Skip to main content
SpringerLink
Log in

Pathologie der Nebenwirkungen von Immune-Checkpoint-Inhibitoren

The pathology of adverse events with immune checkpoint inhibitors

  • Übersichten
  • Published:
Der Pathologe Aims and scope Submit manuscript

Zusammenfassung

Hintergrund

Die onkologische Immuntherapie hat mit der Entwicklung neuer Medikamente stark an Bedeutung gewonnen. Immune-Checkpoint-Inhibitoren (ICI) sind monoklonale Antikörper, die durch Aktivierung antitumoraler T‑Zellen eine effektive Tumorabstoßung induzieren können. Dieser Wirkmechanismus birgt jedoch auch ein Risiko für die Entstehung immunvermittelter unerwünschter Wirkungen (immune related adverse events, irAEs). Die Diagnose und Klassifikation der irAEs entwickelt sich zu einer wichtigen Aufgabe der Pathologie.

Zielsetzung

Praxisorientierte Darstellung der Diagnostik und Klassifikation von irAEs.

Material und Methoden

Übersichtsarbeit auf Basis einer selektiven Literaturrecherche in PubMed und UpToDate ® online.

Ergebnisse

Die häufigsten irAEs betreffen die Haut, den Gastrointestinaltrakt, die Leber und das respiratorische System. Die korrekte Diagnose und Klassifikation dieser irAEs durch ein interdiziplinäres Team aus Diagnostikern und Klinikern ist wesentlich für eine adäquate, stufengerechte Therapie und die Verhinderung von Langzeitfolgen. Weitere wichtige irAEs betreffen die endokrinen Organe, das Herz, die Gelenke, die Niere und das Nervensystem. Aufgrund ihrer Seltenheit oder der eingeschränkten Möglichkeiten zur bioptischen Untersuchung liegen bisher nur eingeschränkte Daten zur Morphologie und Pathophysiologie dieser irAEs vor. Die Durchführung von Autopsien nach ICI-Therapie ist ein wichtiges Element der Qualitätssicherung und dient der besseren Dokumentation der Inzidenz und Pathogenese der irAEs.

Diskussion

Die Pathologie besitzt einen zentralen Stellenwert für die Diagnose und Behandlung der irAEs. Zukünftige Studien werden ein besseres mechanistisches Verständnis der irAEs und eine individualisierte, wissensbasierte Risikobewertung ermöglichen.

Abstract

Background

Immunotherapy has gained importance with the development of new effective cancer treatments. Immune checkpoint inhibitors (ICI) are monoclonal antibodies that promote T‑cell mediated tumor immune rejection. Checkpoint blockade also carries the risk of inducing autoimmune reactions (“immune related adverse events”, irAEs). The diagnosis and classification of irAEs constitute a new and important field in pathology.

Aim

Practice-oriented review of the diagnosis and classification of irAEs.

Materials and methods

Structured, selective literature review based on PubMed und UpToDate ® online.

Results

The most common irAEs affect the skin, the gastrointestinal tract, the liver, and the respiratory system. The correct diagnosis and classification of irAEs by an interdisciplinary care team is essential for appropriate therapy and the prevention of long-term sequelae. Other important irAEs affect the endocrine organs, the heart, the joints, the kidneys and the nervous system. Because of their rarity and/or limited options for bioptic diagnosis, only limited data on the morphology and pathophysiology of these irAEs are currently available. Autopsies carried out after ICI therapy constitute an important element of quality control and allow better documentation of the incidence and pathogenesis of irAEs.

Discussion

Pathology plays a central role in the diagnosis and treatment of irAEs. Future studies may contribute to a better mechanistic understanding of irAEs for individualized knowledge-based risk assessment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3
Abb. 4
Abb. 5

Literatur

  1. Barjaktarevic IZ, Qadir N, Suri A et al (2013) Organizing pneumonia as a side effect of ipilimumab treatment of melanoma. Chest 143:858–861

    Article  PubMed  Google Scholar 

  2. Berthod G, Lazor R, Letovanec I et al (2012) Pulmonary sarcoid-like granulomatosis induced by ipilimumab. J Clin Oncol 30:e156–e159

    Article  PubMed  Google Scholar 

  3. Bertrand A, Kostine M, Barnetche T et al (2015) Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med 13:211

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bot I, Blank CU, Boogerd W et al (2013) Neurological immune-related adverse events of ipilimumab. Pract Neurol 13:278–280

    Article  PubMed  Google Scholar 

  5. Cappelli LC, Gutierrez AK, Baer AN et al (2017) Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis 76:43–50

    Article  PubMed  Google Scholar 

  6. Chen TW, Razak AR, Bedard PL et al (2015) A systematic review of immune-related adverse event reporting in clinical trials of immune checkpoint inhibitors. Ann Oncol 26:1824–1829

    Article  CAS  PubMed  Google Scholar 

  7. Cortazar FB, Marrone KA, Troxell ML et al (2016) Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors. Kidney Int 90:638–647

    Article  CAS  PubMed  Google Scholar 

  8. Del Castillo M, Romero FA, Arguello E et al (2016) The spectrum of serious infections among patients receiving immune checkpoint blockade for the treatment of melanoma. Clin Infect Dis 63:1490–1493

    Article  PubMed  Google Scholar 

  9. Di Giacomo AM, Danielli R, Guidoboni M et al (2009) Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases. Cancer Immunol Immunother 58:1297–1306

    Article  PubMed  Google Scholar 

  10. Dubin K, Callahan MK, Ren B et al (2016) Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat Commun 7:10391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dunn GP, Koebel CM, Schreiber RD (2006) Interferons, immunity and cancer immunoediting. Nature reviews. Immunology 6:836–848

    CAS  PubMed  Google Scholar 

  12. Everett J, Srivastava A, Misdraji J (2017) Fibrin ring granulomas in checkpoint inhibitor-induced hepatitis. Am J Surg Pathol 41:134–137

    Article  PubMed  Google Scholar 

  13. Friedman CF, Proverbs-Singh TA, Postow MA (2016) Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol 2:1346–1353

    Article  PubMed  Google Scholar 

  14. Gautschi O, Brand C, Criblez D et al (2016) Immunvermittelte Nebenwirkungen von onkologischen Immuntherapien. Schweiz Med Forum 16:836–841

    Google Scholar 

  15. Goldinger SM, Stieger P, Meier B et al (2016) Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy. Clin Cancer Res 22:4023–4029

    Article  CAS  PubMed  Google Scholar 

  16. Hammers HJ, Plimack ER, Infante JR et al (2014) Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma. J Clin Oncol 32(suppl):abstr 4504

    Google Scholar 

  17. Hersh EM, O’day SJ, Powderly J et al (2011) A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naive patients with advanced melanoma. Invest New Drugs 29:489–498

    Article  CAS  PubMed  Google Scholar 

  18. Hofmann L, Forschner A, Loquai C et al (2016) Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer 60:190–209

    Article  CAS  PubMed  Google Scholar 

  19. Hoos A (2016) Development of immuno-oncology drugs - from CTLA4 to PD1 to the next generations. Nat Rev Drug Discov 15:235–247

    Article  CAS  PubMed  Google Scholar 

  20. Jaber SH, Cowen EW, Haworth LR et al (2006) Skin reactions in a subset of patients with stage IV melanoma treated with anti-cytotoxic T‑lymphocyte antigen 4 monoclonal antibody as a single agent. Arch Dermatol 142:166–172

    Article  CAS  PubMed  Google Scholar 

  21. Jiang TT, Martinov T, Xin L et al (2016) Programmed death-1 culls peripheral accumulation of high-affinity autoreactive CD4 T cells to protect against autoimmunity. Cell Rep 17:1783–1794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Johncilla M, Misdraji J, Pratt DS et al (2015) Ipilimumab-associated hepatitis: clinicopathologic characterization in a series of 11 cases. Am J Surg Pathol 39:1075–1084

    Article  PubMed  Google Scholar 

  23. Johnson DB, Balko JM, Compton ML et al (2016) Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 375:1749–1755

    Article  PubMed  PubMed Central  Google Scholar 

  24. Johnson DB, Sullivan RJ, Ott PA et al (2016) Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol 2:234–240

    Article  PubMed  Google Scholar 

  25. Khoja L, Atenafu EG, Templeton A et al (2016) The full blood count as a biomarker of outcome and toxicity in ipilimumab-treated cutaneous metastatic melanoma. Cancer Med 5:2792–2799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kleiner DE, Berman D (2012) Pathologic changes in ipilimumab-related hepatitis in patients with metastatic melanoma. Dig Dis Sci 57:2233–2240

    Article  PubMed  PubMed Central  Google Scholar 

  27. Koelzer VH, Buser T, Willi N et al (2016) Grover’s-like drug eruption in a patient with metastatic melanoma under ipilimumab therapy. J Immunother Cancer 4:47

    Article  PubMed  PubMed Central  Google Scholar 

  28. Koelzer VH, Rothschild SI, Zihler D et al (2016) Systemic inflammation in a melanoma patient treated with immune checkpoint inhibitors-an autopsy study. J Immunother Cancer 4:13

    Article  PubMed  PubMed Central  Google Scholar 

  29. Lacouture ME, Wolchok JD, Yosipovitch G et al (2014) Ipilimumab in patients with cancer and the management of dermatologic adverse events. J Am Acad Dermatol 71:161–169

    Article  CAS  PubMed  Google Scholar 

  30. Larkin J, Chiarion-Sileni V, Gonzalez R et al (2015) Combined nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23–34

    Article  PubMed  Google Scholar 

  31. Laubli H, Balmelli C, Bossard M et al (2015) Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma. J Immunother Cancer 3:11

    Article  PubMed  PubMed Central  Google Scholar 

  32. Lord JD, Hackman RC, Moklebust A et al (2010) Refractory colitis following anti-CTLA4 antibody therapy: analysis of mucosal FOXP3+ T cells. Dig Dis Sci 55:1396–1405

    Article  PubMed  Google Scholar 

  33. Lynch TJ, Bondarenko I, Luft A et al (2012) Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol 30:2046–2054

    Article  CAS  PubMed  Google Scholar 

  34. Mehta A, Gupta A, Hannallah F et al (2016) Myocarditis as an immune-related adverse event with ipilimumab/nivolumab combination therapy for metastatic melanoma. Melanoma Res 26:319–320

    Article  PubMed  Google Scholar 

  35. Menzies AM, Johnson DB, Ramanujam S et al (2016) Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol 34(abstr 9515):abstr 9515

    Google Scholar 

  36. Michot JM, Bigenwald C, Champiat S et al (2016) Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 54:139–148

    Article  CAS  PubMed  Google Scholar 

  37. Minor DR, Puzanov I, Callahan MK et al (2015) Severe gastrointestinal toxicity with administration of trametinib in combination with dabrafenib and ipilimumab. Pigment Cell Melanoma Res 28:611–612

    Article  PubMed  PubMed Central  Google Scholar 

  38. Mitchell KA, Kluger H, Sznol M et al (2013) Ipilimumab-induced perforating colitis. J Clin Gastroenterol 47:781–785

    Article  PubMed  Google Scholar 

  39. Naidoo J, Page DB, Li BT et al (2015) Toxicities of the anti-PD–1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol 26:2375–2391

    CAS  PubMed  Google Scholar 

  40. Naidoo J, Wang X, Woo KM et al (2016) Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J Clin Oncol. doi:10.1200/jco.2016.71.0434

    PubMed  Google Scholar 

  41. Nishino M, Ramaiya NH, Awad MM et al (2016) PD-1 inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course. Clin Cancer Res 22:6051–6060

    Article  CAS  PubMed  Google Scholar 

  42. Oble DA, Mino-Kenudson M, Goldsmith J et al (2008) Alpha-CTLA-4 mAb-associated panenteritis: a histologic and immunohistochemical analysis. Am J Surg Pathol 32:1130–1137

    Article  PubMed  Google Scholar 

  43. Okamoto M, Okamoto M, Gotoh K et al (2016) Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy. J Diabetes Investig 7:915–918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Postow M, Wolchok J (2017) Toxicities associated with checkpoint inhibitor immunotherapy. In: UpToDate. http://www.uptodate.com/contents/toxicities-associated-with-checkpoint-inhibitor-immunotherapy. Zugegriffen: 10. Okt 2016

    Google Scholar 

  45. Qin R, Olson A, Singh B et al (2016) Safety and efficacy of radiation therapy in advanced melanoma patients treated with Ipilimumab. Int J Radiat Oncol Biol Phys 96:72–77

    Article  CAS  PubMed  Google Scholar 

  46. Ribas A, Hodi FS, Callahan M et al (2013) Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med 368:1365–1366

    Article  CAS  PubMed  Google Scholar 

  47. Robert C, Ribas A, Wolchok JD et al (2014) Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384:1109–1117

    Article  CAS  PubMed  Google Scholar 

  48. Robert C, Thomas L, Bondarenko I et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526

    Article  CAS  PubMed  Google Scholar 

  49. Robinson MR, Chan CC, Yang JC et al (2004) Cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma: a new cause of uveitis. J Immunother 27:478–479

    Article  PubMed  Google Scholar 

  50. Shahabi V, Berman D, Chasalow SD et al (2013) Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune-related gastrointestinal adverse events. J Transl Med 11:75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sharabi AB, Lim M, Deweese TL et al (2015) Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol 16:e498–e509

    Article  PubMed  Google Scholar 

  52. Snyder A, Makarov V, Merghoub T et al (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371:2189–2199

    Article  PubMed  PubMed Central  Google Scholar 

  53. Spain L, Walls M, Julve K et al (2016) Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature. Ann Oncol. doi:10.1093/annonc/mdw558

    Google Scholar 

  54. Topalian SL, Sznol M, Mcdermott DF et al (2014) Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 32:1020–1030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Topalian SL, Taube JM, Anders RA et al (2016) Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 16:275–287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tumeh PC, Harview CL, Yearley JH et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568–571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Weber JS, D’angelo SP, Minor D et al (2015) Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16:375–384

    Article  CAS  PubMed  Google Scholar 

  58. Weber JS, Kahler KC, Hauschild A (2012) Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 30:2691–2697

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut für Pathologie, Kantonsspital Baselland, Mühlemattstraße 11, 4410, Liestal, Schweiz

    V. H. Koelzer, G. Cathomas &  K. D. Mertz

  2. Translational Research Unit (TRU), Institut für Pathologie, Universität Bern, Bern, Schweiz

    V. H. Koelzer

  3. Institut für Pathologie, Universitätsspital Basel, Basel, Schweiz

    K. Glatz & L. Bubendorf

  4. Institut für Pathologie und Molekularpathologie, Universität Zürich und Universitätsspital Zürich, Zürich, Schweiz

    A. Weber & A. Gaspert

  5. Klinische Pathologie, Institut für Pathologie, Universität Bern, Bern, Schweiz

    A. Lugli

  6. Klinik für Onkologie, Universitätsspital Basel, Basel, Schweiz

    A. Zippelius

  7. Kempf und Pfaltz Histologische Diagnostik, Research Unit, Zürich, Schweiz

    W. Kempf

Authors
  1. V. H. Koelzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. Glatz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. Bubendorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Gaspert
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G. Cathomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Lugli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A. Zippelius
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. W. Kempf
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. K. D. Mertz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K. D. Mertz.

Ethics declarations

Interessenkonflikt

V. H. Koelzer, K. Glatz, L. Bubendorf, A. Weber, A. Gaspert, G. Cathomas, A. Lugli, A. Zippelius, W. Kempf und K. D. Mertz geben an, dass kein Interessenkonflikt besteht.

Alle beschriebenen Untersuchungen am Menschen wurden mit Zustimmung der zuständigen Ethik-Kommission, im Einklang mit nationalem Recht sowie gemäß der Deklaration von Helsinki von 1975 (in der aktuellen, überarbeiteten Fassung) durchgeführt.

Additional information

Redaktion

H.A. Baba, Essen

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Koelzer, V.H., Glatz, K., Bubendorf, L. et al. Pathologie der Nebenwirkungen von Immune-Checkpoint-Inhibitoren. Pathologe 38, 197–208 (2017). https://doi.org/10.1007/s00292-017-0281-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00292-017-0281-1

Schlüsselwörter

Keywords

Search

Navigation