Bullöses Pemphigoid unter Pembrolizumab-Therapie eines metastasierten malignen Melanoms

Zusammenfassung

Pembrolizumab ist ein monoklonaler Antikörper, der an den PD-1-Rezeptor auf T-Zellen bindet und die Interaktion mit den Liganden PD-L1 und PD-L2 auf Krebszellen hemmt. Pembrolizumab wird zunehmend für die Behandlung von fortgeschrittenen Tumorerkrankungen, v. a. für metastasierte maligne Melanome, aber auch für nichtkleinzelliges Lungenkarzinom, Urothelkarzinom und Nierenkarzinom angewendet. Trotz der beeindruckenden klinischen Wirkungen sind die Checkpoint-Inhibitoren mit einer Reihe von Nebenwirkungen verbunden, die als immunbezogene unerwünschte Ereignisse bekannt sind. Zu den bekannten Nebenwirkungen dieser Therapie gehören neben kutanen Nebenwirkungen wie Hautausschlag auch Müdigkeit, Schilddrüsendysfunktion, immunvermittelte Pneumonitis und Kolitis. Zu den kutanen unerwünschten Ereignissen gehören u. a. Pruritus, lichenoide Dermatitis, Psoriasis sowie blasenbildende Erkrankungen wie bullöses Pemphigoid. Die Nebenwirkungen werden durch die immunoregulatorischen Mechanismen des Medikaments erklärt. Hier berichten wir über den Fall eines 72-jährigen Patienten mit metastasiertem malignem Melanom und Prostatakarzinom als Zweittumor, der unter einer Therapie mit Pembrolizumab rasch sowohl eine stabile Erkrankung des Tumors hatte, aber auch zuerst eine immunvermittelte Pneumonitis und im Verlauf dann auch ein bullöses Pemphigoid entwickelte. Dieser Fall ergänzt die Liste möglicher kutaner Nebenwirkungen einer PD-1-Inhibitor-Therapie.

Abstract

Pembrolizumab is a monoclonal antibody that binds on the PD-1 receptor on T cells and inhibits the interaction with the PD-L1 and PD-L2 ligands on cancer cells. Pembrolizumab is indicated for the treatment of advanced tumor diseases, esp. for metastatic malignant melanoma, but also for nonsmall cell lung carcinoma, urothelial carcinoma, and renal carcinoma. Despite its impressive clinical benefits, checkpoint inhibition is associated with a number of inflammatory effects known as immune-related adverse events. The known side effects of this therapy include, beside skin rash, also fatigue, dysfunction of the thyroid gland, pneumonitis, and colitis. Cutaneous side effects include pruritus, lichenoid dermatitis, psoriasis and blistering disorders such as bullous pemphigoid. These are explained by the immunoregulatory mechanisms of the drug. Here we report the case of a 72-year-old male patient with metastatic malignant melanoma on therapy with pembrolizumab and consecutivly in a stable state of the disease, who developed an immune-mediated pneumonitis and additional a bullous pemphigoid. This case might extend the knowledge of possible cutaneous side effects of PD-1 inhibitor therapies.

• Literatur

• 1 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 Immunother 2012; 35: 169-178
• 2 Hodi FS, O’Day SJ, McDermott DF. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711-723
• 3 Rounds A, Kolesar J. Nivolumab for second-line treatment of metastatic squamous non-small-cell lung cancer. Am J Health Syst Pharm 2015; 72: 1851-1855
• 4 Jin HT, Ahmed R, Okazaki T. Role of PD-1 in regulating T-cell immunity. Curr Top Microbiol Immunol 2011; 350: 17-37
• 5 Jour G, Glitza IC, Ellis RM. et al. Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1 antibody therapy: a report on bullous skin eruptions. J Cutan Pathol 2016; 43: 688-696
• 6 Siegel R, DeSantis C, Virgo K. et al. Cancer treatment and survivorship statistics. CA Cancer J Clin 2012; 62: 220-241
• 7 Sibaud V, Meyer N, Lamant L. et al. Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Current Opinion in Oncology 2016; 28: 254-263
• 8 Teulings HE, Limpens J, Jansen SN. et al. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol 2015; 33: 773-781
• 9 Sahuquillo-Torralba A, Ballester-Sanchez R, Pujol-Marco C. et al. Pembrolizumab: a new drug that can induce exacerbations of psoriasis. Actas Dermosifiliogr 2016; 107: 264-266
• 10 Caini S, Boniol M, Botteri E. et al. The risk of developing a second primary cancer in melanoma patients: A comprehensive review of the literature and meta-analysis. Journal of Dermatological Science 2014; 75: 3-9
• 11 Haanen JB, Thienen H, Blank CU. Toxicity patterns with immunomodulating antibodies and their combinations. Semin Oncol 2015; 42: 423-428
• 12 Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 252-264
• 13 Dunn GP, Bruce AT, Ikeda H. et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002; 3: 991-998
• 14 Gettinger SN, Horn L, Gandhi L. et al. Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 2015; 33: 2004-2012
• 15 Garon EB, Rizvi NA, Hui R. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372: 2018-2028
• 16 Naidoo J, Schindler K, Querfeld C. et al. Autoimmune Bullous Skin Disorders with Immune Checkpoint Inhibitors Targeting PD-1 and PD-L1. Cancer Immunol Res 2016; 4: 383-389
• 17 Belum VR, Benhuri B, Lacouture ME. Characterization and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer 2016; 60: 12-25
• 18 Lacouture ME, Wolchok JD, Yosipovitch G. et al. Ipilimumab in patients with cancer and the management of dermatologic adverse events. Journal of the American Academy of Dermatology 2014; 71: 161-169
• 19 Baum S, Sakka N, Artsi O. et al. Diagnosis and classification of autoimmune blistering diseases. Autoimmunity review 2014; 13: 482-489
• 20 Hwang SJ, Carlos G, Chou S. et al. Bullous pemphigoid, an autoantibodymediated disease, is a novel immune-related adverse event in patients treated with anti-programmed cell death 1 antibodies. Melanoma Res 2016; 26: 413-416
• 21 Damsky W, Kole L, Tomayko M. Development of bullous pemphigoid during nivolumab therapy. JAAD Case Reports 2016; 2: 442-444
• 22 Kwon CW, Land AS, Smoller BR. Bullous pemphigoid associated with nivolumab, a programmed cell death 1 protein inhibitor. J Eur Acad Dermatol Venereol 2017; 31: e349-e350
• 23 Mochel MC, Ming ME, Imadojemu S. et al. Cutaneous autoimmune effects in the setting of therapeutic immune checkpoint inhibition for metastatic melanoma. J Cutan Pathol 2016; 43: 787-791
• 24 Rofe O, Bar-Sela G, Keidar Z. et al. Severe bullous pemphigoid associated with pembrolizumab therapy for metastatic melanoma with complete regression. Clin Exp Dermatol 2017; 42: 309-312
• 25 Sowerby L, Dewan AK, Granter S. et al. Rituximab treatment of nivolumab-induced bullous pemphigoid. JAMA Dermatol 2017; 153: 603-605
• 26 Balaji A, Verde F, Suresh K. et al. Pneumonitis From Anti-PD-1/PD-L1 Therapy. Oncology (Williston Park) 2017; 31: 739-746 , 754
• 27 Kubin ME, Hellberg L, Palatsi R. Glucocorticoids: The mode of action in bullous pemphigoid. Exp Dermatol 2017; 26: 1253-1260 . doi:10.1111/exd.13408