Genetic variants associated with immune-mediated liver injury from checkpoint inhibitors.
Journal
Hepatology communications
ISSN: 2471-254X
Titre abrégé: Hepatol Commun
Pays: United States
ID NLM: 101695860
Informations de publication
Date de publication:
01 Sep 2024
01 Sep 2024
Historique:
received:
22
05
2024
accepted:
14
07
2024
medline:
26
8
2024
pubmed:
26
8
2024
entrez:
26
8
2024
Statut:
epublish
Résumé
The clinical features, liver histology, and genetic variants in 57 patients with moderate to severe immune-mediated liver injury from checkpoint inhibitors (ILICI) are presented. Between 2010 and 2022, 57 high-causality ILICI cases were enrolled in the Drug-Induced Liver Injury Network. HLA and selected candidate gene variants were tested for association with ILICI risk compared to the general population and other DILI controls. The 57 high-causality cases were attributed to pembrolizumab (16), ipilimumab (15), ipilimumab and nivolumab (13), and other immune checkpoint inhibitors (13) and occurred at a median of 72 days after the first infusion. Median age was 57.8 years, 66% male, and 89% were non-Hispanic Whites. At DILI onset, 53% had hepatocellular, 35% mixed, and 15% cholestatic, with younger patients more likely to have hepatocellular injury. The incidence of ANA, smooth muscle antibody, and elevated IgG levels was low (17%, 23%, and 0%), but corticosteroids were given to 86%. Microgranulomas and hepatic steatosis were seen in 54% and 46% of the 26 liver biopsies, respectively. The HLA alleles associated with autoimmune hepatitis were not over-represented, but 2 host immune response genes (EDIL3 and SAMA5A) and 3 other genes (GABRP, SMAD3, and SLCO1B1) were associated with ILICI (OR: 2.08-2.4, p<0.01). ILICI typically arises within 12 weeks of initiating immunotherapy and is self-limited in most cases. Genetic variants involved in host T-cell regulation and drug disposition were identified, implicating these pathways in the pathogenesis of ILICI. If validated, these findings could lead to improved diagnostic instruments and possible treatments for ILICI.
Sections du résumé
BACKGROUND
BACKGROUND
The clinical features, liver histology, and genetic variants in 57 patients with moderate to severe immune-mediated liver injury from checkpoint inhibitors (ILICI) are presented.
METHODS
METHODS
Between 2010 and 2022, 57 high-causality ILICI cases were enrolled in the Drug-Induced Liver Injury Network. HLA and selected candidate gene variants were tested for association with ILICI risk compared to the general population and other DILI controls.
RESULTS
RESULTS
The 57 high-causality cases were attributed to pembrolizumab (16), ipilimumab (15), ipilimumab and nivolumab (13), and other immune checkpoint inhibitors (13) and occurred at a median of 72 days after the first infusion. Median age was 57.8 years, 66% male, and 89% were non-Hispanic Whites. At DILI onset, 53% had hepatocellular, 35% mixed, and 15% cholestatic, with younger patients more likely to have hepatocellular injury. The incidence of ANA, smooth muscle antibody, and elevated IgG levels was low (17%, 23%, and 0%), but corticosteroids were given to 86%. Microgranulomas and hepatic steatosis were seen in 54% and 46% of the 26 liver biopsies, respectively. The HLA alleles associated with autoimmune hepatitis were not over-represented, but 2 host immune response genes (EDIL3 and SAMA5A) and 3 other genes (GABRP, SMAD3, and SLCO1B1) were associated with ILICI (OR: 2.08-2.4, p<0.01).
CONCLUSIONS
CONCLUSIONS
ILICI typically arises within 12 weeks of initiating immunotherapy and is self-limited in most cases. Genetic variants involved in host T-cell regulation and drug disposition were identified, implicating these pathways in the pathogenesis of ILICI. If validated, these findings could lead to improved diagnostic instruments and possible treatments for ILICI.
Identifiants
pubmed: 39185906
doi: 10.1097/HC9.0000000000000518
pii: 02009842-202409010-00007
pii:
doi:
Substances chimiques
Immune Checkpoint Inhibitors
0
Ipilimumab
0
Antibodies, Monoclonal, Humanized
0
pembrolizumab
DPT0O3T46P
Nivolumab
31YO63LBSN
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.
Références
Twomey JD, Zhang B. Cancer Immunotherapy Update: FDA-approved checkpoint inhibitors and companion Diagnostics. AAPS. 2021;23:39–50.
Lamba N, Ott PA, Lorgulescu JB. Use of first-line immune checkpoint inhibitors and association with overall survival among patients with metastatic melanoma in the anti-PD1 Era. JAMA Oncology. 2022;5:e225459.
Vafaei S, Zekiy AO, Khanamir RA, Zaman BA, Ghayourvahdat A, Azimizonuzi H, et al. Combination therapy with immune checkpoint inhibitors (ICI’s): A new frontier. Cancer Cell Inter. 2022;2:2–27.
Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins S, Anadkat M, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO Guideline update. J Clin Oncol. 2021;39:4073–126.
Dougan M, Wang Y, Rubio-Tapia A, Lim JK. AGA Clinical Practice Update on diagnosis and management of immune checkpoint inhibitor colitis and hepatitis: Expert review. Gastroenterology. 2021;160:1384–93.
Cunnigham M, Gupta R, Butler M. Checkpoint inhibitor hepatotoxicity: Pathogenesis and Management. Hepatology. 2024;79:198–212.
Tsung I, Dolan R, Lao CD, Fecher L, Riggenbach K, Yeaboah-Koran A, et al. Liver injury is most commonly due to hepatic metastases rather than drug hepatotoxicity during pembrolizumab immunotherapy. Aliment Ther Pharm. 2019;50:800–88.
Li M, Wong D, Vogel AS, Sack JS, Rahma OE, Hodi FS, et al. Effect of corticosteroid dosing on outcomes in high grade immune checkpoint inhibitor hepatitis. Hepatology. 2022;75:531–40.
Fontana RJ, Watkins PB, Bonkovsky HL, Chalasani N, Davern T, Serrano J, et al. Drug-Induced Liver Injury Network (DILIN) prospective study: Rationale, design and conduct. Drug Saf. 2009;32:55–68.
Cirulli ET, Nicoletti P, Abramson K, Andrade RJ, Bjornsson ES, Chalasani N, et al. A missense variant in PTPN22 is a risk factor for drug-induced liver injury. Gastroenterology. 2019;156:1707–16.
Nicoletti P, Dellinger A, Li YJ, Barnhart HX, Chalasani N, Fontana RJ, et al. Identification of reduced ERAP-2 expression and a novel HLA allele as components of a risk score for susceptibility to liver injury due to amoxicillin clavulanate. Gastroenterology. 2023;165:454–66.
Kleiner DE, Chalasani NP, Lee WM, Fontana RJ, Bonkovsky HL, Watkins PB, et al. Hepatic histological findings in suspected drug-induced liver injury: Systematic evaluation and clinical associations. Hepatology. 2014;59:661–70.
Danan G, Benichou C. Causality assessment of adverse reactions to drugs- I A novel method based on the conclusions of international consensus meetings: Application to DILI. J Clin Epidemiol. 1993;46:1323–30.14.
DeBoer Y, Kosinski AS, Urban TJ, Zhao Z, Long N, Chalasani N, et al. Features of AIH in patients with DILI. Clin Gastro & Hepatology. 2017;15:103–12.
DeBoer YS, Van Gerven NMF, Zwiers A, Verwer BJ, van Hoek B, van Erpecum KJ, et al. Genome-wide association study identified variants associated with autoimmune hepatitis type 1. Gastroenterology. 2014;147:443–52.
Chu X, Zhao J, Zhou J, Zhou F, Jian T, Jian S, et al. Association of baseline peripheral-blood eosinophil count with immune checkpoint inhibitor related pneumonitis and clinical outcomes in patients with non-small cell lung cancer receiving immune checkpoint inhibitor. Lung Cancer. 2020;150:76–82.
Chennamadhavuni A, Abushahin L, Jin N, Presley CJ, Manne A. Risk factors and biomarkers for immune related adverse events: A practical guide to identifying high-risk patients and rechallenging immune checkpoint inhibitors. Front Immunol. 2022;13:779691.
Fontana RJ, Kleiner DE, Chalasani N, Bonkovsky H, Gu J, Barnhart H, et al. The impact of patient age and Corticosteroids in patients with sulfonamide hepatotoxicity. Am J Gastroenterol. 2023;118:1566–75.
Purde MT, Niederer R, Wagner NB, Diem S, Berner F, Hasan O, et al. Presence of autoantibodies in serum does not impact the course of immune checkpoint inhibitor-induced hepatitis in a prospective cohort of cancer patients. J Can Res & Clin Oncology. 2022;148:647–55.
Cohen JV, Dougan M, Zubiri L, Reynolds KL, Sullivan RJ, Misdraji J. Liver biopsy findings in patients on immune checkpoint inhibitors. Mod Pathol. 2021;34:426–37.
De Martin EJ, Michot JM, Papouin B, Champiat S, Mateua C, Lambotte O, et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatology. 2018;68:1181–90.
Kleiner DE, Berman D. Pathologic changes in iplimumab-related hepatitis in patients with metastatic melanoma. Dig Dis Sci. 2012;57:2233–40.
Onoyama T, Takeda Y, Yamashita T, Hamamoto W, Sakamoto Y, Koda H, et al. Programmed cell death-1 inhibitor related sclerosing cholangitis: A systematic review. World J Gastro. 2020;26:353–65.
Zen Y, Yeh MM. Checkpoint inhibitor-induced liver injury: A novel from of liver disease emerging in the era of cancer immunotherapy. Semin Diag Pathol. 2019;36:434–40.
Riveiro-Barciela M, Barreira-Diaz A, Callejo-Perez A, Munoz-Couselo E, Diaz-Mejia N, Diaz-Gonzalez A, et al. Retreatment with immune checkpoint inhibitors after a severe immune -related Hepatitis: Results from a Prospective multicenter study. Clin Gastro Hep. 2023;21:732–40.
Dolladille C, Ederhy S, Sassier M, Cautela J, Thuny F, Cohen AA, et al. Immune Checkpoint inhibitor rechallenge after Immune-related adverse events in patients with cancer. JAMA oncology. 2020;6:865–71.
Wolffer M, Battke F, Schulze M, Feldhahan M, Flatz L, Martus P, et al. Biomarkers associated with immune-related adverse events under checkpoint inhibitors in metastatic melanoma. Cancers. 2022;14:302.
Adbel-Wahab N, Diab A, Yu RK, Futreal A, Criswell LA, Tayare JH, et al. Genetic Determinants of Immune related adverse events in patients with melanoma receiving checkpoint inhibitors. Cancer Immunol Immunother. 2021;70:1939–49.
Delgoffe GM, Woo SR, Turnis ME, Gravano DM, Guy C, Overacre AE, et al. Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature. 2013;501:252–6.
Li M, Zhong D, Li G. Regulatory role of local tissue signal Del-1 in cancer and inflammation: A review. Cell Mol Bio Lett. 2021;26:31.
Goris A, Sawcer S, Vandenbroeck K, Carton H, Billiau A, Setakis E, et al. New candidate loci for multiple sclerosis susceptibility revealed by a whole genome association screen in a Belgian population. J Neuroimmunol. 2003;143:65–9.
Tabasum S, Thapa D, Giobbie-Hurder A, Weirather JL, Campisi M, Schol PJ, et al. EDIL3 as an angiogenic target of immune exclusion following checkpoint blockade. Cancer Immunol Res. 2023;11:1493–500.
Leclerc M, Voilin E, Gros G, Corgnac S, de Montpreville V, Validire P, et al. Regulation of anti-tumour CD8 T-cell immunity and checkpoint blockade immunotherapy by Neuropilin-1. Nat Commun. 2019;10:3345.
Jiang SH, Zhu LL, Zhang M, Li RK, Yang Q, Yan JY, et al. GABRP regulates chemokine signalling, macrophage recruitment and tumour progression in pancreatic cancer through tuning KCNN4-mediated Ca(2+) signalling in a GABA-independent manner. Gut. 2019;68:1994–2006.
Park BV, Freeman ZT, Ghasemzadeh A, Chattergoon MA, Rutebemberwa A, Steigner J, et al. TGF beta1-mediated SMAD3 enhances PD-1 expression on antigen-specific T cells in cancer. Cancer Discov. 2016;6:1366–81.
Abe T, Kakyo M, Tokui T, Nakagomi R, Nishio T, Nakai D, et al. Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1. J Biol Chem. 1999;274:17159–63.
Hirano M, Maeda K, Shitara Y, Sugiyama Y. Contribution of OATP2 and OATP8 to the hepatic uptake of pitavastatin in humans. J Pharmacol Exp Ther. 2004;311:139–46.
Prachukthum S, Nunnarumit P, Pienvichit P, Chuansumrit A, Songdej D, Kajanachumpol S, et al. Genetic polymorphisms in Thai neonates with hyperbilirubinemia. Acta Pediatr. 2009;98:1106–10.
Bibossi M, Maroteau C, Dawed AY, Taylor A, Srinivasan S, Melhem AL, et al. Common and rare variants in SLCO1B1 are associated with statin intolerance. MedRxiv. 2022. doi:10.1101/2022.08.08.22278584
doi: 10.1101/2022.08.08.22278584