免疫检查点抑制剂相关不良反应的危险因素与预测因素

doi:10.3760/cma.j.cn371439-20230810-00139

摘要/Abstract

摘要：

免疫检查点抑制剂普遍应用于临床并取得了较好的疗效，但免疫相关不良反应（irAE）通常不可预测且可能导致严重临床后果。目前irAE的危险因素包括性别、体质量指数、肿瘤类别、药物类型、既往的自身免疫性疾病以及肿瘤突变负荷等，预测因素主要有免疫细胞、细胞因子与趋化因子、自身抗体、基因组以及肠道菌群等。进一步对irAE发生的机制、危险因素、预测因素进行研究，可为临床预测与管理irAE提供指导性建议。

关键词: 免疫检查点抑制剂, 药物相关性副作用和不良反应, 危险因素, 预测因素

Abstract:

Immune checkpoint inhibitors are commonly used in clinical practice and have achieved good efficacy， but immune-related adverse events （irAEs） are often unpredictable and may lead to serious clinical consequences. Risk factors for irAEs include gender， body mass index， tumor class， drug type， pre-existing autoimmune disease， and tumor mutational burden； predictors are mainly immune cells， cytokines and chemokines， autoantibodies， genome， and gut microbes. By further investigating the mechanisms， risk factors and predictors for the occurrence of irAEs， guidance for the clinical prediction and management of irAEs is supposed to be provided.

Key words: Immune checkpoint inhibitors, Drug-related side effects and adverse reactions, Risk factors, Predictors

焦盼盼, 薛丽娟, 詹娟. 免疫检查点抑制剂相关不良反应的危险因素与预测因素[J]. 国际肿瘤学杂志, 2023, 50(12): 739-744.

Jiao Panpan, Xue Lijuan, Zhan Juan. Risk factors and predictors of immune-related adverse events induced by immune checkpoint inhibitors[J]. Journal of International Oncology, 2023, 50(12): 739-744.

参考文献 54

[1]	Wang Y, Zhou S, Yang F, et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis[J]. JAMA Oncol, 2019, 5(7): 1008-1019. DOI: 10.1001/jamaoncol.2019.0393. pmid: 31021376
[2]	Lim SY, Lee JH, Gide TN, et al. Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1-based immunotherapy[J]. Clin Cancer Res, 2019, 25(5): 1557-1563. DOI: 10.1158/1078-0432.CCR-18-2795. pmid: 30409824
[3]	Oh DY, Cham J, Zhang L, et al. Immune toxicities elicted by CTLA-4 blockade in cancer patients are associated with early diversification of the T-cell repertoire[J]. Cancer Res, 2017, 77(6): 1322-1330. DOI: 10.1158/0008-5472.CAN-16-2324. pmid: 28031229
[4]	de Moel EC, Rozeman EA, Kapiteijn EH, et al. Autoantibody development under treatment with immune-checkpoint inhibitors[J]. Cancer Immunol Res, 2019, 7(1): 6-11. DOI: 10.1158/2326-6066.CIR-18-0245. pmid: 30425107
[5]	Lee DJ, Lee HJ Jr, Farmer JR, et al. Mechanisms driving immune-related adverse events in cancer patients treated with immune checkpoint inhibitors[J]. Curr Cardiol Rep, 2021, 23(8): 98. DOI: 10.1007/s11886-021-01530-2. pmid: 34196833
[6]	Iwama S, De Remigis A, Callahan MK, et al. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody[J]. Sci Transl Med, 2014, 6(230): 230ra45. DOI: 10.1126/scitranslmed.3008002.
[7]	Liu X, Tang H, Zhou Q, et al. Gut microbiota composition in patients with advanced malignancies experiencing immune-related adverse events[J]. Front Immunol, 2023, 14: 1109281. DOI: 10.3389/fimmu.2023.1109281.
[8]	Wilkinson NM, Chen HC, Lechner MG, et al. Sex differences in immunity[J]. Annu Rev Immunol, 2022, 40: 75-94. DOI: 10.1146/annurev-immunol-101320-125133. pmid: 34985929
[9]	Bui AN, Bougrine A, Buchbinder EI, et al. Female sex is associated with higher rates of dermatologic adverse events among patients with melanoma receiving immune checkpoint inhibitor therapy: a retrospective cohort study[J]. J Am Acad Dermatol, 2022, 87(2): 403-406. DOI: 10.1016/j.jaad.2021.06.885.
[10]	Duma N, Abdel-Ghani A, Yadav S, et al. Sex differences in tolerability to anti-programmed cell death protein 1 therapy in patients with metastatic melanoma and non-small cell lung cancer: are we all equal?[J]. Oncologist, 2019, 24(11): e1148-e1155. DOI: 10.1634/theoncologist.2019-0094.
[11]	Cortellini A, Bersanelli M, Buti S, et al. A multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors: when overweight becomes favorable[J]. J Immunother Cancer, 2019, 7(1): 57. DOI: 10.1186/s40425-019-0527-y. pmid: 30813970
[12]	Eun Y, Kim IY, Sun JM, et al. Risk factors for immune-related adverse events associated with anti-PD-1 pembrolizumab[J]. Sci Rep, 2019, 9(1): 14039. DOI: 10.1038/s41598-019-50574-6. pmid: 31575933
[13]	Khoja L, Day D, Wei-Wu Chen T, et al. Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review[J]. Ann Oncol, 2017, 28(10): 2377-2385. DOI: 10.1093/annonc/mdx286. pmid: 28945858
[14]	Wang F, Yang S, Palmer N, et al. Real-world data analyses unveiled the immune-related adverse effects of immune checkpoint inhibitors across cancer types[J]. NPJ Precis Oncol, 2021, 5(1): 82. DOI: 10.1038/s41698-021-00223-x. pmid: 34508179
[15]	Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivo-lumab and ipilimumab or monotherapy in untreated melanoma[J]. N Engl J Med, 2015, 373(1): 23-34. DOI: 10.1056/NEJMoa1504030.
[16]	Boutros C, Tarhini A, Routier E, et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination[J]. Nat Rev Clin Oncol, 2016, 13(8): 473-486. DOI: 10.1038/nrclinonc.2016.58. pmid: 27141885
[17]	Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma[J]. N Engl J Med, 2015, 372(26): 2521-2532. DOI: 10.1056/NEJMoa1503093.
[18]	Cortellini A, Buti S, Santini D, et al. Clinical outcomes of patients with advanced cancer and pre-existing autoimmune diseases treated with anti-programmed death-1 immunotherapy: a real-world transverse study[J]. Oncologist, 2019, 24(6): e327-e337. DOI: 10.1634/theoncologist.2018-0618.
[19]	Kehl KL, Yang S, Awad MM, et al. Pre-existing autoimmune disease and the risk of immune-related adverse events among patients receiving checkpoint inhibitors for cancer[J]. Cancer Immunol Immunother, 2019, 68(6): 917-926. DOI: 10.1007/s00262-019-02321-z. pmid: 30877325
[20]	Bomze D, Hasan Ali O, Bate A, et al. Association between immune-related adverse events during anti-PD-1 therapy and tumor mutational burden[J]. JAMA Oncol, 2019, 5(11): 1633-1635. DOI: 10.1001/jamaoncol.2019.3221.
[21]	Das R, Bar N, Ferreira M, et al. Early B cell changes predict autoimmunity following combination immune checkpoint blockade[J]. J Clin Invest, 2018, 128(2): 715-720. DOI: 10.1172/JCI96798. pmid: 29309048
[22]	Nishimura K, Konishi T, Ochi T, et al. CD21^lo B cells could be a potential predictor of immune-related adverse events in renal cell carcinoma[J]. J Pers Med, 2022, 12(6): 888. DOI: 10.3390/jpm12060888.
[23]	Subudhi SK, Aparicio A, Gao J, et al. Clonal expansion of CD8 T cells in the systemic circulation precedes development of ipilimumab-induced toxicities[J]. Proc Natl Acad Sci U S A, 2016, 113(42): 11919-11924. DOI: 10.1073/pnas.1611421113.
[24]	Jing Y, Liu J, Ye Y, et al. Multi-omics prediction of immune-related adverse events during checkpoint immunotherapy[J]. Nat Commun, 2020, 11(1): 4946. DOI: 10.1038/s41467-020-18742-9. pmid: 33009409
[25]	Lozano AX, Chaudhuri AA, Nene A, et al. T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma[J]. Nat Med, 2022, 28(2): 353-362. DOI: 10.1038/s41591-021-01623-z. pmid: 35027754
[26]	Osawa H, Shiozawa T, Okauchi S, et al. Absolute increase in the number and proportion of peripheral eosinophils associated with immune checkpoint inhibitor treatment in non-small cell lung cancer patients[J]. Cancer Diagn Progn, 2021, 1(5): 485-490. DOI: 10.21873/cdp.10065. pmid: 35403161
[27]	Chu X, Zhao J, Zhou J, et al. Association of baseline peripheral-blood eosinophil count with immune checkpoint inhibitor-related pneumonitis and clinical outcomes in patients with non-small cell lung cancer receiving immune checkpoint inhibitors[J]. Lung Cancer, 2020, 150: 76-82. DOI: 10.1016/j.lungcan.2020.08.015. pmid: 33080551
[28]	Nakamura Y, Tanaka R, Maruyama H, et al. Correlation between blood cell count and outcome of melanoma patients treated with anti-PD-1 antibodies[J]. Jpn J Clin Oncol, 2019, 49(5): 431-437. DOI: 10.1093/jjco/hyy201. pmid: 30753621
[29]	Zhang Z, Xie T, Qi C, et al. Peripheral blood biomarkers predictive of efficacy outcome and immune-related adverse events in advanced gastrointestinal cancers treated with checkpoint inhibitors[J]. Cancers (Basel), 2022, 14(15): 3736. DOI: 10.3390/cancers14153736.
[30]	Matsukane R, Watanabe H, Minami H, et al. Continuous monito-ring of neutrophils to lymphocytes ratio for estimating the onset, severity, and subsequent prognosis of immune related adverse events[J]. Sci Rep, 2021, 11(1): 1324. DOI: 10.1038/s41598-020-79397-6. pmid: 33446685
[31]	Pavan A, Calvetti L, Dal Maso A, et al. Peripheral blood markers identify risk of immune-related toxicity in advanced non-small cell lung cancer treated with immune-checkpoint inhibitors[J]. Oncologist, 2019, 24(8): 1128-1136. DOI: 10.1634/theoncologist.2018-0563. pmid: 31015312
[32]	Lee PY, Oen KQX, Lim GRS, et al. Neutrophil-to-lymphocyte ratio predicts development of immune-related adverse events and outcomes from immune checkpoint blockade: a case-control study[J]. Cancers (Basel), 2021, 13(6): 1308. DOI: 10.3390/cancers13061308.
[33]	Peng L, Wang Y, Liu F, et al. Peripheral blood markers predictive of outcome and immune-related adverse events in advanced non-small cell lung cancer treated with PD-1 inhibitors[J]. Cancer Immunol Immunother, 2020, 69(9): 1813-1822. DOI: 10.1007/s00262-020-02585-w. pmid: 32350592
[34]	Egami S, Kawazoe H, Hashimoto H, et al. Peripheral blood biomarkers predict immune-related adverse events in non-small cell lung cancer patients treated with pembrolizumab: a multicenter retrospective study[J]. J Cancer, 2021, 12(7): 2105-2112. DOI: 10.7150/jca.53242. pmid: 33754009
[35]	Tanaka R, Okiyama N, Okune M, et al. Serum level of interleukin-6 is increased in nivolumab-associated psoriasiform dermatitis and tumor necrosis factor-α is a biomarker of nivolumab recativity[J]. J Dermatol Sci, 2017, 86(1): 71-73. DOI: 10.1016/j.jdermsci.2016.12.019. pmid: 28069323
[36]	Valpione S, Pasquali S, Campana LG, et al. Sex and interleukin-6 are prognostic factors for autoimmune toxicity following treatment with anti-CTLA4 blockade[J]. J Transl Med, 2018, 16(1): 94. DOI: 10.1186/s12967-018-1467-x. pmid: 29642948
[37]	Tarhini AA, Zahoor H, Lin Y, et al. Baseline circulating IL-17 predicts toxicity while TGF-β1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma[J]. J Immunother Cancer, 2015, 3: 39. DOI: 10.1186/s40425-015-0081-1. pmid: 26380086
[38]	Abolhassani AR, Schuler G, Kirchberger MC, et al. C-reactive protein as an early marker of immune-related adverse events[J]. J Cancer Res Clin Oncol, 2019, 145(10): 2625-2631. DOI: 10.1007/s00432-019-03002-1. pmid: 31492984
[39]	Yu Y, Wang S, Su N, et al. Increased circulating levels of CRP and IL-6 and decreased frequencies of T and B lymphocyte subsets are associated with immune-related adverse events during combination therapy with PD-1 inhibitors for liver cancer[J]. Front Oncol, 2022, 12: 906824. DOI: 10.3389/fonc.2022.906824.
[40]	Lauwyck J, Beckwée A, Santens A, et al. C-reactive protein as a biomarker for immune-related adverse events in melanoma patients treated with immune checkpoint inhibitors in the adjuvant setting[J]. Melanoma Res, 2021, 31(4): 371-377. DOI: 10.1097/CMR.0000000000000748. pmid: 34054056
[41]	Oyanagi J, Koh Y, Sato K, et al. Predictive value of serum protein levels in patients with advanced non-small cell lung cancer treated with nivolumab[J]. Lung Cancer, 2019, 132: 107-113. DOI: 10.1016/j.lungcan.2019.03.020. pmid: 31097082
[42]	Kurimoto C, Inaba H, Ariyasu H, et al. Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors[J]. Cancer Sci, 2020, 111(5): 1468-1477. DOI: 10.1111/cas.14363.
[43]	Ghosh N, Postow M, Zhu C, et al. Lower baseline autoantibody levels are associated with immune-related adverse events from immune checkpoint inhibition[J]. J Immunother Cancer, 2022, 10(1): e004008. DOI: 10.1136/jitc-2021-004008.
[44]	Mathias K, Rouhani S, Olson D, et al. Association between rheumatic autoantibodies and immune-related adverse events[J]. Oncologist, 2023, 28(5): 440-448. DOI: 10.1093/oncolo/oyac252. pmid: 36595378
[45]	Hasan Ali O, Bomze D, Ring SS, et al. BP180-specific IgG is associated with skin adverse events, therapy response, and overall survival in non-small cell lung cancer patients treated with checkpoint inhibitors[J]. J Am Acad Dermatol, 2020, 82(4): 854-861. DOI: 10.1016/j.jaad.2019.08.045. pmid: 31449902
[46]	Tahir SA, Gao J, Miura Y, et al. Autoimmune antibodies correlate with immune checkpoint therapy-induced toxicities[J]. Proc Natl Acad Sci U S A, 2019, 116(44): 22246-22251. DOI: 10.1073/pnas.1908079116.
[47]	Shahabi V, Berman D, Chasalow SD, et al. Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune-related gastrointestinal adverse events[J]. J Transl Med, 2013, 11: 75. DOI: 10.1186/1479-5876-11-75. pmid: 23521917
[48]	Friedlander P, Wood K, Wassmann K, et al. A whole-blood RNA transcript-based gene signature is associated with the development of CTLA-4 blockade-related diarrhea in patients with advanced melanoma treated with the checkpoint inhibitor tremelimumab[J]. J Immunother Cancer, 2018, 6(1): 90. DOI: 10.1186/s40425-018-0408-9. pmid: 30227886
[49]	Abed A, Law N, Calapre L, et al. Human leucocyte antigen genotype association with the development of immune-related adverse events in patients with non-small cell lung cancer treated with single agent immunotherapy[J]. Eur J Cancer, 2022, 172: 98-106. DOI: 10.1016/j.ejca.2022.05.021.
[50]	Hasan Ali O, Berner F, Bomze D, et al. Human leukocyte antigen variation is associated with adverse events of checkpoint inhibitors[J]. Eur J Cancer, 2019, 107: 8-14. DOI: 10.1016/j.ejca.2018.11.009. pmid: 30529903
[51]	Sakurai T, De Velasco MA, Sakai K, et al. Integrative analysis of gut microbiome and host transcriptomes reveals associations between treatment outcomes and immunotherapy-induced colitis[J]. Mol Oncol, 2022, 16(7): 1493-1507. DOI: 10.1002/1878-0261.13062.
[52]	Chaput N, Lepage P, Coutzac C, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab[J]. Ann Oncol, 2017, 28(6): 1368-1379. DOI: 10.1093/annonc/mdx108. pmid: 28368458
[53]	Dubin K, Callahan MK, Ren B, et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis[J]. Nat Commun, 2016, 7: 10391. DOI: 10.1038/ncomms10391. pmid: 26837003
[54]	Andrews MC, Duong CPM, Gopalakrishnan V, et al. Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade[J]. Nat Med, 2021, 27(8): 1432-1441. DOI: 10.1038/s41591-021-01406-6. pmid: 34239137