Journal of Cancer Research and Clinical Oncology

, Volume 145, Issue 2, pp 429–443 | Cite as

Immune checkpoint blockade for Merkel cell carcinoma: actual findings and unanswered questions

  • Marco GalloEmail author
  • Valentina Guarnotta
  • Federica De Cicco
  • Manila Rubino
  • Antongiulio Faggiano
  • Annamaria Colao
  • NIKE Group
Review – Clinical Oncology



Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine carcinoma arising from the skin. We aimed to review and deal with some of the most relevant controversial topics on the correct use of immunotherapy for the treatment of MCC.


The primary search was carried out via PubMed, EMBASE, and the Cochrane Library (until 31st May, 2018), while other articles and guidelines were retrieved from related papers or those referenced in these papers. Additionally, we performed an extensive search on to gather information on the ongoing clinical trials related to this specific topic.


We performed an up-to-date critical review taking into account the results of both retrospective and prospective published studies evaluating these issues: Are there any predictive criteria of response to immunotherapy? What is the correct place of immunotherapy in the treatment algorithm of MCC? What is the best choice after immunotherapy failure? What to do with patients for whom immunotherapy is not been feasible or contraindicated? How long should immunotherapy be prolonged, and what follow-up should be offered after complete response?


The therapeutic landscape of MCC is rapidly evolving: many open issues will probably be resolved, and many other questions are likely to arise in the next few years. The results of ongoing prospective clinical trials and of several other studies on these issues are eagerly awaited.


Merkel cell carcinoma Neuroendocrine tumours Immune checkpoint inhibitors Avelumab Pembrolizumab Therapy 



This review is part of the ‘NIKE’ project (Neuroendocrine tumours Innovation Knowledge and Education) led by Prof Annamaria Colao, which aims at increasing the knowledge on NETs. We would like to acknowledge all the Collaborators of this project: Manuela Albertelli, Barbara Altieri, Elena Ambrosetti, Antonio Bianchi, Lena Bottiglieri, Severo Campione, Silvia Carra, Carla Di Dato, Sergio Di Molfetta, Antonella Di Sarno, Giuseppe Fanciulli, Diego Ferone, Francesco Ferraù, Elisa Giannetta, Federica Grillo, Erika Maria Grossrubatscher, Elia Guadagno, Andrea Isidori, Fabio Lo Calzo, Pasqualino Malandrino, Chiara Martini, Erika Messina, Roberta Modica, Giovanna Muscogiuri, Genoveffa Pizza, Paola Razzore, Laura Rizza, Rosaria Maddalena Ruggeri, Concetta Sciammarella, Giovanni Vitale, and Maria Chiara Zatelli.

Author contributions

All authors have contributed equally to the conception and design of the review. MG, FDC, VG, and MR analyzed data and drafted the article. AF and AC revised the manuscript critically. All authors approved the final article.


This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. Al Homsi MU, Mostafa M, Fahim K (2018) Favorable response to treatment with avelumabin an HIV-positive patient with advanced merkel cell carcinoma previously refractory to chemotherapy. Case Rep Oncol 11(2):467–475. Google Scholar
  2. Albores-Saavedra J, Batich K, Chable-Montero F, Sagy N, Schwartz AM, Henson DE (2010) Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol 37:20–27. Google Scholar
  3. Amaral T, Leiter U, Garbe C (2017) Merkel cell carcinoma: epidemiology, pathogenesis, diagnosis and therapy. Rev Endocr Metab Disord 18:517–532. Google Scholar
  4. Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J et al (2015) Talimogene Laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol 33(25):2780–2788. Google Scholar
  5. Angenendt L, Schliemann C, Lutz M, Rebber E, Schulze AB, Weckesser M et al (2016) Nivolumab in a patient with refractory Hodgkin’s lymphoma after allogeneic stem cell transplantation. Bone Marrow Transpl 51(3):443–445. Google Scholar
  6. Arora R, Shuda M, Guastafierro A, Feng H, Toptan T, Tolstov Y et al (2012) Survivin is a therapeutic target in Merkel cell carcinoma. Sci Transl Med 4(133):133ra56. Google Scholar
  7. Baker M, Cordes L, Brownell I (2018) Avelumab: a new standard for treating metastatic Merkel cell carcinoma. Expert Rev Anticancer Ther 18:319–326. Google Scholar
  8. Barnett R, Barta VS, Jhaveri KD (2017) Preserved renal-allograft function and the PD-1 pathway inhibitor nivolumab. N Engl J Med 376(2):191–192. Google Scholar
  9. BAVENCIO (avelumab) (2018) Summary of product characteristics. Accessed 18 Oct 2018
  10. Becker JC, Lorenz E, Ugurel S, Eigentler TK, Kiecker F, Pföhler C et al (2017) Evaluation of real-world treatment outcomes in patients with distant metastatic Merkel cell carcinoma following second-line chemotherapy in Europe. Oncotarget 8:79731–79741. Google Scholar
  11. Becker JC, Stang A, Hausen AZ, Fischer N, DeCaprio JA, Tothill RW et al (2018) Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC. Cancer Immunol Immunother 67:341–351. Google Scholar
  12. Bhatia S, Miller N, Lu H, Ibrani D, Shinohara M, Byrd DR et al (2016) Pilot trial of intratumoral (IT) G100, a toll-like receptor-4 (TLR4) agonist, in patients (pts) with Merkel cell carcinoma (MCC): Final clinical results and immunologic effects on the tumor microenvironment (TME). 2016 ASCO Annual Meeting. J Clin Oncol 34(15 suppl):3021Google Scholar
  13. Bichakjian CK, Nghiem P, Johnson T et al (2017) Merkel cell carcinoma. In: Amin MB, Edge SB, Greene FL et al (eds) AJCC cancer staging manual, 8th edn. Springer, New York, pp 549–562Google Scholar
  14. Bichakjian CK, Olencki T, Aasi SZ, Alam M, Andersen JS, Blitzblau R et al (2018) Merkel cell carcinoma, Version 1.2018, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 16:742–774. Google Scholar
  15. Blasig H, Bender C, Hassel JC, Eigentler TK, Sachse MM, Hiernickel J et al (2017) Reinduction of PD1-inhibitor therapy: first experience in eight patients with metastatic melanoma. Melanoma Res 27(4):321–325. Google Scholar
  16. Bommareddy PK, Kaufman HL (2017) Avelumab and other recent advances in Merkel cell carcinoma. Future Oncol 13:2771–2783. Google Scholar
  17. Boutros C, Tarhini A, Routier E, Lambotte O, Ladurie FL, Carbonnel F et al (2016) Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol 13:473–486. Google Scholar
  18. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM et al (2018) National comprehensive cancer network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 36(17):1714–1768. Google Scholar
  19. Brunner M, Thurnher D, Pammer J, Geleff S, Heiduschka G, Reinisch CM et al (2008) Expression of VEGF-A/C, VEGF-R2, PDGF-alpha/beta, c-kit, EGFR, Her-2/Neu, Mcl-1 and Bmi-1 in Merkel cell carcinoma. Mod Pathol 21(7):876–884. Google Scholar
  20. Buder K, Lapa C, Kreissl MC, Schirbel A, Herrmann K, Schnack A et al (2014) Somatostatin receptor expression in Merkel cell carcinoma as target for molecular imaging. BMC Cancer 14:268. Google Scholar
  21. Cassler NM, Merrill D, Bichakjian CK, Brownell I (2016) Merkel cell carcinoma therapeutic update. Curr Treat Options Oncol 17:36. Google Scholar
  22. Chacon JA, Schutsky K, Powell DJ (2016) The impact of chemotherapy, radiation and epigenetic modifiers in cancer cell expression of immune inhibitory and stimulatory molecules and anti-tumor efficacy. Vaccines 4(4):43. Google Scholar
  23. Chapuis AG, Afanasiev OK, Iyer JG, Paulson KG, Parvathaneni U, Hwang JH et al (2014) Regression of metastatic Merkel cell carcinoma following transfer of polyomavirus-specific T cells and therapies capable of re-inducing HLA class-I. Cancer Immunol Res 2:27–36. Google Scholar
  24. Clarke CA, Robbins HA, Tatalovich Z, Lynch CF, Pawlish KS, Finch JL (2015) Risk of Merkel cell carcinoma after solid organ transplantation. J Natl Cancer Inst. Google Scholar
  25. D’Angelo SP, Russell J, Lebbé C, Chmielowski B, Gambichler T, Grob JJ et al (2018) Efficacy and Safety of first-line avelumab treatment in patients with stage IV metastatic Merkel cell carcinoma: a preplanned interim analysis of a clinical trial. JAMA Oncol. Google Scholar
  26. Davids MS, Charlton A, Ng SS, Chong ML, Laubscher K, Dar M et al (2009) Response to a novel multitargeted tyrosine kinase inhibitor pazopanib in metastatic Merkel cell carcinoma. J Clin Oncol 27(26):e97–e100. Google Scholar
  27. De Toni EN, Gerbes AL (2017) Tapering of immunosuppression and sustained treatment with nivolumab in a liver transplant recipient. Gastroenterology 152(6):1631–1633. Google Scholar
  28. Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L et al (2004) Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 58:862–870. Google Scholar
  29. Deneve JL, Messina JL, Marzban SS, Gonzalez RJ, Walls BM, Fisher KJ et al (2012) Merkel cell carcinoma of unknown primary origin. Ann Surg Oncol 19:2360–2366. Google Scholar
  30. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR et al (2014) Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 124:687–695. Google Scholar
  31. Eggermont AMM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H et al (2015) Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 16:522–530. Google Scholar
  32. Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S et al (2018) Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 378:1789–1801. Google Scholar
  33. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C et al (2017) Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389(10088):2492–2502. Google Scholar
  34. Engels EA, Frisch M, Goedert JJ, Biggar RJ, Miller RW (2002) Merkel cell carcinoma and HIV infection. Lancet 359:497–498. Google Scholar
  35. Engels EA, Pfeiffer RM, Fraumeni JF Jr, Kasiske BL, Israni AK, Snyder JJ et al (2011) Spectrum of cancer risk among US solid organ transplant recipients. JAMA 306(17):1891–1901. Google Scholar
  36. Eshghi N, Lundeen TF, MacKinnon L, Avery R, Kuo PH (2018) 18F-FDG PET/CT for monitoring response of Merkel cell carcinoma to the novel programmed cell death ligand 1 inhibitor avelumab. Clin Nucl Med. Google Scholar
  37. Faje AT, Sullivan R, Lawrence D, Tritos NA, Fadden R, Klibanski A et al (2014) Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. J Clin Endocrinol Metab 99:4078–4085. Google Scholar
  38. Felicetti F, Nervo A, Piovesan A, Berardelli R, Marchisio F, Gallo M et al (2017) Tyrosine kinase inhibitors rechallenge in solid tumors: a review of literature and a case description with lenvatinib in thyroid cancer. Expert Rev Anticancer Ther 17(12):1093–1098. Google Scholar
  39. Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD et al (2018) Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med 378:1976–1986. Google Scholar
  40. Ghebeh H, Lehe C, Barhoush E, Al-Romaih K, Tulbah A, Al-Alwan M et al (2010) Doxorubicin downregulates cell surface B7-H1 expression and upregulates its nuclear expression in breast cancer cells: role of B7-H1 as an anti-apoptotic molecule. Breast Cancer Res BCR 12(4):R48. httpsGoogle Scholar
  41. Gibney GT, Kudchadkar RR, DeConti RC, Thebeau MS, Czupryn MP, Tetteh L et al (2015) Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma. Clin Cancer Res 21:712–720. Google Scholar
  42. Goh G, Walradt T, Markarov V, Blom A, Riaz N, Doumani R et al (2016) Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy. Oncotarget 7:3403–3415. Google Scholar
  43. Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M et al (2016) Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 17(7):976–983. Google Scholar
  44. Grimaldi AM, Simeone E, Giannarelli D, Muto P, Falivene S, Borzillo V et al (2014) Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy. Oncoimmunology 3:e28780. Google Scholar
  45. Guitera-Rovel P, Lumbroso J, Gautier-Gougis MS, Spatz A, Mercier S, Margulis S et al (2001) Indium-111octreotide scintigraphy of Merkel cell carcinomas and their metastases. Ann Oncol 12:807–811Google Scholar
  46. Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J et al (2018) ESMO Guidelines Committee. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. Google Scholar
  47. Hasan S, Liu L, Triplet J, Li Z, Mansur D (2013) The role of postoperative radiation and chemoradiation in Merkel cell carcinoma: a systematic review of the literature. Front Oncol 3:276. Google Scholar
  48. Hauschild A, Schadendorf D (2016) Checkpoint inhibitors: a new standard of care for advanced Merkel cell carcinoma? Lancet Oncol 17:1337–1339. Google Scholar
  49. Heppt MV, Schlaak M, Eigentler TK, Kähler KC, Kiecker F, Loquai C et al (2017) Checkpoint blockade for metastatic melanoma and Merkel cell carcinoma in HIV-positive patients. Ann Oncol 28(12):3104–3106. Google Scholar
  50. Herz S, Höfer T, Papapanagiotou M, Leyh JC, Meyenburg S, Schadendorf D et al (2016) Checkpoint inhibitors in chronic kidney failure and an organ transplant recipient. Eur J Cancer 67:66–72. Google Scholar
  51. Hodgson NC (2005) Merkel cell carcinoma: changing incidence trends. J Surg Oncol 89:1–4. Google Scholar
  52. Iwasaki T, Matsushita M, Nonaka D, Kuwamoto S, Kato M, Murakami I et al (2015) Comparison of Akt/mTOR/4E-BP1 pathway signal activation and mutations of PIK3CA in Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative carcinomas. Hum Pathol 46(2):210–216. Google Scholar
  53. Iyer JG, Blom A, Doumani R, Lewis C, Tarabadkar ES, Anderson A et al (2016) Response rates and durability of chemotherapy among 62 patients with metastatic Merkel cell carcinoma. Cancer Med 5:2294–2301. Google Scholar
  54. Johnson DB, Sullivan RJ, Ott PA, Carlino MS, Khushalani NI, Ye F et al (2016) Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol 2(2):234–240. Google Scholar
  55. Kanz BA, Pollack MH, Johnpulle R, Puzanov I, Horn L, Morgans A et al (2016) Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or hepatic dysfunction. J Immunother Cancer 4:60. (eCollection 2016)Google Scholar
  56. Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D’Angelo SP et al (2016) Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 17:1374–1385. Google Scholar
  57. Kaufman HL, Russell JS, Hamid O, Bhatia S, Terheyden P, D’Angelo SP et al (2018) Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥ 1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial. J Immunother Cancer 6:7. Google Scholar
  58. Kelly K, Infante JR, Taylor MH, Patel MR, Wong DJ, Iannotti N et al (2018) Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials. Cancer. Google Scholar
  59. KEYTRUDA (pembrolizumab) (2018) Summary of product characteristics. Accessed 18 Oct 2018
  60. Khan SA, Pruitt SL, Xuan L, Gerber DE (2016) Prevalence of autoimmune disease among patients with lung cancer: implications for immunotherapy treatment options. JAMA Oncol 2(11):1507–1508. Google Scholar
  61. Kittai AS, Oldham H, Cetnar J, Taylor M (2017) Immune checkpoint inhibitors in organ transplant patients. J Immunother 40(7):277–281. Google Scholar
  62. Kothapalli A, Khattak MA (2018) Safety and efficacy of anti-PD-1 therapy for metastatic melanoma and non-small-cell lung cancer in patients with viral hepatitis: a case series. Melanoma Res 28(2):155–158. Google Scholar
  63. Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG et al (2016) Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun 7:10501. Google Scholar
  64. Ladwa R, Atkinson V (2017) The cessation of anti-PD-1 antibodies of complete responders in metastatic melanoma. Melanoma Res 27(2):168–170. Google Scholar
  65. Lipson EJ, Sharfman WH, Drake CG, Wollner I, Taube JM, Anders RA et al (2013) Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res 19(2):462–468. Google Scholar
  66. Liu J, Blake SJ, Yong MC, Harjunpää H, Ngiow SF, Takeda K et al (2016) Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov 6:1382–1399. Google Scholar
  67. Long GV, Weber JS, Larkin J, Atkinson V, Grob JJ, Schadendorf D et al (2017) Nivolumab for patients with advanced melanoma treated beyond progression: analysis of 2 phase 3 clinical trials. JAMA Oncol 3(11):1511–1519. Google Scholar
  68. Long GV, Schachter J, Ribas A, Arance A, Grob J-J, Mortier L et al (2018) 4-year survival and outcomes after cessation of pembrolizumab after 2 years in patients with ipilimumab-naive advanced melanoma in keynote-006. 2018 ASCO annual meeting. J Clin Oncol 36(15 suppl):9503Google Scholar
  69. Martini DJ, Lalani AA, Bossé D, Steinharter JA, Harshman LC, Hodi FS et al (2017) Response to single agent PD-1 inhibitor after progression on previous PD-1/PD-L1 inhibitors: a case series. J Immunother Cancer 5(1):66. Google Scholar
  70. Meier G, Waldherr C, Herrmann R, Maecke H, Mueller-Brand J, Pless M (2004) Successful targeted radiotherapy with 90Y-DOTATOC in a patient with Merkel cell carcinoma. A case report. Oncology 66(2):160–163Google Scholar
  71. Menhert JM, Rugo HS, O’Neil BH, Santoro A, Schellens JHM, Cohen RB et al (2017) Pembrolizumab for patients with PD-L1–positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study. Ann Oncol. Google Scholar
  72. Mould DR, Sweeney KR (2007) The pharmacokinetics and pharmacodynamics of monoclonal antibodies—mechanistic modeling applied to drug development. Curr Opin Drug Discov Devel 10(1):84–96Google Scholar
  73. Napolitano S, Brancaccio G, Argenziano G, Martinelli E, Morgillo F, Ciardiello F et al (2018) It is finally time for adjuvant therapy in melanoma. Cancer Treat Rev 69:101–111. Google Scholar
  74. Nathan PD, Gaunt P, Wheatley K et al (2016) UKMCC-01: A phase II study of pazopanib (PAZ) in metastatic Merkel cell carcinoma. J Clin Oncol 34:9542s. Google Scholar
  75. Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L et al (2016) PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med 374:2542–2552. Google Scholar
  76. Nghiem P, Kaufman HL, Bharmal M, Mahnke L, Phatak H, Becker JC (2017) Systematic literature review of efficacy, safety and tolerability outcomes of chemotherapy regimens in patients with metastatic Merkel cell carcinoma. Future Oncol 13:1263–1279. Google Scholar
  77. Nghiem P, Bhatia S, Lipson EJ, Sharfman WH, Kudchadkar RR, Friedlander PA et al (2018) Durable tumor regression and overall survival (OS) in patients with advanced Merkel cell carcinoma (aMCC) receiving pembrolizumab as first-line therapy. 2018 ASCO Annual Meeting. J Clin Oncol 36(15 suppl):9506Google Scholar
  78. OPDIVO (nivolumab) (2018) Summary of product characteristics. Accessed 18 Oct 2018]
  79. Orlov S, Salari F, Kashat L, Walfish PG (2015) Induction of painless thyroiditis in patients receiving programmed death 1 receptor immunotherapy for metastatic malignancies. J Clin Endocrinol Metab 100:1738–1741. Google Scholar
  80. Parker JJ, Jones JC, Strober S, Knox SJ et al (2013) Characterization of direct radiation-induced immune function and molecular signaling changes in an antigen presenting cell line. Clin Immunol 148:44–55. Google Scholar
  81. Paulson KG, Tegeder A, Willmes C, Iyer JG, Afanasiev OK, Schrama D et al (2014) Downregulation of MHC-I expression is prevalent but reversible in Merkel cell carcinoma. Cancer Immunol Res 2(11):1071–1079. Google Scholar
  82. Paulson KG, Perdicchio M, Kulikauskas R, Wagener F, Church CD, Bui K et al (2017) Augmentation of adoptive T-cell therapy for Merkel cell carcinoma with avelumab. J Clin Oncol 35:15s (suppl. abstr 3044)Google Scholar
  83. Peng J, Hamanishi J, Matsumura N, Abiko K, Murat K, Baba T et al (2015) Chemotherapy induces programmed cell death-ligand 1 overexpression via the nuclear factor-kappaB to foster an immunosuppressive tumor microenvironment in ovarian cancer. Cancer Res 75(23):5034–5045. Google Scholar
  84. Postow MA (2015a) Managing immune checkpoint-blocking antibody side effects. Am Soc Clin Oncol Educ Book. Google Scholar
  85. Postow MA, Callahan MK, Wolchok JD (2015b) Immune checkpoint blockade in cancer therapy. J Clin Oncol 33:1974–1982. Google Scholar
  86. Prewett SL, Ajithkumar T (2015) Merkel cell carcinoma: current management and controversies. Clin Oncol (R Coll Radiol) 27:436–444. Google Scholar
  87. Rabinowits G, Lezcano C, Catalano PJ, McHugh P, Becker H, Reilly MM et al (2018) Cabozantinib in patients with advanced Merkel cell carcinoma. Oncologist 23(7):814–821. Google Scholar
  88. Rabinowitz G (2017) Is this the end of cytotoxic chemotherapy in Merkel cell carcinoma? OncoTargets Ther 10:4803–4807. Google Scholar
  89. Ritter C, Fan K, Paulson KG, Nghiem P, Schrama D, Becker JC (2016) Reversal of epigenetic silencing of MHC class I chain-related protein A and B improves immune recognition of Merkel cell carcinoma. Sci Rep 6:21678. Google Scholar
  90. Robert C, Schachter J, Long G, Arance A, Grob JJ, Mortier L et al (2015) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372(26):2521–2532. Google Scholar
  91. Robert C, Ribas A, Hamid O, Daud A, Wolchok JD, Joshua AM et al (2016) Three year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. J Clin Oncol 34:9503Google Scholar
  92. Rojkó L, Reiniger L, Téglási V, Fábián K, Pipek O, Vágvölgyi A et al (2018) Chemotherapy treatment is associated with altered PD-L1 expression in lung cancer patients. J Cancer Res Clin Oncol 144:1219–1226. Google Scholar
  93. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A et al (2016) Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387(10031):1909–1920. Google Scholar
  94. Rossi C, Gilhodes J, Maerevoet M, Herbaux C, Morschhauser F, Brice P et al (2018) Efficacy of chemotherapy or chemo-anti-PD-1 combination after failed anti-PD-1 therapy for relapsed and refractory Hodgkin lymphoma: a series from Lysa centers. Am J Hematol. Google Scholar
  95. Saleh K, Khalifeh-Saleh N, Kourie HR (2018) Is it possible to rechallenge with PD-1/PD-L1 inhibitors after progression? Immunotherapy 10(5):345–347. Google Scholar
  96. Samlowski WE, Moon J, Tuthill RJ, Heinrich MC, Balzer-Haas NS, Merl SA, DeConti RC et al (2010) A phase II trial of imatinib mesylate in merkel cell carcinoma (neuroendocrine carcinoma of the skin): a Southwest Oncology Group study (S0331). Am J Clin Oncol 33(5):495–499. Google Scholar
  97. Schadendorf D, Lebbé C, Zur Hausen A, Avril MF, Hariharan S, Bharmal M et al (2017) Merkel cell carcinoma: Epidemiology, prognosis, therapy and unmet medical needs. Eur J Cancer 71:53–69. Google Scholar
  98. Segal NH, He AR, Doi T, Levy R, Bhatia S, Pishvaian MJ et al (2018) Phase I study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer. Clin Cancer Res 24(8):1816–1823. Google Scholar
  99. Sharabi AB, Lim M, DeWeese TL, Drake CG et al (2015) Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol 16:498–509. Google Scholar
  100. Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW, Formenti SC et al (2017) Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol 18:895–903. Google Scholar
  101. Sheng J, Fang W, Yu J, Chen N, Zhan J, Ma Y et al (2016) Expression of programmed death ligand-1 on tumor cells varies pre and post chemotherapy in non-small cell lung cancer. Sci Rep 6:20090. Google Scholar
  102. Shiver MB, Mahmoud F, Gao L (2015) Response to idelalisib in a patient with stage IV Merkel-cell carcinoma. N Engl J Med 373(16):1580–1582. Google Scholar
  103. Tadmor T, Aviv A, Polliack A (2011) Merkel cell carcinoma, chronic lymphocytic leukemia and other lymphoproliferative disorders: an old bond with possible new viral ties. Ann Oncol 22:250–256. Google Scholar
  104. Tarabadkar ES, Thomas H, Blom A, Parvathaneni U, Olencki T, Nghiem P et al (2018) Clinical benefit from tyrosine kinase inhibitors in metastatic merkel cell carcinoma: a case series of 5 patients. Am J Case Rep 19:505–511. Google Scholar
  105. Taralli S, Sollini M, Milella M, Perotti G, Filice A, Menga M et al (2018)) 18F-FDG and 68 Ga-somatostatin analogs PET/CT in patients with Merkel cell carcinoma: a comparison study. EJNMMI Res. Google Scholar
  106. Tarhini AA, Edington H, Butterfield LH, Lin Y, Shuai Y, Tawbi H et al (2014) Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS One 9:e87705. Google Scholar
  107. Terawaki S, Tanaka Y, Nagakura T, Hayashi T, Shibayama S, Muroi K et al (2007) Specific and high-affinity binding of tetramerized PD-L1 extracellular domain to PD-1-expressing cells: possible application to enhance T cell function. Int Immunol 19(7):881–890Google Scholar
  108. Terheyden P, Becker JC (2017) New developments in the biology and the treatment of metastatic Merkel cell carcinoma. Curr Opin Oncol. Google Scholar
  109. Tilling T, Moll I (2012) Which are the cells of origin in merkel cell carcinoma? J Skin Cancer 2012:680410. Google Scholar
  110. Toker C (1972) Trabecular carcinoma of the skin. Arch Dermatol 105:107–110. Google Scholar
  111. Topalian SL, Bhatia S, Kudchadkar RR, Amin A, Sharfman WH, Lebbe C et al (2018) Nivolumab (Nivo) as neoadjuvant therapy in patients with resectable Merkel cell carcinoma (MCC) in CheckMate 358. 2018 ASCO Annual Meeting. J Clin Oncol 36(15 suppl):9505Google Scholar
  112. Uchi H (2018) Merkel Cell Carcinoma: An Update and Immunotherapy. Front Oncol 8:48. (eCollection 2018)Google Scholar
  113. Villasboas JC, Ansell SM, Witzig TE (2016) Targeting the PD-1 pathway in patients with relapsed classic Hodgkin lymphoma following allogeneic stem cell transplant is safe and effective. Oncotarget 7(11):13260–13264. Google Scholar
  114. Waldherr C, Herrmann R, Maecke H, Mueller-Brand J, Pless M (2004) Successful targeted radiotherapy with 90Y-DOTATOC in a patient with Merkel cell carcinoma. A case report. Oncology 66(2):160–163. Google Scholar
  115. Weber JS, Dummer R, de Pril V, Lebbé C, Hodi FS, MDX010-20 Investigators (2013) Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer 119:1675–1682. Google Scholar
  116. Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL et al (2017) Adjuvant Nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 377:1824–1835. Google Scholar
  117. Wehkamp U, Stern S, Krüger S, Hauschild A, Röcken C, Egberts F (2017) Tropomyosin receptor kinase a expression on merkel cell carcinoma cells. JAMA Dermatol 153(11):1166–1169. Google Scholar
  118. Yared JA, Hardy N, Singh Z, Hajj S, Badros AZ, Kocoglu M et al (2016) Major clinical response to nivolumab in relapsed/refractory Hodgkin lymphoma after allogeneic stem cell transplantation. Bone Marrow Transpl 51(6):850–852. Google Scholar
  119. Zhang P, Su DM, Liang M, Fu J (2008) Chemopreventive agents induce programmed death-1-ligand 1 (PD-L1) surface expression in breast cancer cells and promote PD-L1-mediated T cell apoptosis. Mol Immunol 45(5):1470–1476. Google Scholar
  120. Zhang P, Ma Y, Lv C, Huang M, Li M, Dong B et al (2016) Upregulation of programmed cell death ligand 1 promotes resistance response in non-small-cell lung cancer patients treated with neo-adjuvant chemotherapy. Cancer Sci 107(11):1563–1571. Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Oncological Endocrinology Unit, Department of Medical SciencesUniversity of TurinTurinItaly
  2. 2.Section of Endocrine-Metabolic Diseases, Biomedical Department of Internal and Specialist Medicine (DIBIMIS)University of PalermoPalermoItaly
  3. 3.Department of Clinical Medicine and SurgeryUniversity “Federico II”NaplesItaly
  4. 4.Unit of Gastrointestinal Medical Oncology and Neuroendocrine TumoursEuropean Institute of Oncology, IEOMilanItaly

Personalised recommendations