Skip to main content
Top
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Melanoma | Case report

Severe colitis after PD-1 blockade with nivolumab in advanced melanoma patients: potential role of Th1-dominant immune response in immune-related adverse events: two case reports

Authors: Koji Yoshino, Takayuki Nakayama, Ayumu Ito, Eiichi Sato, Shigehisa Kitano

Published in: BMC Cancer | Issue 1/2019

Login to get access

Abstract

Background

Nivolumab is an immune checkpoint inhibitor specific to the programmed death 1 (PD-1) receptor. Nivolumab has shown clinical responses in many malignancies. Although immune-related adverse events (irAEs) associated with nivolumab are largely tolerable, severe irAEs have occurred in some patients. However, the mechanisms underlying the development of irAEs are not fully clarified.

Case presentation

We report 2 patients with metastatic melanoma who developed colitis, an irAEs caused by nivolumab. Both patients experienced colitis after nivolumab administration. Pathological examination of the colon showed robust infiltration of CD8+ cells and T-bet expressing CD4+ cells in both cases, indicating helper T cells (Th) 1 to be responsible for the dominant response. Additionally, we observed the serum C-reactive protein level (CRP) as well as interleukin-6 (IL-6) reflected the clinical course of irAEs clearly in the two cases.

Conclusion

Our two cases suggested that the development of irAEs due to nivolumab is associated with Th1 dominant response. CRP as well as IL-6 was found to be a potential biomarker for irAEs. Our findings may help to understand the mechanisms underlying irAEs caused by nivolumab and manage irAEs in clinical practice.
Appendix
Available only for authorised users
Literature
1.
go back to reference Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.CrossRef Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.CrossRef
2.
go back to reference Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, Powderly JD, Heist RS, Carvajal RD, Jackman DM, 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 Off J Am Soc Clin Oncol. 2015;33(18):2004–12.CrossRef Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, Powderly JD, Heist RS, Carvajal RD, Jackman DM, 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 Off J Am Soc Clin Oncol. 2015;33(18):2004–12.CrossRef
3.
go back to reference Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, et al. Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34.CrossRef Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, et al. Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34.CrossRef
4.
go back to reference Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–7.CrossRef Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–7.CrossRef
5.
go back to reference Weber JS, Dummer R, de Pril V, Lebbe C, Hodi FS, Investigators MDX. 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. 2013;119(9):1675–82.CrossRef Weber JS, Dummer R, de Pril V, Lebbe C, Hodi FS, Investigators MDX. 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. 2013;119(9):1675–82.CrossRef
6.
go back to reference Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44.CrossRef Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44.CrossRef
7.
go back to reference Beck KE, Blansfield JA, Tran KQ, Feldman AL, Hughes MS, Royal RE, Kammula US, Topalian SL, Sherry RM, Kleiner D, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24(15):2283–9.CrossRef Beck KE, Blansfield JA, Tran KQ, Feldman AL, Hughes MS, Royal RE, Kammula US, Topalian SL, Sherry RM, Kleiner D, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24(15):2283–9.CrossRef
8.
go back to reference Igari F, Sato E, Horimoto Y, Takahashi Y, Isomura T, Arakawa A, Kitano S, Saito M. Diagnostic significance of intratumoral CD8+ tumor-infiltrating lymphocytes in medullary carcinoma. Hum Pathol. 2017;70:129–38.CrossRef Igari F, Sato E, Horimoto Y, Takahashi Y, Isomura T, Arakawa A, Kitano S, Saito M. Diagnostic significance of intratumoral CD8+ tumor-infiltrating lymphocytes in medullary carcinoma. Hum Pathol. 2017;70:129–38.CrossRef
9.
go back to reference Kahler KC, Hassel JC, Heinzerling L, Loquai C, Mossner R, Ugurel S, Zimmer L, Gutzmer R, Cutaneous side effects" Committee of the Work Group Dermatological O: management of side effects of immune checkpoint blockade by anti-CTLA-4 and anti-PD-1 antibodies in metastatic melanoma. J Dtsch Dermatol Ges 2016;14(7):662–681.PubMed Kahler KC, Hassel JC, Heinzerling L, Loquai C, Mossner R, Ugurel S, Zimmer L, Gutzmer R, Cutaneous side effects" Committee of the Work Group Dermatological O: management of side effects of immune checkpoint blockade by anti-CTLA-4 and anti-PD-1 antibodies in metastatic melanoma. J Dtsch Dermatol Ges 2016;14(7):662–681.PubMed
10.
go back to reference Som A, Mandaliya R, Alsaadi D, Farshidpour M, Charabaty A, Malhotra N, Mattar MC. Immune checkpoint inhibitor-induced colitis: a comprehensive review. World J Clin Cases. 2019;7(4):405–18.CrossRef Som A, Mandaliya R, Alsaadi D, Farshidpour M, Charabaty A, Malhotra N, Mattar MC. Immune checkpoint inhibitor-induced colitis: a comprehensive review. World J Clin Cases. 2019;7(4):405–18.CrossRef
11.
go back to reference Lord JD, Hackman RC, Moklebust A, Thompson JA, Higano CS, Chielens D, Steinbach G, McDonald GB. Refractory colitis following anti-CTLA4 antibody therapy: analysis of mucosal FOXP3+ T cells. Dig Dis Sci. 2010;55(5):1396–405.CrossRef Lord JD, Hackman RC, Moklebust A, Thompson JA, Higano CS, Chielens D, Steinbach G, McDonald GB. Refractory colitis following anti-CTLA4 antibody therapy: analysis of mucosal FOXP3+ T cells. Dig Dis Sci. 2010;55(5):1396–405.CrossRef
12.
go back to reference Oble DA, Mino-Kenudson M, Goldsmith J, Hodi FS, Seliem RM, Dranoff G, Mihm M, Hasserjian R, Lauwers GY. Alpha-CTLA-4 mAb-associated panenteritis: a histologic and immunohistochemical analysis. Am J Surg Pathol. 2008;32(8):1130–7.CrossRef Oble DA, Mino-Kenudson M, Goldsmith J, Hodi FS, Seliem RM, Dranoff G, Mihm M, Hasserjian R, Lauwers GY. Alpha-CTLA-4 mAb-associated panenteritis: a histologic and immunohistochemical analysis. Am J Surg Pathol. 2008;32(8):1130–7.CrossRef
13.
go back to reference Chen ML, Sundrud MS. Cytokine networks and T-cell subsets in inflammatory bowel diseases. Inflamm Bowel Dis. 2016;22(5):1157–67.CrossRef Chen ML, Sundrud MS. Cytokine networks and T-cell subsets in inflammatory bowel diseases. Inflamm Bowel Dis. 2016;22(5):1157–67.CrossRef
14.
go back to reference Fuss IJ, Neurath M, Boirivant M, Klein JS, de la Motte C, Strong SA, Fiocchi C, Strober W. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol. 1996;157(3):1261–70.PubMed Fuss IJ, Neurath M, Boirivant M, Klein JS, de la Motte C, Strong SA, Fiocchi C, Strober W. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol. 1996;157(3):1261–70.PubMed
15.
go back to reference Yamauchi R, Araki T, Mitsuyama K, Tokito T, Ishii H, Yoshioka S, Kuwaki K, Mori A, Yoshimura T, Tsuruta O, et al. The characteristics of nivolumab-induced colitis: an evaluation of three cases and a literature review. BMC Gastroenterol. 2018;18(1):135.CrossRef Yamauchi R, Araki T, Mitsuyama K, Tokito T, Ishii H, Yoshioka S, Kuwaki K, Mori A, Yoshimura T, Tsuruta O, et al. The characteristics of nivolumab-induced colitis: an evaluation of three cases and a literature review. BMC Gastroenterol. 2018;18(1):135.CrossRef
16.
go back to reference Reddy HG, Schneider BJ, Tai AW. Immune checkpoint inhibitor-associated colitis and hepatitis. Clin Transl Gastroenterol. 2018;9(9):180.CrossRef Reddy HG, Schneider BJ, Tai AW. Immune checkpoint inhibitor-associated colitis and hepatitis. Clin Transl Gastroenterol. 2018;9(9):180.CrossRef
17.
go back to reference Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306.CrossRef Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306.CrossRef
18.
go back to reference Coutzac C, Adam J, Soularue E, Collins M, Racine A, Mussini C, Boselli L, Kamsukom N, Mateus C, Charrier M, et al. Colon immune-related adverse events: anti-CTLA-4 and anti-PD-1 blockade induce distinct Immunopathological entities. J Crohns Colitis. 2017;11(10):1238–46.CrossRef Coutzac C, Adam J, Soularue E, Collins M, Racine A, Mussini C, Boselli L, Kamsukom N, Mateus C, Charrier M, et al. Colon immune-related adverse events: anti-CTLA-4 and anti-PD-1 blockade induce distinct Immunopathological entities. J Crohns Colitis. 2017;11(10):1238–46.CrossRef
19.
go back to reference Gavin MA, Torgerson TR, Houston E, DeRoos P, Ho WY, Stray-Pedersen A, Ocheltree EL, Greenberg PD, Ochs HD, Rudensky AY. Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc Natl Acad Sci U S A. 2006;103(17):6659–64.CrossRef Gavin MA, Torgerson TR, Houston E, DeRoos P, Ho WY, Stray-Pedersen A, Ocheltree EL, Greenberg PD, Ochs HD, Rudensky AY. Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc Natl Acad Sci U S A. 2006;103(17):6659–64.CrossRef
20.
go back to reference Tarhini AA, Zahoor H, Lin Y, Malhotra U, Sander C, Butterfield LH, Kirkwood JM. Baseline circulating IL-17 predicts toxicity while TGF-beta1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma. J Immunother Cancer. 2015;3:39.CrossRef Tarhini AA, Zahoor H, Lin Y, Malhotra U, Sander C, Butterfield LH, Kirkwood JM. Baseline circulating IL-17 predicts toxicity while TGF-beta1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma. J Immunother Cancer. 2015;3:39.CrossRef
21.
go back to reference Abraham C, Cho J. Interleukin-23/Th17 pathways and inflammatory bowel disease. Inflamm Bowel Dis. 2009;15(7):1090–100.CrossRef Abraham C, Cho J. Interleukin-23/Th17 pathways and inflammatory bowel disease. Inflamm Bowel Dis. 2009;15(7):1090–100.CrossRef
22.
go back to reference Panes J, Jairath V, Levesque BG. Advances in use of endoscopy, radiology, and biomarkers to monitor inflammatory bowel diseases. Gastroenterology. 2017;152(2):362–73 e3.CrossRef Panes J, Jairath V, Levesque BG. Advances in use of endoscopy, radiology, and biomarkers to monitor inflammatory bowel diseases. Gastroenterology. 2017;152(2):362–73 e3.CrossRef
23.
go back to reference Soubieres AA, Poullis A. Emerging role of novel biomarkers in the diagnosis of inflammatory bowel disease. World J Gastrointest Pharmacol Ther. 2016;7(1):41–50.CrossRef Soubieres AA, Poullis A. Emerging role of novel biomarkers in the diagnosis of inflammatory bowel disease. World J Gastrointest Pharmacol Ther. 2016;7(1):41–50.CrossRef
24.
go back to reference Kucera R, Topolcan O, Treskova I, Kinkorova J, Windrichova J, Fuchsova R, Svobodova S, Treska V, Babuska V, Novak J, et al. Evaluation of IL-2, IL-6, IL-8 and IL-10 in malignant melanoma diagnostics. Anticancer Res. 2015;35(6):3537–41.PubMed Kucera R, Topolcan O, Treskova I, Kinkorova J, Windrichova J, Fuchsova R, Svobodova S, Treska V, Babuska V, Novak J, et al. Evaluation of IL-2, IL-6, IL-8 and IL-10 in malignant melanoma diagnostics. Anticancer Res. 2015;35(6):3537–41.PubMed
25.
go back to reference Simeone E, Gentilcore G, Giannarelli D, Grimaldi AM, Caraco C, Curvietto M, Esposito A, Paone M, Palla M, Cavalcanti E, et al. Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma. Cancer Immunol Immunother. 2014;63(7):675–83.CrossRef Simeone E, Gentilcore G, Giannarelli D, Grimaldi AM, Caraco C, Curvietto M, Esposito A, Paone M, Palla M, Cavalcanti E, et al. Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma. Cancer Immunol Immunother. 2014;63(7):675–83.CrossRef
26.
go back to reference Dolan RD, McSorley ST, Horgan PG, Laird B, McMillan DC. The role of the systemic inflammatory response in predicting outcomes in patients with advanced inoperable cancer: systematic review and meta-analysis. Crit Rev Oncol Hematol. 2017;116:134–46.CrossRef Dolan RD, McSorley ST, Horgan PG, Laird B, McMillan DC. The role of the systemic inflammatory response in predicting outcomes in patients with advanced inoperable cancer: systematic review and meta-analysis. Crit Rev Oncol Hematol. 2017;116:134–46.CrossRef
27.
go back to reference Fang S, Wang Y, Sui D, Liu H, Ross MI, Gershenwald JE, Cormier JN, Royal RE, Lucci A, Schacherer CW, et al. C-reactive protein as a marker of melanoma progression. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33(12):1389–96.CrossRef Fang S, Wang Y, Sui D, Liu H, Ross MI, Gershenwald JE, Cormier JN, Royal RE, Lucci A, Schacherer CW, et al. C-reactive protein as a marker of melanoma progression. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33(12):1389–96.CrossRef
Metadata
Title
Severe colitis after PD-1 blockade with nivolumab in advanced melanoma patients: potential role of Th1-dominant immune response in immune-related adverse events: two case reports
Authors
Koji Yoshino
Takayuki Nakayama
Ayumu Ito
Eiichi Sato
Shigehisa Kitano
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-6138-7

Other articles of this Issue 1/2019

BMC Cancer 1/2019 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine