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Cytokine changes during immune-related adverse events and corticosteroid treatment in melanoma patients receiving immune checkpoint inhibitors

Cancer Immunology, Immunotherapy volume 70, pages 2209–2221 (2021)Cite this article

Abstract

Background

Immune checkpoint inhibitors (ICIs) often cause immune-related adverse events (irAEs), most of which are treated with corticosteroids despite evidence suggesting that corticosteroids may blunt antitumor efficacy. We sought to identify cytokine changes that correlate with irAEs and study the impact of corticosteroid treatment on cytokine levels.

Methods

We analyzed expression of 34 cytokines in 52 melanoma patients who developed irAEs during therapy with ICIs. Luminex serum assay was performed at baseline, 1, 2, and 3 months after starting ICI. Baseline cytokine levels and longitudinal log2 fold-change was compared with incidence and grade of irAEs. Cytokine patterns were compared between patients based on development of irAEs and steroid treatment.

Results

There were no differences in baseline cytokine levels between patients who developed grade 1–2 irAEs (N = 28) vs. grade 3–4 irAEs (N = 24). Dermatitis patients (N = 8) had significantly higher baseline Ang-1 (p = 0.006) and CD40L (p = 0.005). Pneumonitis patients (N = 4) had significantly higher baseline IL-17 (p = 0.009). Colitis patients (N = 8) had a trend toward decreased GCSF (p = 0.08). Through Spearman’s correlation analysis, patients who developed irAEs without receiving corticosteroids (N = 23) exhibited harmonization of cytokine fold-change, with 0/276 pairwise comparisons demonstrating significant divergence. In contrast, corticosteroid treatment in patients with irAEs (N = 15) altered fold-change to a discordant pattern (42/276 diverged, 15.2%). This discordant cytokine pattern in patients receiving corticosteroids is similar to the cytokine pattern in patients who did not develop irAEs (N = 8) during the longitudinal profiling period (41/276, 14.9%).

Conclusions

Baseline levels of certain cytokines correlate with specific irAEs in melanoma patients receiving ICIs. irAEs drive a concordant pattern of cytokine fold-change, which is disrupted by corticosteroid treatment.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Ang:

Angiopoietin

CCL:

Chemokine (C–C motif) ligand

CD40L:

Cluster of differentiation 40 ligand

CTCAE:

NIH Common terminology criteria for adverse events

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

CXCL:

Chemokine (C-X-C motif) ligand

CX3-CL1:

Chemokine (C-X3-C motif) ligand 1

DFCI:

Dana-farber cancer institute

EGF:

Epidermal growth factor

EMR:

Electronic medical record

FGF2:

Fibroblast growth factor 2

GCP-2:

Granulocyte chemotactic protein 2

GCSF:

Granulocyte colony-stimulating factor

GROb:

Growth regulated oncogene beta

ICIs:

Immune checkpoint inhibitors

IFNγ:

Interferon gamma

IL:

Interleukin

IL-1RA:

Interleukin 1 receptor antagonist

IP10:

Interferon gamma-induced protein 10

irAEs:

Immune-related adverse events

IRB:

Institutional review board

MIC:

MHC class I chain-related (A and B)

MHC:

Major histocompatibility complex

PD-1:

Programmed cell death protein 1

PD-L1:

Programmed death-ligand 1

TNF-α :

Tumor necrosis factor alpha

VEGF-A :

Vascular endothelial growth factor A

References

  1. West HJ (2015) Immune checkpoint inhibitors. JAMA Oncol 1(1):115–115

    Article  Google Scholar 

  2. Eun Y, Kim IY, Sun J-M et al (2019) Risk factors for immune-related adverse events associated with anti-PD-1 pembrolizumab. Sci Rep 9(1):14039. https://doi.org/10.1038/s41598-019-50574-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Abdel-Rahman O, Eltobgy M, Oweira H, Giryes A, Tekbas A, Decker M (2017) Immune-related musculoskeletal toxicities among cancer patients treated with immune checkpoint inhibitors: a systematic review. Immunotherapy 9(14):1175–1183. https://doi.org/10.2217/imt-2017-0108

    CAS  Article  PubMed  Google Scholar 

  4. Weber JS, Kahler KC, Hauschild A (2012) Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol: Off J Am Soc Clin Oncol 30(21):2691–2697. https://doi.org/10.1200/JCO.2012.41.6750

    CAS  Article  Google Scholar 

  5. Rahma O, Ott P (2018) General principles of immune-related toxicities. In: Marc Ernstoff IP, Robert Caroline, Diab Adi, Hersey Peter (eds) SITC’s guide to managing immunotherapy toxicity. Society for Immunotherapy of Cancer, USA

    Google Scholar 

  6. Khan S, Khan SA, Luo X et al (2019) Immune dysregulation in cancer patients developing immune-related adverse events. Br J Cancer 120(1):63–68. https://doi.org/10.1038/s41416-018-0155-1

    CAS  Article  PubMed  Google Scholar 

  7. Faje AT, Lawrence D, Flaherty K et al (2018) High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer 124(18):3706–3714. https://doi.org/10.1002/cncr.31629

    CAS  Article  PubMed  Google Scholar 

  8. Arbour KC, Mezquita L, Long N et al (2018) Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non–small-cell lung cancer. J Clin Oncol 36(28):2872–2878. https://doi.org/10.1200/jco.2018.79.0006

    CAS  Article  PubMed  Google Scholar 

  9. Das S, Johnson DB (2019) Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer 7(1):306–306. https://doi.org/10.1186/s40425-019-0805-8

    Article  PubMed  PubMed Central  Google Scholar 

  10. Scott SC, Pennell NA (2018) Early use of systemic corticosteroids in patients with advanced nsclc treated with nivolumab. J Thorac Oncol 13(11):1771–1775. https://doi.org/10.1016/j.jtho.2018.06.004

    Article  PubMed  Google Scholar 

  11. Fucà G, Galli G, Poggi M et al (2019) Modulation of peripheral blood immune cells by early use of steroids and its association with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors. ESMO Open 4(1):e000457–e000457. https://doi.org/10.1136/esmoopen-2018-000457

    Article  PubMed  PubMed Central  Google Scholar 

  12. Esfahani K, Elkrief A, Calabrese C et al (2020) Moving towards personalized treatments of immune-related adverse events. Nat Rev Clin Oncol. https://doi.org/10.1038/s41571-020-0352-8

    Article  PubMed  Google Scholar 

  13. Common terminology criteria for adverse events (ctcae) v5.0. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_8.5x11.pdf

  14. Tarhini AA, Zahoor H, Lin Y et al (2015) 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 3:39. https://doi.org/10.1186/s40425-015-0081-1

    Article  PubMed  PubMed Central  Google Scholar 

  15. O’Connor JM, Fessele KL, Steiner J et al (2018) Speed of adoption of immune checkpoint inhibitors of programmed cell death 1 protein and comparison of patient ages in clinical practice vs pivotal clinical trials. JAMA Oncol 4(8):e180798–e180798. https://doi.org/10.1001/jamaoncol.2018.0798

    Article  PubMed  PubMed Central  Google Scholar 

  16. Haslam A, Prasad V (2019) Estimation of the percentage of us patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw Open 2(5):e192535. https://doi.org/10.1001/jamanetworkopen.2019.2535

    Article  PubMed  PubMed Central  Google Scholar 

  17. Herbst RS, Soria J-C, Kowanetz M et al (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528):563–567. https://doi.org/10.1038/nature14011

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Yamazaki N, Kiyohara Y, Uhara H et al (2017) Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase 2 study for advanced melanoma. Cancer Sci 108(5):1022–1031. https://doi.org/10.1111/cas.13226

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Bridge JA, Lee JC, Daud A, Wells JW, Bluestone JA (2018) Cytokines, chemokines, and other biomarkers of response for checkpoint inhibitor therapy in skin cancer. Front Med (Lausanne) 5:351. https://doi.org/10.3389/fmed.2018.00351

    Article  Google Scholar 

  20. Head L, Gorden N, Gulick RV et al (2019) Biomarkers to predict immune-related adverse events with checkpoint inhibitors. J Clin Oncol 37:131–131. https://doi.org/10.1200/JCO.2019.37.8_suppl.131

    Article  Google Scholar 

  21. Valpione S, Pasquali S, Campana LG et al (2018) Sex and interleukin-6 are prognostic factors for autoimmune toxicity following treatment with anti-CTLA4 blockade. J Transl Med 16(1):94. https://doi.org/10.1186/s12967-018-1467-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Lim SY, Lee JH, Gide TN et al (2019) Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1–based immunotherapy. Clin Cancer Res 25(5):1557–1563. https://doi.org/10.1158/1078-0432.ccr-18-2795

    CAS  Article  PubMed  Google Scholar 

  23. Kurimoto C, Inaba H, Ariyasu H et al (2020) Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors. Cancer Sci 111(5):1468–1477. https://doi.org/10.1111/cas.14363

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Tanaka R, Okiyama N, Okune M et al (2017) Serum level of interleukin-6 is increased in nivolumab-associated psoriasiform dermatitis and tumor necrosis factor-α is a biomarker of nivolumab recativity. J Dermatol Sci 86(1):71–73. https://doi.org/10.1016/j.jdermsci.2016.12.019

    CAS  Article  PubMed  Google Scholar 

  25. Phillips GS, Wu J, Hellmann MD et al (2019) Treatment outcomes of immune-related cutaneous adverse events. J Clin Oncol 37(30):2746–2758. https://doi.org/10.1200/jco.18.02141

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Xing P, Zhang F, Wang G et al (2019) Incidence rates of immune-related adverse events and their correlation with response in advanced solid tumours treated with NIVO or NIVO+IPI: a systematic review and meta-analysis. J ImmunoTher Cancer. 7(1):341. https://doi.org/10.1186/s40425-019-0779-6

    Article  PubMed  PubMed Central  Google Scholar 

  27. Goldinger SM, Stieger P, Meier B et al (2016) Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy. Clin Cancer Res 22(16):4023–4029. https://doi.org/10.1158/1078-0432.ccr-15-2872

    CAS  Article  PubMed  Google Scholar 

  28. Kuroda K, Sapadin A, Shoji T, Fleischmajer R, Lebwohl M (2001) Altered expression of angiopoietins and tie2 endothelium receptor in psoriasis. J Investig Dermatol 116(5):713–720. https://doi.org/10.1046/j.1523-1747.2001.01316.x

    CAS  Article  PubMed  Google Scholar 

  29. Chen L, Marble DJ, Agha R et al (2008) The progression of inflammation parallels the dermal angiogenesis in a keratin 14 IL-4-transgenic model of atopic dermatitis. Microcirculation 15(1):49–64. https://doi.org/10.1080/10739680701418416

    CAS  Article  PubMed  Google Scholar 

  30. Klein D (2018) The Tumor vascular endothelium as decision maker in cancer therapy. Front Oncol 8:367–367. https://doi.org/10.3389/fonc.2018.00367

    Article  PubMed  PubMed Central  Google Scholar 

  31. Schoenberger SP, Toes REM, van der Voort EIH, Offringa R, Melief CJM (1998) T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 393(6684):480–483. https://doi.org/10.1038/31002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Mehling A, Loser K, Varga G et al (2001) Overexpression of CD40 ligand in murine epidermis results in chronic skin inflammation and systemic autoimmunity. J Exp Med 194(5):615–628. https://doi.org/10.1084/jem.194.5.615

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Ohta Y, Hamada Y (2004) In situ expression of CD40 and CD40 ligand in psoriasis. Dermatology 209(1):21–28. https://doi.org/10.1159/000078582

    CAS  Article  PubMed  Google Scholar 

  34. Molinero LL, Gruber M, Leoni J, Woscoff A, Zwirner NW (2003) Up-regulated expression of MICA and proinflammatory cytokines in skin biopsies from patients with seborrhoeic dermatitis. Clin Immunol 106(1):50–54. https://doi.org/10.1016/s1521-6616(03)00003-2

    CAS  Article  PubMed  Google Scholar 

  35. Chong S, Lan H, Zeng K, Zhao X (2016) Serum fractalkine (CX3CL1) concentration correlates with clinical severity in pediatric atopic dermatitis patients. Ann Clin Lab Sci 46(2):168–173

    CAS  PubMed  Google Scholar 

  36. Staumont-Sallé D, Fleury S, Lazzari A et al (2014) CX3CL1 (fractalkine) and its receptor CX3CR1 regulate atopic dermatitis by controlling effector T cell retention in inflamed skin. J Exp Med 211(6):1185–1196. https://doi.org/10.1084/jem.20121350

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Bae O-N, Noh M, Chun Y-J, Jeong TC (2015) Keratinocytic vascular endothelial growth factor as a novel biomarker for pathological skin condition. Biomol Therapeutics 23(1):12–18. https://doi.org/10.4062/biomolther.2014.102

    CAS  Article  Google Scholar 

  38. Delaunay M, Prévot G, Collot S, Guilleminault L, Didier A, Mazières J (2019) Management of pulmonary toxicity associated with immune checkpoint inhibitors. Eur Respir Rev 28(154):190012. https://doi.org/10.1183/16000617.0012-2019

    Article  PubMed  Google Scholar 

  39. Suresh K, Voong KR, Shankar B et al (2018) Pneumonitis in non-small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors. J Thorac Oncol 13(12):1930–1939. https://doi.org/10.1016/j.jtho.2018.08.2035

    CAS  Article  PubMed  Google Scholar 

  40. Naidoo J, Cottrell TR, Lipson EJ et al (2020) Chronic immune checkpoint inhibitor pneumonitis. J Immunother Cancer 8(1):e000840. https://doi.org/10.1136/jitc-2020-000840

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wang DY, Salem JE, Cohen JV et al (2018) Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol 4(12):1721–1728. https://doi.org/10.1001/jamaoncol.2018.3923

    Article  PubMed  PubMed Central  Google Scholar 

  42. Suresh K, Naidoo J, Zhong Q et al (2019) The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis. J Clin Investig 129(10):4305–4315. https://doi.org/10.1172/JCI128654

    Article  PubMed  PubMed Central  Google Scholar 

  43. Schoenfeld JD, Nishino M, Severgnini M, Manos M, Mak RH, Hodi FS (2019) Pneumonitis resulting from radiation and immune checkpoint blockade illustrates characteristic clinical, radiologic and circulating biomarker features. J ImmunoTher Cancer 7(1):112. https://doi.org/10.1186/s40425-019-0583-3

    Article  PubMed  PubMed Central  Google Scholar 

  44. Gurczynski SJ, Moore BB (2018) IL-17 in the lung: the good, the bad, and the ugly. Am J Physiol Lung Cell Mol Physiol 314(1):L6–L16. https://doi.org/10.1152/ajplung.00344.2017

    CAS  Article  PubMed  Google Scholar 

  45. Fong DJ, Hogaboam CM, Matsuno Y, Akira S, Uematsu S, Joshi AD (2010) Toll-like receptor 6 drives interleukin-17A expression during experimental hypersensitivity pneumonitis. Immunology 130(1):125–136. https://doi.org/10.1111/j.1365-2567.2009.03219.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Kim S, Shannon V, Sheshadri A et al (2018) TH1/17 hybrid CD4+ cells in bronchial alveolar lavage fluid from leukemia patients with checkpoint inhibitor-induced pneumonitis. J Clini Oncol 36:204–204. https://doi.org/10.1200/JCO.2018.36.5_suppl.204

    Article  Google Scholar 

  47. Wang YN, Lou DF, Li DY et al (2020) Elevated levels of IL-17A and IL-35 in plasma and bronchoalveolar lavage fluid are associated with checkpoint inhibitor pneumonitis in patients with non-small cell lung cancer. Oncol Lett 20(1):611–622. https://doi.org/10.3892/ol.2020.11618

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Marthey L, Mateus C, Mussini C et al (2016) Cancer immunotherapy with anti-CTLA-4 monoclonal antibodies induces an inflammatory bowel disease. J Crohns Colitis 10(4):395–401. https://doi.org/10.1093/ecco-jcc/jjv227

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Abu-Sbeih H, Faleck DM, Ricciuti B et al (2020) Immune checkpoint inhibitor therapy in patients With preexisting inflammatory bowel disease. J Clini Oncol 38(6):576–583. https://doi.org/10.1200/jco.19.01674

    CAS  Article  Google Scholar 

  50. Tyan K, Grover S, Dougan M et al (2020) Association of vitamin D intake with decreased risk of immune checkpoint inhibitor-induced colitis. J Clini Oncol 38:89–89. https://doi.org/10.1200/JCO.2020.38.5_suppl.89

    Article  Google Scholar 

  51. Grover S, Dougan M, Tyan K et al (2020) Vitamin D intake is associated with decreased risk of immune checkpoint inhibitor-induced colitis. Cancer 126(16):3758–3767. https://doi.org/10.1002/cncr.32966

    CAS  Article  PubMed  Google Scholar 

  52. Yoshino K, Nakayama T, Ito A, Sato E, Kitano S (2019) 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. BMC Cancer 19(1):1019. https://doi.org/10.1186/s12885-019-6138-7

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Meshkibaf S, Martins AJ, Henry GT, Kim SO (2016) Protective role of G-CSF in dextran sulfate sodium-induced acute colitis through generating gut-homing macrophages. Cytokine 78:69–78. https://doi.org/10.1016/j.cyto.2015.11.025

    CAS  Article  PubMed  Google Scholar 

  54. Barahona-Garrido J, Yamamoto-Furusho JK (2008) New treatment options in the management of IBD - focus on colony stimulating factors. Biologics Targets Ther 2(3):501–504. https://doi.org/10.2147/btt.s3543

    CAS  Article  Google Scholar 

  55. Puzanov I, Diab A, Abdallah K et al (2017) Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J ImmunoTher Cancer 5(1):95. https://doi.org/10.1186/s40425-017-0300-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. Haratani K, Hayashi H, Chiba Y et al (2018) Association of immune-related adverse events with nivolumab efficacy in non–small-cell lung cancer. JAMA Oncol 4(3):374–378. https://doi.org/10.1001/jamaoncol.2017.2925

    Article  PubMed  Google Scholar 

  57. Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS (2016) Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res 22(4):886–894. https://doi.org/10.1158/1078-0432.ccr-15-1136

    CAS  Article  PubMed  Google Scholar 

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Funding

The authors thank the Parker Institute of Immunotherapy for their support of this project (5812101).

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Affiliations

  1. Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA

    Kevin Tyan, Rizwan Haq, Elizabeth I. Buchbinder, Patrick A. Ott, F. Stephen Hodi & Osama E. Rahma

  2. Center for Immuno-Oncology, Department of Medical Oncology, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA

    Kevin Tyan, Joanna Baginska, Martha Brainard, Mariano Severgnini, Michael Manos, Rizwan Haq, Elizabeth I. Buchbinder, Patrick A. Ott, F. Stephen Hodi & Osama E. Rahma

  3. Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA

    Anita Giobbie-Hurder

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Contributions

O.E.R, F.S.H, and K.T designed the study. AG-H designed the statistical plan and performed the key analyses. K.T, J.B, M.B, M.M, and O.E.R generated and collected the data. M.S, R.H, E.B, and P.O assisted in data interpretation. K.T and O.E.R wrote the manuscript. All authors reviewed and edited the manuscript.

Corresponding author

Correspondence to Osama E. Rahma.

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Conflict of interest

The authors report the following competing interests: RH has research grant support from Novartis and BMS as well as a consulting arrangement with Tango Therapeutics. EB has served on advisory boards for Array Biopharma, Bristol-Myers Squibb (BMS), Trieza Therapeutics and Novartis, and she also receives clinical trial support from Eli Lilly, Novartis, BMS, Genentech and BVD. PO reports the following: advisory roles for Alexion, Array, BMS, Celldex, CytomX, Genentech, Merck, Neon Therapeutics, Novartis, Pfizer, and TRM Oncology; institutional grants from Armo Biosciences, AstraZeneca/MedImmune, BMS, Celldex, CytomX, Genentech, Merck, Neon Therapeutics, Novartis, and Pfizer; and a speaking engagement from Medscape. SH reports the following: grants from BMS and Novartis; personal fees from BMS, Merck, Serono, Novartis, Takeda, Surface Pharmaceuticals, Genentech/Roche, Compass Therapeutics, Apricity, Bayer, Aduro, Partners Therapeutics, Sanofi, Pfizer, Pionyr Immunotherapeutics, 7 Hills Pharma, Verastem Oncology, Rheos Medicines, and Kairos Therapeutics; equity in Torque Therapeutics; and patents #20100111973 and #7250291 issued as well as #20170248603, #20160340407, #20160046716, #20140004112, #20170022275, #20170008962, and “Methods of Using Pembrolizumab and Trebananib” pending. OER has research support from Merck. Speaker for activities supported by educational grants from BMS and Merck. Consultant for Merck, Celgene, Five Prime, GSK, Bayer, Roche/Genentech, Puretech, Imvax, and Sobi. In addition, OER has patent “Methods of using pembrolizumab and trebananib” pending.

Ethical approval

Patients evaluated in this study were identified from the Dana-Farber Cancer Institute melanoma bio-specimen banking protocol (DFCI IRB approved protocol 05-042).

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Patients evaluated in this study were identified from the Dana-Farber Cancer Institute melanoma bio-specimen banking protocol (DFCI IRB approved protocol 05-042).

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Tyan, K., Baginska, J., Brainard, M. et al. Cytokine changes during immune-related adverse events and corticosteroid treatment in melanoma patients receiving immune checkpoint inhibitors. Cancer Immunol Immunother 70, 2209–2221 (2021). https://doi.org/10.1007/s00262-021-02855-1

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Keywords

  • Immunotherapy
  • irAE
  • Cytokine
  • Toxicity
  • Melanoma
  • Steroid