Cargando…

Cytokines in CAR T Cell–Associated Neurotoxicity

Chimeric antigen receptor (CAR) T cells provide new therapeutic options for patients with relapsed/refractory hematologic malignancies. However, neurotoxicity is a frequent, and potentially fatal, complication. The spectrum of manifestations ranges from delirium and language dysfunction to seizures,...

Descripción completa

Detalles Bibliográficos
Autores principales: Gust, Juliane, Ponce, Rafael, Liles, W. Conrad, Garden, Gwenn A., Turtle, Cameron J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772425/
https://www.ncbi.nlm.nih.gov/pubmed/33391257
http://dx.doi.org/10.3389/fimmu.2020.577027
_version_ 1783629867428872192
author Gust, Juliane
Ponce, Rafael
Liles, W. Conrad
Garden, Gwenn A.
Turtle, Cameron J.
author_facet Gust, Juliane
Ponce, Rafael
Liles, W. Conrad
Garden, Gwenn A.
Turtle, Cameron J.
author_sort Gust, Juliane
collection PubMed
description Chimeric antigen receptor (CAR) T cells provide new therapeutic options for patients with relapsed/refractory hematologic malignancies. However, neurotoxicity is a frequent, and potentially fatal, complication. The spectrum of manifestations ranges from delirium and language dysfunction to seizures, coma, and fatal cerebral edema. This novel syndrome has been designated immune effector cell–associated neurotoxicity syndrome (ICANS). In this review, we draw an arc from our current understanding of how systemic and potentially local cytokine release act on the CNS, toward possible preventive and therapeutic approaches. We systematically review reported correlations of secreted inflammatory mediators in the serum/plasma and cerebrospinal fluid with the risk of ICANS in patients receiving CAR T cell therapy. Possible pathophysiologic impacts on the CNS are covered in detail for the most promising candidate cytokines, including IL-1, IL-6, IL-15, and GM-CSF. To provide insight into possible final common pathways of CNS inflammation, we place ICANS into the context of other systemic inflammatory conditions that are associated with neurologic dysfunction, including sepsis-associated encephalopathy, cerebral malaria, thrombotic microangiopathy, CNS infections, and hepatic encephalopathy. We then review in detail what is known about systemic cytokine interaction with components of the neurovascular unit, including endothelial cells, pericytes, and astrocytes, and how microglia and neurons respond to systemic inflammatory challenges. Current therapeutic approaches, including corticosteroids and blockade of IL-1 and IL-6 signaling, are reviewed in the context of what is known about the role of cytokines in ICANS. Throughout, we point out gaps in knowledge and possible new approaches for the investigation of the mechanism, prevention, and treatment of ICANS.
format Online
Article
Text
id pubmed-7772425
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-77724252020-12-31 Cytokines in CAR T Cell–Associated Neurotoxicity Gust, Juliane Ponce, Rafael Liles, W. Conrad Garden, Gwenn A. Turtle, Cameron J. Front Immunol Immunology Chimeric antigen receptor (CAR) T cells provide new therapeutic options for patients with relapsed/refractory hematologic malignancies. However, neurotoxicity is a frequent, and potentially fatal, complication. The spectrum of manifestations ranges from delirium and language dysfunction to seizures, coma, and fatal cerebral edema. This novel syndrome has been designated immune effector cell–associated neurotoxicity syndrome (ICANS). In this review, we draw an arc from our current understanding of how systemic and potentially local cytokine release act on the CNS, toward possible preventive and therapeutic approaches. We systematically review reported correlations of secreted inflammatory mediators in the serum/plasma and cerebrospinal fluid with the risk of ICANS in patients receiving CAR T cell therapy. Possible pathophysiologic impacts on the CNS are covered in detail for the most promising candidate cytokines, including IL-1, IL-6, IL-15, and GM-CSF. To provide insight into possible final common pathways of CNS inflammation, we place ICANS into the context of other systemic inflammatory conditions that are associated with neurologic dysfunction, including sepsis-associated encephalopathy, cerebral malaria, thrombotic microangiopathy, CNS infections, and hepatic encephalopathy. We then review in detail what is known about systemic cytokine interaction with components of the neurovascular unit, including endothelial cells, pericytes, and astrocytes, and how microglia and neurons respond to systemic inflammatory challenges. Current therapeutic approaches, including corticosteroids and blockade of IL-1 and IL-6 signaling, are reviewed in the context of what is known about the role of cytokines in ICANS. Throughout, we point out gaps in knowledge and possible new approaches for the investigation of the mechanism, prevention, and treatment of ICANS. Frontiers Media S.A. 2020-12-16 /pmc/articles/PMC7772425/ /pubmed/33391257 http://dx.doi.org/10.3389/fimmu.2020.577027 Text en Copyright © 2020 Gust, Ponce, Liles, Garden and Turtle http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Gust, Juliane
Ponce, Rafael
Liles, W. Conrad
Garden, Gwenn A.
Turtle, Cameron J.
Cytokines in CAR T Cell–Associated Neurotoxicity
title Cytokines in CAR T Cell–Associated Neurotoxicity
title_full Cytokines in CAR T Cell–Associated Neurotoxicity
title_fullStr Cytokines in CAR T Cell–Associated Neurotoxicity
title_full_unstemmed Cytokines in CAR T Cell–Associated Neurotoxicity
title_short Cytokines in CAR T Cell–Associated Neurotoxicity
title_sort cytokines in car t cell–associated neurotoxicity
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772425/
https://www.ncbi.nlm.nih.gov/pubmed/33391257
http://dx.doi.org/10.3389/fimmu.2020.577027
work_keys_str_mv AT gustjuliane cytokinesincartcellassociatedneurotoxicity
AT poncerafael cytokinesincartcellassociatedneurotoxicity
AT lileswconrad cytokinesincartcellassociatedneurotoxicity
AT gardengwenna cytokinesincartcellassociatedneurotoxicity
AT turtlecameronj cytokinesincartcellassociatedneurotoxicity