免疫检查点抑制剂在膀胱尿路上皮癌中的研究进展
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摘要
膀胱尿路上皮癌(UBC)是常见的恶性肿瘤,可分为非肌层浸润性尿路上皮癌(NMIUC)、肌层浸润性尿路上皮癌(MIUC)和转移性尿路上皮癌(mUC)。mUC的一线治疗方案是以铂类为基础的化疗。然而,很多患者因基础状况较差无法耐受化疗的不良反应。即使能够接受化疗的患者,其获益也往往十分有限。目前,对尿路上皮肿瘤免疫学特征的研究有了很大的进展,尤其是免疫检查点抑制剂的相关研究,有望优化UBC的一线和二线治疗。本文旨在对免疫检查点抑制剂的研究进展作一综述,包括免疫检查点抑制剂的作用原理、疗效评价标准、免疫检查点抑制剂的联合应用和早期应用的探索,以及药物的不良反应及其处理。
Bladder urothelial carcinoma(UBC) is one of the common malignant tumors, including non-muscle-invasive urothelial carcinoma(NMIUC), muscle-invasive urothelial carcinoma(MIUC) and metastatic urothelial carcinoma(mUC). The first-line treatment of mUC is platinum-based chemotherapy. However, many patients can't tolerate chemotherapy's side effects due to their poor baseline conditions. Even patients are able to endure such side effects, their benefits are likely to be limited. Luckily, the study of the immunological characteristics of urinary tract epithelium cancer has made great progress, especially immune checkpoint blockade related research, which has the potential to optimize UBC's therapy. This paper is intended to review the progress of immune checkpoint blockade treatment in bladder urothelial cell carcinoma, including immune checkpoint blockade's basic principle, the efficacy evaluation criteria, the combined use of immune checkpoint blockade, the application in early stage of tumor and the adverse reactions.
Bladder urothelial carcinoma(UBC) is one of the common malignant tumors, including non-muscle-invasive urothelial carcinoma(NMIUC), muscle-invasive urothelial carcinoma(MIUC) and metastatic urothelial carcinoma(mUC). The first-line treatment of mUC is platinum-based chemotherapy. However, many patients can't tolerate chemotherapy's side effects due to their poor baseline conditions. Even patients are able to endure such side effects, their benefits are likely to be limited. Luckily, the study of the immunological characteristics of urinary tract epithelium cancer has made great progress, especially immune checkpoint blockade related research, which has the potential to optimize UBC's therapy. This paper is intended to review the progress of immune checkpoint blockade treatment in bladder urothelial cell carcinoma, including immune checkpoint blockade's basic principle, the efficacy evaluation criteria, the combined use of immune checkpoint blockade, the application in early stage of tumor and the adverse reactions.
引文
1 Smith S G,Zaharoff D A.Future directions in bladder cancer immunotherapy:towards adaptive immunity[J].Immunotherapy,2016,8(3):351-365.
2 Buchbinder E I,Desai A.CTLA-4 and PD-1 pathways:similarities,differences,and implications of their inhibition[J].Am J Clin Oncol,2016,39(1):98-106.
3 Powles T,Eder J P,Fine G D,et al.MPDL3280A(anti-PD-L1)treatment leads to clinical activity in metastatic bladder cancer[J].Nature,2014,515(7528):558-562.
4 Nakanishi J,Wada Y,Matsumoto K,et al.Overexpression of B7-H1(PD-L1)significantly associates with tumor grade and postoperative prognosis in human urothelial cancers[J].Cancer Immunol Immunother,2007,56(8):1173-1182.
5 Inman B A,Sebo T J,Frigola X,et al.PD-L1(B7-H1)expression by urothelial carcinoma of the bladder and BCG-induced granulomata:associations with localized stage progression[J].Cancer,2007,109(8):1499-1505.
6 Boorjian S A,Sheinin Y,Crispen P L,et al.T-cell coregulatory molecule expression in urothelial cell carcinoma:clinicopathologic correlations and association with survival[J].Clin Cancer Res,2008,14(15):4800-4888.
7 Chiou V L,Burotto M.Pseudoprogression and immune-related response in solid tumors[J].J Clin Oncol,2015,33(31):3541-3543.
8 Hodi F S,Hwu W J,Kefford R,et al.Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab[J].J Clin Oncol,2016,34(13):1510-1517.
9 Dreicer R.Immunomodulatory treatment in urothelialcancer[J].Lancet Oncol,2016,17(11):1475-1477.
10 Bertrand A,Kostine M,Barnetche T,et al.Immune related adverse events associated with anti-CTLA-4 antibodies:systematic review and meta analysis[J].BMC Med,2015,13:211-211.
11 Carthon B C,Wolchok J D,Yuan J,et al.Preoperative CTLA-4 blockade:tolerability and immune monitoring in the setting of a presurgical clinical trial[J].Clin Cancer Res,2010,16(10):2861-2871.
12 Massard C,Gordon M S,Sharma S,et al.Safety and Efficacy of Durvalumab(MEDI4736),an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor,in Patients With Advanced Urothelial Bladder Cancer[J].J Clin Oncol,2016,34(26):3119-3125.
13 Apolo A B,Infante J R,Balmanoukian A,et al.Avelumab,an Anti-Programmed Death-Ligand 1 Antibody,In Patients With Refractory Metastatic Urothelial Carcinoma:Results From a Multicenter,Phase Ib Study[J].J Clin Oncol,2017,35(19):2117-2124.
14 Apolo A B.PDL1:The Illusion of an Ideal Biomarker[J].Eur Urol Focus,2016,1(3):269-271.
15 Rosenberg J E,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,multicentre,phase 2 trial[J].Lancet,2016,387(10031):1909-1920.
16 Davarpanah N N,YunoA,Trepel J B,et al.Immunotherapy:a new treatment paradigm in bladder cancer[J].Curr Opin Oncol,2017,29(3):184-195.
17 Balar A V,Galsky M D,Rosenberg J E,et al.Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma:a single-arm,multicentre,phase 2 trial[J].Lancet,2017,389(10064):67-76.
18 McDaniel A S,Alva A,Zhan T,et al.Expression of PDL1(B7-H1)Before and After Neoadjuvant Chemotherapy in Urothelial Carcinoma[J].Eur Urol Focus,2016,1(3):265-268.
19 KamatA M,Bellmunt J,Matthew D,et al.Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma[J].J Immunother Cancer,2017,5(1):68-68.
20 Larkin J,Chiarion-Sileni V,Gonzalez R,et al.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma[J].N Engl J Med,2015,373(1):23-34.
21 Postow M A,Chesney J,Pavlick A C,et al.Nivolumab and ipilimumab versus ipilimumab in untreated melanoma[J].N Engl J Med,2015,372(21):2006-2017.
22 Carthon B C,Wolchok J D,Yuan J,et al.Preoperative CTLA-4 blockade:tolerability and immune monitoring in the setting of a presurgical clinical trial[J].Clin Cancer Res,2010,16(10):2861-2871.
23 Bardoli A D,Afshar M,Viney R,et al.The PD-1/PD-L1 axis in the pathogenesis of urothelial bladder cancer and evaluating its potential as a therapeutic target[J].Future Oncol,2016,12(5):595-600.
24 Inman B A,Sebo T J,Frigola X,et al.PD-L1(B7-H1)expression by urothelial carcinoma of the bladder and BCG-induced granulomata:associations with localized stage progression[J].Cancer,2007,109(8):1499-1505.
25 Postow M A.Managing immune checkpoint-blocking antibody side effects[J].Am Soc Clin Oncol Educ Book,2015,35:76-83.
26 Champiat S,Lambotte O,Barreau E,et al.Management of immune checkpoint blockade dysimmune toxicities:a collaborative position paper[J].Ann Oncol,2016,27(4):559-574.
27 Teply B A,Lipson E J.Identification and management of toxicities from immune checkpoint-blocking drugs[J].Oncology(Williston Park),2014,28(suppl 3):30-38.
28 Weber J S,Yang J C,Atkins M B,et al.Toxicities of immunotherapy for the practitioner[J].J Clin Oncol,2015,33(18):2092-2099.
29 Jago C B,Yates J,Camara N O,et al.Differential expression of CTLA-4 among T cell subsets[J].Clin Exp Immunol,2004,136(3):463-471.
30 Yao S,Zhu Y,Chen L.Advances in targeting cell surface signalling molecules for immune modulation[J].Nat Rev Drug Discov,2013,12(2):130-146.
2 Buchbinder E I,Desai A.CTLA-4 and PD-1 pathways:similarities,differences,and implications of their inhibition[J].Am J Clin Oncol,2016,39(1):98-106.
3 Powles T,Eder J P,Fine G D,et al.MPDL3280A(anti-PD-L1)treatment leads to clinical activity in metastatic bladder cancer[J].Nature,2014,515(7528):558-562.
4 Nakanishi J,Wada Y,Matsumoto K,et al.Overexpression of B7-H1(PD-L1)significantly associates with tumor grade and postoperative prognosis in human urothelial cancers[J].Cancer Immunol Immunother,2007,56(8):1173-1182.
5 Inman B A,Sebo T J,Frigola X,et al.PD-L1(B7-H1)expression by urothelial carcinoma of the bladder and BCG-induced granulomata:associations with localized stage progression[J].Cancer,2007,109(8):1499-1505.
6 Boorjian S A,Sheinin Y,Crispen P L,et al.T-cell coregulatory molecule expression in urothelial cell carcinoma:clinicopathologic correlations and association with survival[J].Clin Cancer Res,2008,14(15):4800-4888.
7 Chiou V L,Burotto M.Pseudoprogression and immune-related response in solid tumors[J].J Clin Oncol,2015,33(31):3541-3543.
8 Hodi F S,Hwu W J,Kefford R,et al.Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab[J].J Clin Oncol,2016,34(13):1510-1517.
9 Dreicer R.Immunomodulatory treatment in urothelialcancer[J].Lancet Oncol,2016,17(11):1475-1477.
10 Bertrand A,Kostine M,Barnetche T,et al.Immune related adverse events associated with anti-CTLA-4 antibodies:systematic review and meta analysis[J].BMC Med,2015,13:211-211.
11 Carthon B C,Wolchok J D,Yuan J,et al.Preoperative CTLA-4 blockade:tolerability and immune monitoring in the setting of a presurgical clinical trial[J].Clin Cancer Res,2010,16(10):2861-2871.
12 Massard C,Gordon M S,Sharma S,et al.Safety and Efficacy of Durvalumab(MEDI4736),an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor,in Patients With Advanced Urothelial Bladder Cancer[J].J Clin Oncol,2016,34(26):3119-3125.
13 Apolo A B,Infante J R,Balmanoukian A,et al.Avelumab,an Anti-Programmed Death-Ligand 1 Antibody,In Patients With Refractory Metastatic Urothelial Carcinoma:Results From a Multicenter,Phase Ib Study[J].J Clin Oncol,2017,35(19):2117-2124.
14 Apolo A B.PDL1:The Illusion of an Ideal Biomarker[J].Eur Urol Focus,2016,1(3):269-271.
15 Rosenberg J E,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,multicentre,phase 2 trial[J].Lancet,2016,387(10031):1909-1920.
16 Davarpanah N N,YunoA,Trepel J B,et al.Immunotherapy:a new treatment paradigm in bladder cancer[J].Curr Opin Oncol,2017,29(3):184-195.
17 Balar A V,Galsky M D,Rosenberg J E,et al.Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma:a single-arm,multicentre,phase 2 trial[J].Lancet,2017,389(10064):67-76.
18 McDaniel A S,Alva A,Zhan T,et al.Expression of PDL1(B7-H1)Before and After Neoadjuvant Chemotherapy in Urothelial Carcinoma[J].Eur Urol Focus,2016,1(3):265-268.
19 KamatA M,Bellmunt J,Matthew D,et al.Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma[J].J Immunother Cancer,2017,5(1):68-68.
20 Larkin J,Chiarion-Sileni V,Gonzalez R,et al.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma[J].N Engl J Med,2015,373(1):23-34.
21 Postow M A,Chesney J,Pavlick A C,et al.Nivolumab and ipilimumab versus ipilimumab in untreated melanoma[J].N Engl J Med,2015,372(21):2006-2017.
22 Carthon B C,Wolchok J D,Yuan J,et al.Preoperative CTLA-4 blockade:tolerability and immune monitoring in the setting of a presurgical clinical trial[J].Clin Cancer Res,2010,16(10):2861-2871.
23 Bardoli A D,Afshar M,Viney R,et al.The PD-1/PD-L1 axis in the pathogenesis of urothelial bladder cancer and evaluating its potential as a therapeutic target[J].Future Oncol,2016,12(5):595-600.
24 Inman B A,Sebo T J,Frigola X,et al.PD-L1(B7-H1)expression by urothelial carcinoma of the bladder and BCG-induced granulomata:associations with localized stage progression[J].Cancer,2007,109(8):1499-1505.
25 Postow M A.Managing immune checkpoint-blocking antibody side effects[J].Am Soc Clin Oncol Educ Book,2015,35:76-83.
26 Champiat S,Lambotte O,Barreau E,et al.Management of immune checkpoint blockade dysimmune toxicities:a collaborative position paper[J].Ann Oncol,2016,27(4):559-574.
27 Teply B A,Lipson E J.Identification and management of toxicities from immune checkpoint-blocking drugs[J].Oncology(Williston Park),2014,28(suppl 3):30-38.
28 Weber J S,Yang J C,Atkins M B,et al.Toxicities of immunotherapy for the practitioner[J].J Clin Oncol,2015,33(18):2092-2099.
29 Jago C B,Yates J,Camara N O,et al.Differential expression of CTLA-4 among T cell subsets[J].Clin Exp Immunol,2004,136(3):463-471.
30 Yao S,Zhu Y,Chen L.Advances in targeting cell surface signalling molecules for immune modulation[J].Nat Rev Drug Discov,2013,12(2):130-146.