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IL-2-mediated hepatotoxicity : knowledge gap identification based on the irAOP concept

Roser, Luise A. ; Sakellariou, Christina LU orcid ; Lindstedt, Malin LU ; Neuhaus, Vanessa ; Dehmel, Susann ; Sommer, Charline ; Raasch, Martin ; Flandre, Thierry ; Roesener, Sigrid and Hewitt, Philip , et al. (2024) In Journal of Immunotoxicology 21(1).
Abstract

Drug-induced hepatotoxicity constitutes a major reason for non-approval and post-marketing withdrawal of pharmaceuticals. In many cases, preclinical models lack predictive capacity for hepatic damage in humans. A vital concern is the integration of immune system effects in preclinical safety assessment. The immune-related Adverse Outcome Pathway (irAOP) approach, which is applied within the Immune Safety Avatar (imSAVAR) consortium, presents a novel method to understand and predict immune-mediated adverse events elicited by pharmaceuticals and thus targets this issue. It aims to dissect the molecular mechanisms involved and identify key players in drug-induced side effects. As irAOPs are still in their infancy, there is a need for a... (More)

Drug-induced hepatotoxicity constitutes a major reason for non-approval and post-marketing withdrawal of pharmaceuticals. In many cases, preclinical models lack predictive capacity for hepatic damage in humans. A vital concern is the integration of immune system effects in preclinical safety assessment. The immune-related Adverse Outcome Pathway (irAOP) approach, which is applied within the Immune Safety Avatar (imSAVAR) consortium, presents a novel method to understand and predict immune-mediated adverse events elicited by pharmaceuticals and thus targets this issue. It aims to dissect the molecular mechanisms involved and identify key players in drug-induced side effects. As irAOPs are still in their infancy, there is a need for a model irAOP to validate the suitability of this tool. For this purpose, we developed a hepatotoxicity-based model irAOP for recombinant human IL-2 (aldesleukin). Besides producing durable therapeutic responses against renal cell carcinoma and metastatic melanoma, the boosted immune activation upon IL-2 treatment elicits liver damage. The availability of extensive data regarding IL-2 allows both the generation of a comprehensive putative irAOP and to validate the predictability of the irAOP with clinical data. Moreover, IL-2, as one of the first cancer immunotherapeutics on the market, is a blueprint for various biological and novel treatment regimens that are under investigation today. This review provides a guideline for further irAOP-directed research in immune-mediated hepatotoxicity.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
adverse event, Adverse outcome pathway, drug-induced liver injury, hepatotoxicity, immune safety, immunotherapy, interleukin-2, preclinical model
in
Journal of Immunotoxicology
volume
21
issue
1
article number
2332177
publisher
Informa Healthcare
external identifiers
  • scopus:85189450632
  • pmid:38578203
ISSN
1547-691X
DOI
10.1080/1547691X.2024.2332177
language
English
LU publication?
yes
id
178f5362-5aff-4c9a-9af4-d439c48e2dfd
date added to LUP
2024-04-23 13:16:13
date last changed
2024-04-24 02:59:34
@article{178f5362-5aff-4c9a-9af4-d439c48e2dfd,
  abstract     = {{<p>Drug-induced hepatotoxicity constitutes a major reason for non-approval and post-marketing withdrawal of pharmaceuticals. In many cases, preclinical models lack predictive capacity for hepatic damage in humans. A vital concern is the integration of immune system effects in preclinical safety assessment. The immune-related Adverse Outcome Pathway (irAOP) approach, which is applied within the Immune Safety Avatar (imSAVAR) consortium, presents a novel method to understand and predict immune-mediated adverse events elicited by pharmaceuticals and thus targets this issue. It aims to dissect the molecular mechanisms involved and identify key players in drug-induced side effects. As irAOPs are still in their infancy, there is a need for a model irAOP to validate the suitability of this tool. For this purpose, we developed a hepatotoxicity-based model irAOP for recombinant human IL-2 (aldesleukin). Besides producing durable therapeutic responses against renal cell carcinoma and metastatic melanoma, the boosted immune activation upon IL-2 treatment elicits liver damage. The availability of extensive data regarding IL-2 allows both the generation of a comprehensive putative irAOP and to validate the predictability of the irAOP with clinical data. Moreover, IL-2, as one of the first cancer immunotherapeutics on the market, is a blueprint for various biological and novel treatment regimens that are under investigation today. This review provides a guideline for further irAOP-directed research in immune-mediated hepatotoxicity.</p>}},
  author       = {{Roser, Luise A. and Sakellariou, Christina and Lindstedt, Malin and Neuhaus, Vanessa and Dehmel, Susann and Sommer, Charline and Raasch, Martin and Flandre, Thierry and Roesener, Sigrid and Hewitt, Philip and Parnham, Michael J. and Sewald, Katherina and Schiffmann, Susanne}},
  issn         = {{1547-691X}},
  keywords     = {{adverse event; Adverse outcome pathway; drug-induced liver injury; hepatotoxicity; immune safety; immunotherapy; interleukin-2; preclinical model}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Informa Healthcare}},
  series       = {{Journal of Immunotoxicology}},
  title        = {{IL-2-mediated hepatotoxicity : knowledge gap identification based on the irAOP concept}},
  url          = {{http://dx.doi.org/10.1080/1547691X.2024.2332177}},
  doi          = {{10.1080/1547691X.2024.2332177}},
  volume       = {{21}},
  year         = {{2024}},
}