免疫检查点抑制剂治疗晚期恶性肿瘤出现超进展性疾病研究现状

doi:10.3760/cma.j.issn.1673-422X.2020.02.006

摘要/Abstract

摘要：

免疫检查点抑制剂目前已成为多种晚期恶性肿瘤患者长期生存获益的极其重要的治疗手段。然而,少数患者会发生超进展性疾病(HPD),导致生存期缩短及生命质量急剧下降,对此尚缺乏有效的解救治疗手段。近期研究显示,HPD的发生与高龄、肿瘤复发、多病灶转移等临床因素相关;可能的发生机制包括抑制性免疫调节、调节性T细胞聚集、异常炎症反应及原癌基因激活、抑癌基因突变等多种途径。合理筛选、精准检测、密切监测以及联合治疗可能降低免疫治疗发生HPD的风险。

关键词: 肿瘤, 免疫疗法, 免疫检查点抑制剂, 超进展性疾病

Abstract:

Immune checkpoint inhibitors have become extremely important treatments to benefit long-term survival of patients with a variety of advanced malignant tumors. However, a small number of patients will develop hyperprogressive disease (HPD), leading to a sharp decline in survival and quality of life, and there is still a lack of effective rescue treatment. Recent studies have shown that the occurrence of HPD is related to clinical factors such as advanced age, tumor recurrence and multi-focus metastasis. The possible mechanisms include inhibitory immune regulation, regulatory T cell aggregation, abnormal inflammatory response, proto-oncogene activation, tumor suppressor gene mutation and other pathways. Reasonable screening, accurate detection, close monitoring and combined treatment may reduce the risk of immunotherapy for HPD.

Key words: Neoplasms, Immunotherapy, Immune checkpoint inhibitors, Hyperprogressive disease

周生余. 免疫检查点抑制剂治疗晚期恶性肿瘤出现超进展性疾病研究现状[J]. 国际肿瘤学杂志, 2020, 47(2): 93-97.

Zhou Shengyu. Research status of immune checkpoint inhibitors in the treatment of advanced malignant tumors with hyperprogressive diseases[J]. Journal of International Oncology, 2020, 47(2): 93-97.

参考文献 45

[1]	Ferris RL, Blumenschein G Jr, Fayette J , et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck[J]. N Engl J Med, 2016,375(19):1856-1867. DOI: 10.1056/NEJMoa 1602252. doi: 10.1056/NEJMoa1602252
[2]	Borghaei H, Paz-Ares L, Horn L , et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer[J]. N Engl J Med, 2015,373(17):1627-1639. DOI: 10.1056/NEJMoa 1507643. doi: 10.1056/NEJMoa1507643
[3]	Motzer RJ, Escudier B, McDermott DF , et al. Nivolumab versus everolimus in advanced renal-cell carcinoma[J]. N Engl J Med, 2015,373(19):1803-1813. DOI: 10.1056/NEJMoa1510665. doi: 10.1056/NEJMoa1510665
[4]	Champiat S, Ferrara R, Massard C , et al. Hyperprogressive disease: recognizing a novel pattern to improve patient management[J]. Nat Rev Clin Oncol, 2018,15(12):748-762. DOI: 10.1038/s41571-018-0111-2. doi: 10.1038/s41571-018-0111-2
[5]	Champiat S, Dercle L, Ammari S , et al. Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1[J]. Clin Cancer Res, 2017,23(8):1920-1928. DOI: 10.1158/1078-0432.CCR-16-1741.
[6]	Saâda-Bouzid E, Defaucheux C, Karabajakian A , et al. Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma[J]. Ann Oncol, 2017,28(7):1605-1611. DOI: 10.1093/annonc/mdx178. doi: 10.1093/annonc/mdx178
[7]	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(11):1543-1552. DOI: 10.1001/jamaoncol.2018.3676. doi: 10.1001/jamaoncol.2018.3676
[8]	Kato S, Goodman A, Walavalkar V , et al. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate[J]. Clin Cancer Res, 2017,23(15):4242-4250. DOI: 10.1158/1078-0432.CCR-16-3133. doi: 10.1158/1078-0432.CCR-16-3133
[9]	Sasaki A, Nakamura Y, Mishima S , et al. Predictive factors for hyperprogressive disease during nivolumab as anti-PD1 treatment in patients with advanced gastric cancer[J]. Gastric Cancer, 2019,22(4):793-802. DOI: 10.1007/s10120-018-00922-8. doi: 10.1007/s10120-018-00922-8
[10]	Funazo T, Nomizo T, Kim YH . Liver metastasis is associated with poor progression-free survival in patients with non-small cell lung cancer treated with nivolumab[J]. J Thorac Oncol, 2017,12(9):e140-e141. DOI: 10.1016/j.jtho.2017.04.027. doi: 10.1016/j.jtho.2017.04.027
[11]	Weiss GJ, Beck J, Braun DP , et al. Tumor cell-free DNA copy number instability predicts therapeutic response to immunotherapy[J]. Clin Cancer Res, 2017,23(17):5074-5081. DOI: 10.1158/1078-0432.CCR-17-0231. doi: 10.1158/1078-0432.CCR-17-0231
[12]	Zaretsky JM, Garcia-Diaz A, Shin DS , et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma[J]. N Engl J Med, 2016 , 375(9):819-829. DOI: 10.1056/NEJMoa1604958. doi: 10.1056/NEJMoa1604958
[13]	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. DOI: 10.1038/ncomms10501. doi: 10.1038/ncomms10501
[14]	Lo Russo G, Moro M, Sommariva M , et al. Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade[J]. Clin Cancer Res, 2019,25(3):989-999. DOI: 10.1158/1078-0432.CCR-18-1390. doi: 10.1158/1078-0432.CCR-18-1390
[15]	Adams TA, Vail PJ, Ruiz A , et al. Composite analysis of immunological and metabolic markers defines novel subtypes of triple negative breast cancer[J]. Mod Pathol, 2018,31(2):288-298. DOI: 10.1038/modpathol.2017.126. doi: 10.1038/modpathol.2017.126
[16]	Kubota K, Moriyama M, Furukawa S , et al. CD163⁺CD204⁺ tumor-associated macrophages contribute to T cell regulation via interleukin-10 and PD-L1 production in oral squamous cell carcinoma [J]. Sci Rep, 2017,7(1):1755. DOI: 10.1038/s41598-017-01661-z. doi: 10.1038/s41598-017-01661-z
[17]	Lamichhane P, Karyampudi L, Shreeder B , et al. IL10 release upon PD-1 blockade sustains immunosuppression in ovarian cancer[J]. Cancer Res, 2017,77(23):6667-6678. DOI: 10.1158/0008-5472.CAN-17-0740. doi: 10.1158/0008-5472.CAN-17-0740
[18]	Sun Z, Fourcade J, Pagliano O , et al. IL10 and PD-1 cooperate to limit the activity of tumor-specific CD8⁺ T cells [J]. Cancer Res, 2015 , 75(8):1635-1644. DOI: 10.1158/0008-5472.CAN-14-3016. doi: 10.1158/0008-5472.CAN-14-3016
[19]	Mantovani A, Sica A . Macrophages, innate immunity and cancer: balance, tolerance, and diversity[J]. Curr Opin Immunol, 2010,22(2):231-237. DOI: 10.1016/j.coi.2010.01.009. doi: 10.1016/j.coi.2010.01.009
[20]	Spranger S, Spaapen RM, Zha Y , et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells Sci Transl Med, 2013, 5(200): 200ra116. DOI: 10.1126/scitranslmed.3006504.
[21]	Engblom C, Pfirschke C, Pittet MJ . The role of myeloid cells in cancer therapies[J]. Nat Rev Cancer, 2016,16(7):447-462. DOI: 10.1038/nrc.2016.54. doi: 10.1038/nrc.2016.54
[22]	Gao J, Shi LZ, Zhao H , et al. Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA4 therapy[J]. Cell, 2016, 167(2):397-404. e9. DOI: 10.1016/j.cell.2016.08.069. doi: 10.1016/j.cell.2016.08.069
[23]	Mandai M, Hamanishi J, Abiko K , et al. Dual faces of IFNγ in cancer progression: a role of PD-L1 induction in the determination of pro- and antitumor immunity[J]. Clin Cancer Res, 2016,22(10):2329-2334. DOI: 10.1158/1078-0432.CCR-16-0224. doi: 10.1158/1078-0432.CCR-16-0224
[24]	Huang RY, Francois A, McGray AR , et al. Compensatory upregulation of PD-1, LAG-3, and CTLA-4 limits the efficacy of single-agent checkpoint blockade in metastatic ovarian cancer[J]. Oncoimmunology, 2016,6(1):e1249561. DOI: 10.1080/2162402X.2016.1249561. doi: 10.1080/2162402X.2016.1249561
[25]	Kahan SM, Wherry EJ, Zajac AJ . T cell exhaustion during persistent viral infections[J]. Virology. 2015, 479-480:180-193. DOI: 10.1016/j.virol.2014.12.033. doi: 10.1016/j.virol.2014.12.033
[26]	Togasaki K, Sukawa Y, Kanai T , et al. Clinical efficacy of immune checkpoint inhibitors in the treatment of unresectable advanced or recurrent gastric cancer: an evidence-based review of therapies[J]. Onco Targets Ther, 2018,11:8239-8250. DOI: 10.2147/OTT.S152514.
[27]	Barnaba V, Schinzari V . Induction, control, and plasticity of Treg cells: the immune regulatory network revised?[J]. Eur J Immunol, 2013,43(2):318-322. DOI: 10.1002/eji.201243265.
[28]	Lowther DE, Goods BA, Lucca LE , et al. PD-1 marks dysfunctional regulatory T cells in malignant gliomas[J]. JCI Insight, 2016, 1(5). pii: e85935. DOI: 10.1172/jci.insight.85935.
[29]	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(12):3560-3572. DOI: 10.1002/eji.201444688.
[30]	Moorman JP, Wang JM, Zhang Y , et al. Tim-3 pathway controls regulatory and effector T cell balance during hepatitis C virus infection[J]. J Immunol, 2012,189(2):755-766. DOI: 10.4049/jimmunol.1200162.
[31]	Nakamura K, Smyth MJ . Targeting cancer-related inflammation in the era of immunotherapy[J]. Immunol Cell Biol, 2017,95(4):325-332. DOI: 10.1038/icb.2016.126.
[32]	Dulos J, Carven GJ, van Boxtel SJ , 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(2):169-178. DOI: 10.1097/CJI.0b013e318247a4e7.
[33]	Koenen HJ, Smeets RL, Vink PM , et al. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells[J]. Blood, 2008,112(6):2340-2352. DOI: 10.1182/blood-2008-01-133967.
[34]	Kargl J, Busch SE, Yang GH , et al. Neutrophils dominate the immune cell composition in non-small cell lung cancer[J]. Nat Commun, 2017,8:14381. DOI: 10.1038/ncomms14381.
[35]	Fabre J, Giustiniani J, Garbar C , et al. Targeting the tumor microenvironment: the protumor effects of IL-17 related to cancer type[J]. Int J Mol Sci, 2016, 17(9). pii: E1433. DOI: 10.3390/ijms17091433.
[36]	Dong Y, Sun Q, Zhang X . PD-1 and its ligands are important immune checkpoints in cancer[J]. Oncotarget, 2017,8(2):2171-2186. DOI: 10.18632/oncotarget.13895.
[37]	龙丽, 段赵宁, 蔡海贝 , 等. NFATc1对裸鼠上皮性卵巢癌移植瘤脉管生成的影响[J]. 中国病理生理杂志, 2016,32(2):193-200. DOI: 10.3969/j.issn.1000-4718.2016.02.001.
[38]	Ratner L, Waldmann TA, Janakiram M , et al. Rapid progression of adult T-cell leukemia-lymphoma after PD-1 inhibitor therapy[J]. N Engl J Med, 2018,378(20):1947-1948. DOI: 10.1056/NEJMc1803181.
[39]	Du S, McCall N, Park K , et al. Blockade of tumor-expressed PD-1 promotes lung cancer growth[J]. Oncoimmunology, 2018,7(4):e1408747. DOI: 10.1080/2162402X.2017.1408747.
[40]	Dong ZY, Zhong WZ, Zhang XC , et al. Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma[J]. Clin Cancer Res, 2017,23(12):3012-3024. DOI: 10.1158/1078-0432.
[41]	Mariathasan S, Turley SJ, Nickles D , et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells[J]. Nature, 2018,554(7693):544-548. DOI: 10.1038/nature25501.
[42]	Xiong D, Wang Y, Singavi AK , et al. Immunogenomic landscape contributes to hyperprogressive disease after anti-PD-1 immunotherapy for cancer[J]. iScience, 2018,9:258-277. DOI: 10.1016/j.isci.2018.10.021.
[43]	Niknafs N, Kim D, Kim R , et al. MuPIT interactive: webserver for mapping variant positions to annotated, interactive 3D structures[J]. Hum Genet, 2013,132(11):1235-1243. DOI: 10.1007/s00439-013-1325-0.
[44]	Gossage L, Eisen T, Maher ER . VHL, the story of a tumour suppressor gene[J]. Nat Rev Cancer, 2015,15(1):55-64. DOI: 10.1038/nrc3844. doi: 10.1038/nrc3844
[45]	Kammerer-Jacquet SF, Crouzet L, Brunot A , et al. Independent association of PD-L1 expression with noninactivated VHL clear cell renal cell carcinoma-A finding with therapeutic potential[J]. Int J Cancer, 2017,140(1):142-148. DOI: 10.1002/ijc.30429.