Top

Journal of Cancer Research and Clinical Oncology

Published in:

Open Access 01-03-2022 | NSCLC | Original Article – Cancer Research

Presence of autoantibodies in serum does not impact the occurrence of immune checkpoint inhibitor-induced hepatitis in a prospective cohort of cancer patients

Authors: Mette-Triin Purde, Rebekka Niederer, Nikolaus B. Wagner, Stefan Diem, Fiamma Berner, Omar Hasan Ali, Dorothea Hillmann, Irina Bergamin, Markus Joerger, Martin Risch, Christoph Niederhauser, Tobias L. Lenz, Martin Früh, Lorenz Risch, David Semela, Lukas Flatz

Published in: Journal of Cancer Research and Clinical Oncology | Issue 3/2022

Abstract

Purpose

Immune checkpoint inhibitor (ICI)-induced hepatitis belongs to the frequently occurring immune-related adverse events (irAEs), particularly with the combination therapy involving ipilimumab and nivolumab. However, predisposing factors predicting the occurrence of ICI-induced hepatitis are barely known. We investigated the association of preexisting autoantibodies in the development of ICI-induced hepatitis in a prospective cohort of cancer patients.

Methods

Data from a prospective biomarker cohort comprising melanoma and non-small cell lung cancer (NSCLC) patients were used to analyze the incidence of ICI-induced hepatitis, putatively associated factors, and outcome.

Results

40 patients with melanoma and 91 patients with NSCLC received ICI between July 2016 and May 2019. 11 patients developed ICI-induced hepatitis (8.4%). Prior to treatment, 45.5% of patients in the hepatitis cohort and 43.8% of the control cohort showed elevated titers of autoantibodies commonly associated with autoimmune liver diseases (p = 0.82). We found two nominally significant associations between the occurrence of ICI-induced hepatitis and HLA alleles associated with autoimmune liver diseases among NSCLC patients. Of note, significantly more patients with ICI-induced hepatitis developed additional irAEs in other organs (p = 0.0001). Neither overall nor progression-free survival was affected in the hepatitis group.

Conclusion

We found nominally significant associations of ICI-induced hepatitis with two HLA alleles. ICI-induced hepatitis showed no correlation with liver-specific autoantibodies, but frequently co-occurred with irAEs affecting other organs. Unlike other irAEs, ICI-induced hepatitis is not associated with a better prognosis.

Available only for authorised users

(2017) “Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.” 2019, from https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf

Aizawa Y, Hokari A (2017) Autoimmune hepatitis: current challenges and future prospects. Clin Exp Gastroenterol 10:9–18. https://doi.org/10.2147/CEG.S101440CrossRefPubMedPubMedCentral

Ali OH, Bomze D, Ring S et al (2019) BP180-specific IgG is associated with skin adverse events, therapy response and overall survival in non-small cell lung cancer patients treated with checkpoint inhibitors. J Am Acad Dermatol. https://doi.org/10.1016/j.jaad.2019.08.045CrossRefPubMedPubMedCentral

Anderson KS, Cramer DW, Sibani S et al (2015) Autoantibody signature for the serologic detection of ovarian cancer. J Proteome Res 14(1):578–586. https://doi.org/10.1021/pr500908nCrossRefPubMed

Beck PR, Belfield A, Spooner RJ, Blumgart LH, Wood CB (1979) Serum enzymes in colorectal cancer. Cancer 43(5):1772–1776. https://doi.org/10.1002/1097-0142(197905)43:5%3c1772::aid-cncr2820430529%3e3.0.co;2-yCrossRefPubMed

Benichou C, Danan G, Flahault A (1993) Causality assessment of adverse reactions to drugs—II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol 46(11):1331–1336. https://doi.org/10.1016/0895-4356(93)90102-7CrossRefPubMed

Biewenga M, van der Kooij MK, Wouters M et al (2021) Checkpoint inhibitor induced hepatitis and the relation with liver metastasis and outcome in advanced melanoma patients. Hepatol Int 15(2):510–519. https://doi.org/10.1007/s12072-021-10151-4CrossRefPubMed

Brahmer JR, Lacchetti C, Schneider BJ et al (2018) 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. https://doi.org/10.1200/JCO.2017.77.6385CrossRefPubMed

Cao R, Wang LP (2012) Serological diagnosis of liver metastasis in patients with breast cancer. Cancer Biol Med 9(1):57–62. https://doi.org/10.3969/j.issn.2095-3941.2012.01.011CrossRefPubMedPubMedCentral

Chan EK, Damoiseaux J, Carballo OG et al (2015) Report of the first international consensus on standardized nomenclature of antinuclear antibody HEp-2 cell patterns 2014–2015. Front Immunol 6:412. https://doi.org/10.3389/fimmu.2015.00412CrossRefPubMedPubMedCentral

Chen RL, Wang QX, Ma X (2019) Precision medicine for autoimmune hepatitis. J Dig Dis 20(7):331–337. https://doi.org/10.1111/1751-2980.12786CrossRefPubMed

De Martin E, Michot JM, Papouin B et al (2018) Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol 68(6):1181–1190. https://doi.org/10.1016/j.jhep.2018.01.033CrossRefPubMed

Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. https://doi.org/10.1016/j.ejca.2008.10.026CrossRefPubMed

European Association for the Study of the Liver. Electronic address eee, Clinical Practice Guideline Panel C, Panel m and representative EGB (2019) EASL clinical practice guidelines: drug-induced liver injury. J Hepatol 70(6):1222–1261. https://doi.org/10.1016/j.jhep.2019.02.014CrossRef

Fontana RJ, Watkins PB, Bonkovsky HL et al (2009) Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct. Drug Saf 32(1):55–68. https://doi.org/10.2165/00002018-200932010-00005CrossRefPubMedPubMedCentral

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-15-1136CrossRefPubMed

Hasan Ali O, Diem S, Markert E et al (2016) Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer. Oncoimmunology 5(11):e1231292. https://doi.org/10.1080/2162402X.2016.1231292CrossRefPubMedPubMedCentral

Iorgulescu JB, Harary M, Zogg CK et al (2018) Improved risk-adjusted survival for melanoma brain metastases in the era of checkpoint blockade immunotherapies: results from a national cohort. Cancer Immunol Res 6(9):1039–1045. https://doi.org/10.1158/2326-6066.CIR-18-0067CrossRefPubMedPubMedCentral

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(8):1075–1084. https://doi.org/10.1097/PAS.0000000000000453CrossRefPubMed

Kanz BA, Pollack MH, Johnpulle R et al (2016) Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or hepatic dysfunction. J Immunother Cancer 4:60. https://doi.org/10.1186/s40425-016-0166-5CrossRefPubMedPubMedCentral

Karamchandani DM, Chetty R (2018) Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists’ perspective. J Clin Pathol 71(8):665–671. https://doi.org/10.1136/jclinpath-2018-205143CrossRefPubMed

Kehl KL, Yang S, Awad MM, Palmer N, Kohane IS, Schrag D (2019) Pre-existing autoimmune disease and the risk of immune-related adverse events among patients receiving checkpoint inhibitors for cancer. Cancer Immunol Immunother 68(6):917–926. https://doi.org/10.1007/s00262-019-02321-zCrossRefPubMed

Lee CW, Ronnekleiv-Kelly S (2019) Autoimmune diseases of the biliary tract: a review. Surg Clin North Am 99(2):185–201. https://doi.org/10.1016/j.suc.2018.11.003CrossRefPubMed

Massari F, Di Nunno V, Cubelli M et al (2018) Immune checkpoint inhibitors for metastatic bladder cancer. Cancer Treat Rev 64:11–20. https://doi.org/10.1016/j.ctrv.2017.12.007CrossRefPubMed

Nadeau BA, Fecher LA, Owens SR, Razumilava N (2018) Liver toxicity with cancer checkpoint inhibitor therapy. Semin Liver Dis 38(4):366–378. https://doi.org/10.1055/s-0038-1667358CrossRefPubMed

Nishida N, Kudo M (2019) Liver damage related to immune checkpoint inhibitors. Hepatol Int 13(3):248–252. https://doi.org/10.1007/s12072-018-9921-7CrossRefPubMed

Nisihara R, Machoski MCC, Neppel A, Maestri CA, Messias-Reason I, Skare TL (2018) Anti-nuclear antibodies in patients with breast cancer. Clin Exp Immunol 193(2):178–182. https://doi.org/10.1111/cei.13136CrossRefPubMedPubMedCentral

Okada N, Kawazoe H, Takechi K et al (2019) Association between immune-related adverse events and clinical efficacy in patients with melanoma treated with nivolumab: a multicenter retrospective study. Clin Ther 41(1):59–67. https://doi.org/10.1016/j.clinthera.2018.11.004CrossRefPubMed

Okamoto M, Ogawa Y, Watanabe A et al (2004) Autoantibodies to DFS70/LEDGF are increased in alopecia areata patients. J Autoimmun 23(3):257–266. https://doi.org/10.1016/j.jaut.2004.07.004CrossRefPubMed

Owen DH, Burkart J, Patel S et al (2018) 1772PImmune related adverse events across cancer types: incidence, risk factors and survival. Ann Oncol. https://doi.org/10.1093/annonc/mdy300.088CrossRef

Sato K, Akamatsu H, Murakami E et al (2018) Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab. Lung Cancer 115:71–74. https://doi.org/10.1016/j.lungcan.2017.11.019CrossRefPubMed

Shah NJ, Al-Shbool G, Blackburn M et al (2019) Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection. J Immunother Cancer 7(1):353. https://doi.org/10.1186/s40425-019-0771-1CrossRefPubMedPubMedCentral

Silva IPD, Batten M, Long GV (2018) Reinvigorating tumour-infiltrating lymphocytes from checkpoint inhibitor resistant melanomas. Br J Cancer 119(6):661–662. https://doi.org/10.1038/s41416-018-0218-3CrossRefPubMedPubMedCentral

Slight-Webb S, Lu R, Ritterhouse LL et al (2016) Autoantibody-positive healthy individuals display unique immune profiles that may regulate autoimmunity. Arthritis Rheumatol 68(10):2492–2502. https://doi.org/10.1002/art.39706CrossRefPubMedPubMedCentral

Suzman DL, Pelosof L, Rosenberg A, Avigan MI (2018) Hepatotoxicity of immune checkpoint inhibitors: an evolving picture of risk associated with a vital class of immunotherapy agents. Liver Int 38(6):976–987. https://doi.org/10.1111/liv.13746CrossRefPubMed

Tahir SA, Gao J, Miura Y et al (2019) Autoimmune antibodies correlate with immune checkpoint therapy-induced toxicities. Proc Natl Acad Sci U S A 116(44):22246–22251. https://doi.org/10.1073/pnas.1908079116CrossRefPubMedPubMedCentral

Tsung I, Dolan R, Lao CD et al (2019) Liver injury is most commonly due to hepatic metastases rather than drug hepatotoxicity during pembrolizumab immunotherapy. Aliment Pharmacol Ther 50(7):800–808. https://doi.org/10.1111/apt.15413CrossRefPubMed

von Elm E, Altman DG, Egger M et al (2014) The strengthening the reporting of observational studies in epidemiology (STROBE) Statement: guidelines for reporting observational studies. Int J Surg 12(12):1495–1499. https://doi.org/10.1016/j.ijsu.2014.07.013CrossRef

Wang PF, Chen Y, Song SY et al (2017) Immune-related adverse events associated with anti-PD-1/PD-L1 treatment for malignancies: a meta-analysis. Front Pharmacol 8:730. https://doi.org/10.3389/fphar.2017.00730CrossRefPubMedPubMedCentral

Winter J, Lenders MM, Gassenmaier M et al (2021) Prognostic role of gamma-glutamyl transferase in metastatic melanoma patients treated with immune checkpoint inhibitors. Cancer Immunol Immunother 70(4):1089–1099. https://doi.org/10.1007/s00262-020-02768-5CrossRefPubMed

Zen Y, Yeh MM (2018) Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury. Mod Pathol 31(6):965–973. https://doi.org/10.1038/s41379-018-0013-yCrossRefPubMed

Title: Presence of autoantibodies in serum does not impact the occurrence of immune checkpoint inhibitor-induced hepatitis in a prospective cohort of cancer patients
Authors: Mette-Triin Purde
Rebekka Niederer
Nikolaus B. Wagner
Stefan Diem
Fiamma Berner
Omar Hasan Ali
Dorothea Hillmann
Irina Bergamin
Markus Joerger
Martin Risch
Christoph Niederhauser
Tobias L. Lenz
Martin Früh
Lorenz Risch
David Semela
Lukas Flatz
Publication date: 01-03-2022
Publisher: Springer Berlin Heidelberg
Keywords: NSCLC
Melanoma
Melanoma
NSCLC
Hepatitis
Checkpoint Inhibitors
Published in: Journal of Cancer Research and Clinical Oncology / Issue 3/2022
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-021-03870-6

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 3/2022

Treatment and follow-up of rare testis tumours

Correction to: MicroRNA-338-5p plays a tumor suppressor role in glioma through inhibition of the MAPK-signaling pathway by binding to FOXD1

Biopsy-detected Gleason grade 5 tumor is an additional prognostic factor in metastatic hormone-sensitive prostate cancer

A multicenter clinical study: personalized medication for advanced gastrointestinal carcinomas with the guidance of patient-derived tumor xenograft (PDTX)

Solitary colorectal liver metastasis: overview of treatment strategies and role of prognostic factors

Horizontal tumor extent (HZTE) has limited prognostic significance in 2018 FIGO stage I endocervical adenocarcinoma (ECA): a retrospective study of 416 cases

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials