶性肿瘤展现出强大持久的治疗效果,以Simpuleucel-T为代表的肿瘤疫苗曾一度成为肿瘤免疫治疗里程碑式的成功范例。肿瘤免疫治疗已取得了突破性进展,研究前景不可估量。
With the rapid development of tumor immunology,immunotherapy for malignant tumors is becoming a research focus,offering an effective opportunity for the treatment of patients with advanced tumors. Immune checkpoint inhibitors,such as programmed cell death 1 receptor/programmed cell death 1 ligand 1 antibody and CTLA-4 antibody,are an important research hotspot of immunotherapy for advanced cancers. FDA has approved some immune checkpoint antibodies for the treatment of advanced metastatic melanoma,non-small cell lung cancer,renal cell carcinoma,uroepithelium carcinoma,and non-Hodgkin's lymphoma,and the efficacy and safety for above tumors has been confirmed. In addition,chemiric antigen receptor T-cell therapy treatment showed a strong and persistent therapeutic effect for hematologic malignancy,as another successful case of immunotherapy. Cancer vaccine such as Simpuleucel-T was also another milestone in the development of tumor immunotherapy. Currently,immunotherapy for malignant tumors is presenting a promising future.

关键词(KeyWords)： 肿瘤;免疫治疗;程序性死亡受体1;程序性死亡受体配体1;嵌合抗原受体T细胞疗法
neoplasms;immunotherapy;programmed cell death 1 receptor;programmed cell death 1 ligand 1;chimeric antigen receptor T-cell

Abstract:

Keywords:

基金项目(Foundation):

作者(Authors): 李汉忠;张玉石;郑国洋;
LI Han-zhong;ZHANG Yu-shi;ZHENG Guo-yang;Department of Urology,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences &Peking Union Medical College;

参考文献(References)：

• [1]Panaccio M,Zalcberg JR,Thompson CH,et al.Heterogeneity of the human transferrin receptor and use of anti-transferrin receptor antibodies to detect tumours in vivo[J].Immunol Cell Biol,1987,65:461-472.
• [2]Burnet FM.The concept of immunological surveillance[J].Prog Exp Tumor Res,1970,13:1-27.
• [3]Traversari C,van der Bruggen P,Luescher IF,et al.A nonapeptide encoded by human gene MAGE-1 is recognized on HLA-A1 by cytolytic T lymphocytes directed against tumor antigen MZ2-E[J].J Exp Med,1992,176:1453-1457.
• [4]Jensen PE.Recent advances in antigen processing and presentation[J].Nat Immunol,2007,8:1041-1048.
• [5]Topalian SL,Drake CG,Pardoll DM.Targeting the PD-1/B7-H1(PD-L1)pathway to activate anti-tumor immunity[J].Curr Opin Immunol,2012,24:207-212.
• [6]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[J].EMBO J,1992,11:3887-3895.
• [7]Keir ME,Butte MJ,Freeman GJ,et al.PD-1 and its ligands in tolerance and immunity[J].Annu Rev Immunol,2008,26:677-704.
• [8]Dong H,Zhu G,Tamada K,et al.B7-H1,a third member of the B7 family,co-stimulates T-cell proliferation and interleukin-10 secretion[J].Nat Med,1999,5:1365-1369.
• [9]Latchman Y,Wood CR,Chernova T,et al.PD-L2 is a second ligand for PD-1 and inhibits T cell activation[J].Nat Immunol,2001,2:261-268.
• [10]Buchbinder EI,Desai A.CTLA-4 and PD-1 Pathways:Similarities,Differences,and Implications of Their Inhibition[J].Am J Clin Oncol,2016,39:98-106.
• [11]Fife BT,Pauken KE,Eagar TN,et al.Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCRinduced stop signal[J].Nat Immunol,2009,10:1185-1192.
• [12]Keir ME,Liang SC,Guleria I,et al.Tissue expression of PD-L1 mediates peripheral T cell tolerance[J].J Exp Med,2006,203:883-895.
• [13]Chemnitz JM,Parry RV,Nichols KE,et al.SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation,but only receptor ligation prevents T cell activation[J].J Immunol,2004,173:945-954.
• [14]Parry RV,Chemnitz JM,Frauwirth KA,et al.CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms[J].Mol Cell Biol,2005,25:9543-9553.
• [15]Homet Moreno B,Ribas A.Anti-programmed cell death protein-1/ligand-1 therapy in different cancers[J].Br J Cancer,2015,112:1421-1427.
• [16]Motzer RJ,Rini BI,Mc Dermott DF,et al.Nivolumab for metastatic renal cell carcinoma:results of a randomized phase II trial[J].J Clin Oncol,2015,33:1430-1437.
• [17]Topalian SL,Hodi FS,Brahmer JR,et al.Safety,activity,and immune correlates of anti-PD-1 antibody in cancer[J].N Engl J Med,2012,366:2443-2454.
• [18]Motzer RJ,Escudier B,Mc Dermott DF,et al.Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma[J].N Engl J Med,2015,373:1803-1813.
• [19]Rosenberg JE,Hoffman-Censits J,Powles T,et al.Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy:a single arm,phase 2 trial[J].Lancet,2016,387:1909-1920.
• [20]Gandini S,Massi D,MandalàM.PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies:A systematic review and meta-analysis[J].Crit Rev Oncol Hematol,2016,100:88-98.
• [21]Mc Dermott DF,Sosman JA,Sznol M,et al.Atezolizumab,an Anti-Programmed Death-Ligand 1 Antibody,in Metastatic Renal Cell Carcinoma:Long-Term Safety,Clinical Activity,and Immune Correlates from a Phase Ia Study[J].J Clin Oncol,2016,34:833-842.
• [22]Robert C,Long GV,Brady B,et al.Nivolumab in previously untreated melanoma without BRAF mutation[J].N Engl J Med,2015,372:320-330.
• [23]Brahmer J,Reckamp KL,Baas P,et al.Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer[J].N Engl J Med,2015,373:123-135.
• [24]Hammers HJ,Plimack ER,Infante JR,et al.Safety and Efficacy of Nivolumab in Combination with Ipilimumab in Metastatic Renal Cell Carcinoma:The Check Mate 016 Study[J].J Clin Oncol,2017,35:3851-3858.
• [25]Weinstock M,Mc Dermott D.Targeting PD-1/PD-L1 in the treatment of metastatic renal cell carcinoma[J].Ther Adv Urol,2015,7:365-377.
• [26]Anassi E,Ndefo UA.Sipuleucel-T(provenge)injection:the first immunotherapy agent(vaccine)for hormone-refractory prostate cancer[J].P T,2011,36:197-202.
• [27]Cheever MA,Higano CS.PROVENGE(Sipuleucel-T)in prostate cancer:the first FDA-approved therapeutic cancer vaccine[J].Clin Caner Res,2011,17:3520-3526.
• [28]Small EJ,Schellhammer PF,Higano CS,et al.Placebocontrolled phase III trial of immunologic therapy with sipuleucel-T(APC8015)in patients with metastatic,asymptomatic hormone refractory prostate cancer[J].J Clin Oncol,2006,24:3089-3094.
• [29]Kantoff PW,Higano CS,Shore ND,et al.Sipuleucel-T immunotherapy for castration-resistant prostate cancer[J].N Engl Med,2010,363:411-422.
• [30]Gross G,Waks T,Eshhar Z.Expression of immunoglobulinT-cell receptor chimeric molecules as functional receptors with antibody-type specificity[J].Proc Natl Acad Sci U S A,1989,86:10024-10028.
• [31]Porter DL,Levine BL,Kalos M,et al.Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia[J].N Engl J Med,2011,365:725-733.
• [32]Cheadle EJ,Gornall H,Baldan V,et al.CAR-T cells:Driving the road from the laboratory to the clinic[J].Immunol Rev,2014,257:91-106.
• [33]Sadelain M,Rivière I,Riddell S.Therapeutic T cell engineering[J].Nature,2017,545:423-431.
• [34]Bukowski RM.Natural history and therapy of metastatic renal cell carcinoma:the role of interleukin-2[J].Cancer,1997,80:1198-1220.