皮肤免疫相关不良事件与PD-1/PD-L1抑制剂临床疗效相关性的研究进展

doi:10.3760/cma.j.cn371439-20210604-0040

摘要/Abstract

摘要：

以PD-1/PD-L1抑制剂为代表的免疫治疗已成为恶性肿瘤的主要治疗方法。然而,免疫治疗带来的不良反应也不容忽视。其中,皮肤免疫相关不良事件（irAE）最为常见,绝大多数的皮肤irAE属于Ⅰ~Ⅱ级,并不影响PD-1/PD-L1抑制剂的应用。其发病机制尚未完全明了,最常见的类型为皮疹、瘙痒及白癜风,而国产PD-1抑制剂卡瑞利珠单抗特有的不良反应为反应性皮肤毛细血管增生症（RCCEP）。临床发现,在恶性黑色素瘤与非小细胞肺癌中,皮肤irAE可预测PD-1/PD-L1抑制剂的临床疗效,特别是RCCEP可作为预测卡瑞利珠单抗治疗非小细胞肺癌、肝癌及食管癌的疗效预测指标。

Abstract:

Immunotherapy represented by PD-1/PD-L1 inhibitors has become the main treatment of malignant tumors. However,the adverse events caused by immunotherapy can not be ignored. Among them,dermatological immune-related adverse events （irAEs） occur with the highest incidence. Most dermatological irAEs belong to grade Ⅰ-Ⅱ, which does not affect the application of PD-1/PD-L1 inhibitors. The pathogenesis of dermatological irAEs is not fully understood. The most common types of dermatological irAEs are rash,pruritus and vitiligo. The domestic PD-1 inhibitor camrelizumab has unique adverse reactions of reactive cutaneous capillary endothelia proliferation （RCCEP）. It is found that dermatological irAEs can predict the clinical efficacy of PD-1/PD-L1 inhibitors in patients with malignant melanoma and non-small cell lung cancer （NSCLC）,especially RCCEP can be used as a potential biomarker of the efficacy of camrelizumab in the treatment of NSCLC, hepatocarcinoma, and esophageal cancer.

Key words: Treatment outcome, Dermatological immune-related adverse events, PD-1/PD-L1 inhibitors

丁心静, 丁江华. 皮肤免疫相关不良事件与PD-1/PD-L1抑制剂临床疗效相关性的研究进展[J]. 国际肿瘤学杂志, 2022, 49(4): 225-228.

Ding Xinjing, Ding Jianghua. Research progress on the correlation between dermatological immune-related adverse events and clinical outcome of PD-1/PD-L1 inhibitors[J]. Journal of International Oncology, 2022, 49(4): 225-228.

参考文献 35

[1]	中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)免疫检查点抑制剂临床应用指南2020[M]. 北京: 人民卫生出版社, 2020: 11-17.
[2]	Zhang JY, Yan YY, Li JJ, et al. PD-1/PD-L1 based combinational cancer therapy: icing on the cake[J]. Front Pharmacol, 2020, 11: 722. DOI: 10.3389/fphar.2020.00722. doi: 10.3389/fphar.2020.00722
[3]	Jones NL, Xiu J, Rocconi RP, et al. Immune checkpoint expression, microsatellite instability, and mutational burden: identifying immune biomarker phenotypes in uterine cancer[J]. Gynecol Oncol, 2020, 156(2): 393-399. DOI: 10.1016/j.ygyno.2019.11.035. doi: 10.1016/j.ygyno.2019.11.035
[4]	Yi M, Jiao D, Xu H, et al. Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors[J]. Mol Cancer, 2018, 17(1): 129. DOI: 10.1186/s12943-018-0864-3. doi: 10.1186/s12943-018-0864-3
[5]	Puzanov I, Diab A, Abdallah K, et al. Managing toxicities asso-ciated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group[J]. J Immunother Cancer, 2017, 5(1): 95. DOI: 10.1186/s40425-017-0300-z. doi: 10.1186/s40425-017-0300-z pmid: 29162153
[6]	Mineiro Dos Santos Garrett NF, Carvalho da Costa AC, Barros Ferreira E, et al. Prevalence of dermatological toxicities in patients with melanoma undergoing immunotherapy: systematic review and meta-analysis[J]. PLoS One, 2021, 16(8): e255716. DOI: 10.1371/journal.pone.0255716. doi: 10.1371/journal.pone.0255716
[7]	Chen X, Ma L, Wang X, et al. Reactive capillary hemangiomas: a novel dermatologic toxicity following anti-PD-1 treatment with SHR-1210[J]. Cancer Biol Med, 2019, 16(1): 173-181. DOI: 10.20892/j.issn.2095-3941.2018.0172. doi: 10.20892/j.issn.2095-3941.2018.0172
[8]	艾超, 冀召帅, 唐蕾, 等. PD-1/PD-L1抑制剂抗肿瘤临床研究进展[J]. 临床药物治疗杂志, 2021, 19(9): 8-13. DOI: 10.3969/j.issn.1672-3384.2021.09.002. doi: 10.3969/j.issn.1672-3384.2021.09.002
[9]	马越, 朱圣文, 孙蕾, 等. 我国已上市PD-1/PD-L1抑制剂经济性评价的系统分析[J]. 中国药房, 2021, 32(15): 1885-1893. DOI: 10.6039/j.issn.1001-0408.2021.15.16. doi: 10.6039/j.issn.1001-0408.2021.15.16
[10]	Rogado J, Sánchez-Torres JM, Romero-Laorden N, et al. Immune-related adverse events predict the therapeutic efficacy of anti-PD-1 antibodies in cancer patients[J]. Eur J Cancer, 2019, 109: 21-27. DOI: 10.1016/j.ejca.2018.10.014. doi: S0959-8049(18)31453-9 pmid: 30682533
[11]	Albandar HJ, Fuqua J, Albandar JM, et al. Immune-related adverse events (irAE) in cancer immune checkpoint inhibitors (ICI) and survival outcomes correlation: to rechallenge or not?[J]. Cancers (Basel), 2021, 13(5): 989. DOI: 10.3390/cancers13050989. doi: 10.3390/cancers13050989
[12]	De Velasco G, Je Y, Bossé D, et al. Comprehensive meta-analysis of key immune-related adverse events from CTLA-4 and PD-1/PD-L1 inhibitors in cancer patients[J]. Cancer Immunol Res, 2017, 5(4): 312-318. DOI: 10.1158/2326-6066.CIR-16-0237. doi: 10.1158/2326-6066.CIR-16-0237
[13]	Curry JL, Tetzlaff MT, Nagarajan P, et al. Diverse types of dermatologic toxicities from immune checkpoint blockade therapy[J]. J Cutan Pathol, 2017, 44(2): 158-176. DOI: 10.1111/cup.12858. doi: 10.1111/cup.12858
[14]	Belum VR, Benhuri B, Postow MA, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor[J]. Eur J Cancer, 2016, 60: 12-25. DOI: 10.1016/j.ejca.2016.02.010. doi: 10.1016/j.ejca.2016.02.010 pmid: 27043866
[15]	Rovers JFJ, Bovenschen HJ. Dermatological side effects rarely interfere with the continuation of checkpoint inhibitor immunotherapy for cancer[J]. Int J Dermatol, 2020, 59(12): 1485-1490. DOI: 10.1111/ijd.15163. doi: 10.1111/ijd.15163
[16]	Wang X, Suppa M, Bruderer P, et al. A late dermatologic presentation of bullous pemphigoid induced by anti-PD-1 therapy and associated with unexplained neurological disorder[J]. Case Rep Oncol, 2021, 14(2): 861-867. DOI: 10.1159/000514806. doi: 10.1159/000514806
[17]	Sibaud V. Dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy[J]. Am J Clin Dermatol, 2018, 19(3): 345-361. DOI: 10.1007/s40257-017-0336-3. doi: 10.1007/s40257-017-0336-3
[18]	Patel A B, Pacha O. Skin reactions to immune checkpoint inhibitors[J]. Adv Exp Med Biol, 2020, 1244: 235-246. DOI: 10.1007/978-3-030-41008-7_11. doi: 10.1007/978-3-030-41008-7_11
[19]	Wang F, Qin S, Sun X, et al. Reactive cutaneous capillary endothelial proliferation in advanced hepatocellular carcinoma patients treated with camrelizumab: data derived from a multicenter phase 2 trial[J]. J Hematol Oncol, 2020, 13(1): 47. DOI: 10.1186/s13045-020-00886-2. doi: 10.1186/s13045-020-00886-2
[20]	Teng Y, Guo R, Sun J, et al. Reactive capillary hemangiomas induced by camrelizumab (SHR-1210), an anti-PD-1 agent[J]. Acta Oncol, 2019, 58(3): 388-389. DOI: 10.1080/0284186X.2019.1567935. doi: 10.1080/0284186X.2019.1567935 pmid: 30700195
[21]	Rivera N, Boada A, Bielsa MI, et al. Hair repigmentation during immunotherapy treatment with an anti-programmed cell death 1 and anti-programmed cell death ligand 1 agent for lung cancer[J]. JAMA Dermatol, 2017, 153(11): 1162-1165. DOI: 10.1001/jamadermatol.2017.2106. doi: 10.1001/jamadermatol.2017.2106
[22]	Berner F, Bomze D, Diem S, et al. Association of checkpoint inhibitor-induced toxic effects with shared cancer and tissue antigens in non-small cell lung cancer[J]. JAMA Oncol, 2019, 5(7): 1043-1047. DOI: 10.1001/jamaoncol.2019.0402. doi: 10.1001/jamaoncol.2019.0402
[23]	Palermo B, Franzese O, Donna CD, et al. Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients[J]. Oncoimmunology, 2018, 7(12): e1465163. DOI: 10.1080/2162402X.2018.1465163. doi: 10.1080/2162402X.2018.1465163
[24]	Goldinger SM, Stieger P, Meier B, et al. Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy[J]. Clin Cancer Res, 2016, 22(16): 4023-4029. DOI: 10.1158/1078-0432.CCR-15-2872. doi: 10.1158/1078-0432.CCR-15-2872 pmid: 26957557
[25]	Rahimi A, Hossein-Nataj H, Hajheydari Z, et al. Expression analysis of PD-1 and Tim-3 immune checkpoint receptors in patients with vitiligo; positive association with disease activity[J]. Exp Dermatol, 2019, 28(6): 674-681. DOI: 10.1111/exd.13952. doi: 10.1111/exd.13952 pmid: 31046170
[26]	Finlay WJJ, Coleman JE, Edwards JS, et al. Anti-PD1 ‘SHR-1210’ aberrantly targets pro-angiogenic receptors and this polyspecificity can be ablated by paratope refinement[J]. MAbs, 2019, 11(1): 26-44. DOI: 10.1080/19420862.2018.1550321. doi: 10.1080/19420862.2018.1550321
[27]	Wu X, Zhang X, Shu P, et al. Reactive cutaneous capillary endothelial proliferation caused by camrelizumab (SHR-1210) through activation of HIF-1α/VEGF signaling pathway[J]. J Thorac Oncol, 2020, 15(2): S25-S26. DOI: 10.1016/j.jtho.2019.12.068. doi: 10.1016/j.jtho.2019.12.068
[28]	Quach HT, Dewan AK, Davis EJ, et al. Association of anti-programmed cell death 1 cutaneous toxic effects with outcomes in patients with advanced melanoma[J]. JAMA Oncol, 2019, 5(6): 906-908. DOI: 10.1001/jamaoncol.2019.0046. doi: 10.1001/jamaoncol.2019.0046
[29]	Bottlaender L, Amini-Adle M, Maucort-Boulch D, et al. Cuta-neous adverse events: a predictor of tumour response under anti-PD-1 therapy for metastatic melanoma, a cohort analysis of 189 patients[J]. J Eur Acad Dermatol Venereol, 2020, 34(9): 2096-2105. DOI: 10.1111/jdv.16311. doi: 10.1111/jdv.16311
[30]	Swami U, Monga V, Bossler AD, et al. Durable clinical benefit in patients with advanced cutaneous melanoma after discontinuation of anti-PD-1 therapies due to immune-related adverse events[J]. J Oncol, 2019, 2019: 1856594. DOI: 10.1155/2019/1856594. doi: 10.1155/2019/1856594
[31]	Hasan Ali O, Diem S, Markert E, et al. Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer[J]. Oncoimmunology, 2016, 5(11): e1231292. DOI: 10.1080/2162402X.2016.1231292. doi: 10.1080/2162402X.2016.1231292
[32]	Aso M, Toi Y, Sugisaka J, et al. Association between skin reaction and clinical benefit in patients treated with anti-programmed cell death 1 monotherapy for advanced non-small cell lung cancer[J]. Oncologist, 2020, 25(3): e536-e544. DOI: 10.1634/theoncologist.2019-0550. doi: 10.1634/theoncologist.2019-0550
[33]	Zhou C, Chen G, Huang Y, et al. A randomized phase 3 study of camrelizumab plus chemotherapy as 1^st line therapy for advanced/metastatic non-squamous non-small cell lung cancer[J]. J Thorac Oncol, 2019, 14(10): S215-S216. DOI: 10.1016/j.jtho.2019.08.425. doi: 10.1016/j.jtho.2019.08.425
[34]	Huang J, Xu J, Chen Y, et al. Camrelizumab versus investigator’s choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a multicentre, randomised, open-label, phase 3 study[J]. Lancet Oncol, 2020, 21(6): 832-842. DOI: 10.1016/S1470-2045(20)30110-8. doi: S1470-2045(20)30110-8 pmid: 32416073
[35]	Qin S, Ren Z, Meng Z, et al. Camrelizumab in patients with pre-viously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial[J]. Lancet Oncol, 2020, 21(4): 571-580. DOI: 10.1016/S1470-2045(20)30011-5. doi: 10.1016/S1470-2045(20)30011-5