Journal Article

DZNE-2024-01086

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Targeting TGFβ-activated kinase-1 activation in microglia reduces CAR T immune effector cell-associated neurotoxicity syndrome.

Vinnakota, J. M. ; Biavasco, F. ; Schwabenland, M. ; Chhatbar, C. ; Adams, R. C. ; Erny, D. ; Duquesne, S. ; El Khawanky, N. ; Schmidt, D. ; Fetsch, V. ; Zähringer, A. ; Salié, H. ; Athanassopoulos, D. ; Braun, L. M. ; Javorniczky, N. R. ; Ho, J. N. H. G. ; Kierdorf, K. ; Marks, R. ; Wäsch, R. ; Simonetta, F. ; Andrieux, G. ; Pfeifer, D. ; Monaco, G. ; Capitini, C. ; Fry, T. J. ; Blank, T. ; Blazar, B. R. ; Wagner, E. ; Theobald, M. ; Sommer, C. ; Stelljes, M. ; Reicherts, C. ; Jeibmann, A. ; Schittenhelm, J. ; Monoranu, C.-M. ; Rosenwald, A. ; Kortüm, M. ; Rasche, L. ; Einsele, H. ; Meyer, P. T. ; Brumberg, J. ; Völkl, S. ; Mackensen, A. ; Coras, R. ; von Bergwelt-Baildon, M. ; Albert, N. L. ; Bartos, L. M. ; Brendel, M.DZNE* ; Holzgreve, A. ; Mack, M. ; Boerries, M. ; Mackall, C. L. ; Duyster, J. ; Henneke, P. ; Priller, J.Extern* ; Köhler, N. ; Strübing, F.Extern* ; Bengsch, B. ; Ruella, M. ; Subklewe, M. ; von Baumgarten, L. ; Gill, S. ; Prinz, M. ; Zeiser, R.

2024
Nature Research London

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Please use a persistent id in citations: doi:10.1038/s43018-024-00764-7

Abstract: Cancer immunotherapy with chimeric antigen receptor (CAR) T cells can cause immune effector cell-associated neurotoxicity syndrome (ICANS). However, the molecular mechanisms leading to ICANS are not well understood. Here we examined the role of microglia using mouse models and cohorts of individuals with ICANS. CD19-directed CAR (CAR19) T cell transfer in B cell lymphoma-bearing mice caused microglia activation and neurocognitive deficits. The TGFβ-activated kinase-1 (TAK1)-NF-κB-p38 MAPK pathway was activated in microglia after CAR19 T cell transfer. Pharmacological TAK1 inhibition or genetic Tak1 deletion in microglia using Cx3cr1CreER:Tak1fl/fl mice resulted in reduced microglia activation and improved neurocognitive activity. TAK1 inhibition allowed for potent CAR19-induced antilymphoma effects. Individuals with ICANS exhibited microglia activation in vivo when studied by translocator protein positron emission tomography, and imaging mass cytometry revealed a shift from resting to activated microglia. In summary, we prove a role for microglia in ICANS pathophysiology, identify the TAK1-NF-κB-p38 MAPK axis as a pathogenic signaling pathway and provide a rationale to test TAK1 inhibition in a clinical trial for ICANS prevention after CAR19 T cell-based cancer immunotherapy.

Keyword(s): Animals (MeSH) ; Mice (MeSH) ; MAP Kinase Kinase Kinases: metabolism (MeSH) ; MAP Kinase Kinase Kinases: genetics (MeSH) ; Microglia: immunology (MeSH) ; Microglia: metabolism (MeSH) ; Neurotoxicity Syndromes: etiology (MeSH) ; Neurotoxicity Syndromes: immunology (MeSH) ; Humans (MeSH) ; Receptors, Chimeric Antigen: immunology (MeSH) ; Immunotherapy, Adoptive: methods (MeSH) ; p38 Mitogen-Activated Protein Kinases: metabolism (MeSH) ; NF-kappa B: metabolism (MeSH) ; Lymphoma, B-Cell: immunology (MeSH) ; Antigens, CD19: immunology (MeSH) ; Female (MeSH) ; T-Lymphocytes: immunology (MeSH) ; Signal Transduction (MeSH) ; MAP kinase kinase kinase 7 ; MAP Kinase Kinase Kinases ; Receptors, Chimeric Antigen ; p38 Mitogen-Activated Protein Kinases ; NF-kappa B ; Antigens, CD19 ; cell-associated neurotoxicity

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Contributing Institute(s):

1. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DEAL Nature ; Essential Science Indicators ; IF >= 20 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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