肿瘤免疫检查点抑制剂的心脏不良反应及管理策略
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摘要
免疫检查点抑制剂(ICIs)通过对T细胞免疫检查点的调控,诱导T细胞活化以抑制肿瘤细胞生长,目前已应用于恶性黑色素瘤、非小细胞肺癌、肾癌等多种恶性肿瘤的治疗,显著延长部分患者生存期,是当前肿瘤治疗领域的前沿热点。但其亦有免疫相关毒性反应,其中ICIs导致心脏相关不良反应虽发生率低,但致死率高,目前尚无大样本研究,本文就多例个案报道和相关ICIs毒性反应管理策略进行简要阐述,总结出重点监测、早期诊断治疗以及密切随访等处理措施,以期提高临床医生对ICIs心脏不良反应的关注,更好地把握其管理策略,降低相关死亡率。
Immune checkpoint inhibitors(ICIs) induce T cells activation to inhibit tumor cells growth through the regulation of T cells' immune checkpoints. ICIs have been used for the treatment of malignant melanoma,non-small cell lung cancer,renal carcinoma and other malignant tumors,they have prolonged the overall survival of some patients,and they are a hot spot in the field of tumor treatment. But they also have immune-related adverse events,although the incidence of tumor immune checkpoint inhibitors-related cardiac adverse reactions is low,but its mortality is high,and there is no large sample study. This article gives a brief account of multiple case reports and ICIs toxicity management strategies,summarizes intensive monitoring,early diagnosis/treatment and close follow-up measures,in order to improve clinicians' attention to adverse cardiac reactions of ICIs,grasp its management strategy better,reduce the related mortality rate.
Immune checkpoint inhibitors(ICIs) induce T cells activation to inhibit tumor cells growth through the regulation of T cells' immune checkpoints. ICIs have been used for the treatment of malignant melanoma,non-small cell lung cancer,renal carcinoma and other malignant tumors,they have prolonged the overall survival of some patients,and they are a hot spot in the field of tumor treatment. But they also have immune-related adverse events,although the incidence of tumor immune checkpoint inhibitors-related cardiac adverse reactions is low,but its mortality is high,and there is no large sample study. This article gives a brief account of multiple case reports and ICIs toxicity management strategies,summarizes intensive monitoring,early diagnosis/treatment and close follow-up measures,in order to improve clinicians' attention to adverse cardiac reactions of ICIs,grasp its management strategy better,reduce the related mortality rate.
引文
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[31]Moslehi JJ,Salem JE,Sosman JA,et al.Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis[J].Lancet,2018,391(10124):933.
[32]Lubli H,Balmelli C,Bossard M,et al.Aucte heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma[J].J Immuno Therapy Cancer,2015,3:11.
[33]Semper H,Muehlberg F,Schuiz-Menger J,et al.Drug-induced myocarditis after nivolumab treatment in a patient with PDL1-negative squamous cell carcinoma of the lung[J].Lung Cancer,2016,99:117-119.
[34]Johunson DB,Balko JM,Compton ML,et al.Fulminant myocarditis with combination immune checkpoint blockade[J].NEngl J Med,2016,375(18):1749-1755.
[35]Frigeri M,Meyrer P,Banfi C,et al.Immune checkpoint inhibitorassociated myocarditis:a new challenge for cardiologists[J].Can JCardiol,2018,34(1):92.
[36]Haanen JBAG,Carbonnel F,Robert C,et al.Management of toxicities from immunotherapy:ESMO clinical practice guidelines for diagnosis,treatment and follow-up[J].Ann Oncol,2017,28:119-142.
[2]Robert C,Schadendorf D,Messina M,et al.Efficacy and safety of retreatment with ipilimumab in patients with pretreated advanced melanoma who progressed after initially achieving disease control[J].Clin Cancer Res,2013,19(8):2232-2239.
[3]Borghaei H,Paz-Ares L,Horn L,et al.Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer[J].N Engl JMed,2015,373(17):1627-1639.
[4]Brahmer J,Reckamp KL,Baas P,et al.Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer[J].N Engl J Med,2015,373(2):123-135.
[5]Herbst RS,Baas P,Kim DW,et al.Pembrolizumab versus docetaxel for previously treated,PD-L1-positive,advanced non-small-cell lung cancer(KEYNOTE-010):a randomised controlled trial[J].Lancet,2016,387(127):1540-1550.
[6]Rittmeyer A,Barlesi F,Waterkamp D,et al.Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer(OAK):a phase 3,open-label,multicentre randomized controlled trial[J].Lancet,2017,389(166):255-265.
[7]Kaufman HL,Russell J,Hamid O,et al.Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma:a multicentre,single-group,open-label,phase 2 trial[J].Lancet Oncol,2016,17(10):1374-1385.
[8]Antonia SJ,Villegas A,Daniel D,et al.Durvalumab after chemoradiotherapy in stageⅢnon-small-cell lung cancer[J].N Engl JMed,2017,377(20):1919-1929.
[9]Qureshi OS,Zheng Y,Nakamura K,et al.Trans-endocytosis of CD80 and CD86:a molecular basis for the cell-extrinsic function of CTLA-4[J].Science,2011,332(6029):600-603.
[10]Stadler S,Weina K,Gebhardt C,et al.New therapeutic options for advanced non-resectable malignant melanoma[J].Adv Med Sci,2015,60(1):83-88.
[11]Basso D,Fogar P,Falconi M,et al.Pancreatic tumors and immature immunosuppressive myeloid cells in blood and spleen:role of inhibitory co-stimulatory molecules PDL1 and CTLA4.An in vivo and in vitro study[J].PLoS One,2013,8(1):e54824.
[12]Chen S,Liu H,Su N,et al.Myeloid-derived suppressor cells promote age-related increase of lung cancer growth via B7-H1[J].Exp Gerontol,2015,61:84-91.
[13]Keir ME,Liang SC,Guleria I,et al.Tissue expression of PD-L1mediates peripheral T cell tolerance[J].J Exp Med,2006,203(4):883-895.
[14]Dong H,Strome SE,Salomao DR,et al.Tumor-associated B7-H1promotes T-cell apoptosis:a potential mechanism of immune evasion[J].Nat Med,2002,8(8):793-800.
[15]Boussiotis VA.Molecular and biochemical aspects of the PD-1checkpoint pathway[J].N Engl J Med,2016,375(18):1767-1778.
[16]Muro K,Chung HC,Shankaran V,et al.Pembrolizumab for patients with PD-L1-positive advanced gastric cancer(KEYNOTE-012):a multicentre,open-label,phase 1b trial[J].Lancet Oncol,2016,17(6):717-726.
[17]Bang YJ,Muro K,Fuchs CS,et al.KEYNOTE-059 cohort 2:Safety and efficacy of pembrolizumab(pembro)plus 5-fluorouracil(5-FU)and cisplatin for first-line(1L)treatment of advanced gastric cancer[J].Clin Oncol,2017,35(15):4012-4012.
[18]Robert C,Schachter J,Long GV,et al.Pembrolizumab versus lpilimumab in advanced melanoma[J].N Engl J Med,2015,372(26):2521-2532.
[19]Topalian SL,Sznol M,Mc Dermott DF,et al.Survival,durable tumor remission,and long-term safety in patients with advanced melanoma receiving nivolumab[J].J Clin Oncol,2014,32(10):1020-1030.
[20]Joseph RW,Cappel M,Goedjen B,et al.Lichenoid dermatitis in three patients with metastatic melanoma treated with anti-PD-1therapy[J].Cancer Immunol Res,2015,3(1):18-22.
[21]Hwang SJ,Carlos G,Wakade D,et al.Cutaneous adverse events(AEs)of anti-programmed cell death(PD)-1 therapy in patients with metastatic melanoma:A single-institution cohort[J].J Am Acad Dermatol,2016,74(3):455-461.
[22]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.
[23]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.
[24]De Velasco G,Je Y,BosséD,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.
[25]Fehrenbacher L,Spira A,Ballinger M,et al.Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer(POPLAR):a multicentre,open-label,phase 2 randomised controlled trial[J].Lancet,2016,387(10030):1837-1846.
[26]Puzanov I,Diab A,Abdallah K,et al.Managing toxicities associated with immune checkpoint inhibitors:consensus recommendations from the Society for Immunotherapy of Cancer(SITC)Toxicity Management Working Group[J].J Immunol Therapy Cancer,2017,5:95.
[27]Weber JS,Kahler KC,Hauschild A.Management of immunerelated adverse events and kinetics of response with ipilimumab[J].J Clin Oncol,2012,30(21):2691-2697.
[28]Boutros C,Tarhini A,Routier E,et al.Safety profiles of antiCTLA-4 and anti-PD-1 antibodies alone and in combination[J].Nat Rev Clin Oncol,2016,13(8):473-486.
[29]Lenneman CG,Sawyer DB.Cardio-Oncology:An update on cardiotoxicity of cancer-related treatment[J].Circ Res,2016,118(6):1008-1020.
[30]Tocchetti CG,Galdiero MR,Varricchi G,et al.Tocchetti,Maria Rosaria Galdiero,GildaVarricchi.Cardiac toxicity in patients treated with immune checkpoint inhibitors:it is now time for cardio-immuno-oncology[J].J Am College Cardiol,2017,71(16):1755-1764.
[31]Moslehi JJ,Salem JE,Sosman JA,et al.Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis[J].Lancet,2018,391(10124):933.
[32]Lubli H,Balmelli C,Bossard M,et al.Aucte heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma[J].J Immuno Therapy Cancer,2015,3:11.
[33]Semper H,Muehlberg F,Schuiz-Menger J,et al.Drug-induced myocarditis after nivolumab treatment in a patient with PDL1-negative squamous cell carcinoma of the lung[J].Lung Cancer,2016,99:117-119.
[34]Johunson DB,Balko JM,Compton ML,et al.Fulminant myocarditis with combination immune checkpoint blockade[J].NEngl J Med,2016,375(18):1749-1755.
[35]Frigeri M,Meyrer P,Banfi C,et al.Immune checkpoint inhibitorassociated myocarditis:a new challenge for cardiologists[J].Can JCardiol,2018,34(1):92.
[36]Haanen JBAG,Carbonnel F,Robert C,et al.Management of toxicities from immunotherapy:ESMO clinical practice guidelines for diagnosis,treatment and follow-up[J].Ann Oncol,2017,28:119-142.