药学学报, 2019, 54(10): 1735-1740
引用本文:
袁司辰, 赵慧锋, 吴昊姝, 曹戟. 靶向肿瘤PD-1/PD-L1抗体药物治疗中出现疾病“超进展”现象及其合理应用研究进展[J]. 药学学报, 2019, 54(10): 1735-1740.
YUAN Si-chen, ZHAO Hui-feng, WU Hao-shu, CAO Ji. Advances in hyperprogressive disease of PD-1/PD-L1 antibody drugs and rational drug therapy[J]. Acta Pharmaceutica Sinica, 2019, 54(10): 1735-1740.

靶向肿瘤PD-1/PD-L1抗体药物治疗中出现疾病“超进展”现象及其合理应用研究进展
袁司辰, 赵慧锋, 吴昊姝, 曹戟
浙江大学药学院, 浙江 杭州 310058
摘要:
随着靶向程序性死亡受体-1(programmed cell death 1,PD-1)/程序性死亡受体配体-1(programmed cell death1 ligand 1,PD-L1)药物在多种恶性实体瘤的临床治疗中取得突破性的成就,靶向肿瘤免疫检查点调控肿瘤已被认为是极具前景的新型肿瘤治疗方式,并已开启了肿瘤免疫治疗的新时代。然而,近年来研究发现靶向PD-1/PD-L1抗体药物在治疗过程中出现的疾病"超进展"现象(hyperprogressive disease),已成为一个亟待解决的关键问题。本文综述了有关靶向PD-1/PD-L1抗体药物疾病"超进展"现象的研究现状,从3个方面总结了因阻断PD-1/PD-L1信号轴而造成的疾病"超进展"潜在原因;并在此基础上,进一步基于生物标志物在靶向PD-1/PD-L1抗体药物的合理应用方面做一简单探讨。
关键词:    程序性死亡受体-1      程序性死亡受体配体-1      疾病“超进展”      生物标志物      药物合理应用     
Advances in hyperprogressive disease of PD-1/PD-L1 antibody drugs and rational drug therapy
YUAN Si-chen, ZHAO Hui-feng, WU Hao-shu, CAO Ji
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
Abstract:
With the significant breakthrough that programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) antibody drugs achieved promising clinical outcomes across various tumor types, immunotherapy targeting immune checkpoint has been considered a promising way to treat cancer. However, most recently studies suggest that the hyperprogressive disease occurred frequently during the therapy of using PD-1/PD-L1 antibody drugs and has become an urgent problem to be solved. In this review, we summarize the progress and potential reasons of hyperprogressive disease caused by PD-1/PD-L1 blockade, and further discuss its application based on the rational use of biomarkers for searching the benefit patients.
Key words:    programmed cell death 1    programmed cell death 1 ligand 1    hyperprogressive disease    biomarker    rational drug therapy   
收稿日期: 2019-07-17
DOI: 10.16438/j.0513-4870.2019-0569
基金项目: 国家自然科学基金资助项目(81872885);浙江省科学技术协会“育才工程”(2018YCGC002).
通讯作者: 曹戟,Tel:86-571-88208401,E-mail:caoji88@zju.edu.cn
Email: caoji88@zju.edu.cn
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参考文献:
[1] 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.
[2] Francisco LM, Salinas VH, Brown KE, et al. PD-L1 regulates the development, maintenance and function of induced-regulatory T cells[J]. J Exp Med, 2009, 206:3015-3029.
[3] Champiat S, Dercle L, Ammari S, et al. Hyperprogressive disease (HPD) is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1[J]. Clin Cancer Res, 2016, 23:1920-1928.
[4] Fuentes-Antrás J, Provencio M, Díaz-Rubio E. Hyperprogression as a distinct outcome after immunotherapy[J]. Cancer Treat Rev, 2018, 70:16-21.
[5] Ferrara R, Mezquita L, Texier M, et al. Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy[J]. JAMA Oncol, 2018, 4:1543-1552.
[6] Tanaka Yuko. Hyperprogressive Disease after Treatment with Pembrolizumab in Lung Adenocarcinoma:An Autopsy Case Study[R]. Japan:Yuko Tanaka, 2019.
[7] Aoki M, Shoji H, Nagashima K, et al. Hyperprogressive disease during nivolumab or irinotecan treatment in patients with advanced gastric cancer[J]. J Clin Oncol, 2019, 4:124.
[8] Gershon RK, Eardley DD, Durum S, et al. Contrasuppression. A novel immunoregulatory activity[J]. J Exp Med, 1981, 153:1533-1546.
[9] Barnaba V, Schinzari V. Induction, control, and plasticity of Treg cells:the immune regulatory network revised?[J]. Eur J Immunol, 2013, 43:318-322.
[10] Krupnick AS, Gelman AE, Barchet W, et al. Cutting edge:murine vascular endothelium activates and induces the generation of allogeneic CD4+25+ Foxp3+ regulatory T cells[J]. J Immunol, 2005, 175:6265.
[11] Asano T, Meguri Y, Yoshioka T, et al. PD-1 modulates regulatory T-cell homeostasis during low-dose interleukin-2 therapy[J]. Blood, 2017, 129:2186-2197.
[12] Francavilla V. PD-L1 negatively regulates CD4+ CD25+ Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV[J]. J Clin Invest, 2009, 119:551.
[13] Peligero C, Argilaguet J, Güerri-Fernandez R, et al. PD-L1 blockade differentially impacts regulatory T cells from HIVinfected individuals depending on plasma viremia[J]. PLoS Pathog, 2015, 11:e1005270.
[14] Ellestad KK, Thangavelu G, Ewen CL, et al. PD-1 is not required for natural or peripherally induced regulatory T cells:severe autoimmunity despite normal production of regulatory T cells[J]. Eur J Immunol, 2014, 44:3560-3572.
[15] Koyama S, Akbay EA, Li YY, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints[J]. Nat Commun, 2016, 7:10501.
[16] Huang RY, Francois A, Mcgray AR, et al. Compensatory upregulation of PD-1, LAG-3, and CTLA-4 limits the efficacy of singleagent checkpoint blockade in metastatic ovarian cancer[J]. Oncoimmunology, 2017, 6:e1249561.
[17] Pentcheva-Hoang T, Egen JG, Wojnoonski K, et al. B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse[J]. Immunity, 2004, 21:401-413.
[18] Freeman GJ, Sharpe AH, Keir ME, et al. PD-1 and its ligands in tolerance and immunity[J]. Annu Rev Immunol, 2008, 26:677-704.
[19] Dong Y, Sun Q, Zhang X. PD-1 and its ligands are important immune checkpoints in cancer[J]. Oncotarget, 2017, 8:2171.
[20] Xu W, Gu JJ, Ren QL, et al. NFATC1 promotes cell growth and tumorigenesis in ovarian cancer up-regulating c-Myc through ERK1/2/p38 MAPK signal pathway[J]. Tumor Biol, 2016, 37:4493-4500.
[21] Dulos J, Carven, Gregory J, et al. PD-1 blockade augments Th1 and Th17 and suppresses Th2 responses in peripheral blood from patients with prostate and advanced melanoma cancer[J]. J Immunother, 2012, 35:169-178.
[22] Lamichhane P, Karyampudi L, Shreeder B, et al. IL-10 release upon PD-1 blockade sustains immunosuppression in ovarian cancer[J]. Cancer Res, 2017, 77:6667-6678.
[23] Nakamura K, Smyth MJ. Targeting cancer-related inflammation in the era of immunotherapy[J]. Immunol Cell Biol, 2017, 95:325-332.
[24] Sica A, Larghi P, Mancino A, et al. Macrophage polarization in tumour progression[J]. Semin Cancer Biol, 2008, 18:349-355.
[25] Denardo DG, Barreto JB, Andreu P, et al. CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages[J]. Cancer Cell, 2009, 16:91-102.
[26] Allavena P, Sica A, Garlanda C, et al. The Yin-Yang of tumorassociated macrophages in neoplastic progression and immune surveillance[J]. Immunol Rev, 2008, 222:155-161.
[27] Kato S, Goodman AM, Walavalkar V, et al. Hyper-progressors after immunotherapy:analysis of genomic alterations associated with accelerated growth rate[J]. Clin Cancer Res, 2017, 23:4242-4250.
[28] Zuazo-Ibarra M, Arasanz H, Fernández-Hinojal G, et al. Senescent CD4 T cells unequivocally identify primary resistance and risk of hyperprogression to PD-L1/PD-1 immune checkpoint blockade in lung cancer[J]. bioRxiv, 2018. DOI:10.1101/320176.