Vinnakota, Janaki Manoja and Biavasco, Francesca and Schwabenland, Marius and Chhatbar, Chintan and Adams, Rachael and Erny, Daniel and Duquesne, Sandra and El Khawanky, Nadia and Schmidt, Dominik and Fetsch, Viktor and Zaehringer, Alexander and Salie, Henrike and Athanassopoulos, Dimitrios and Braun, Lukas and Javorniczky, Nora and Ho, Jenny and Kierdorf, Katrin and Marks, Reinhard and Waesch, Ralph and Simonetta, Federico and Andrieux, Geoffroy and Pfeifer, Dietmar and Monaco, Gianni and Capitini, Christian and Fry, Terry and Blank, Thomas and Blazar, Bruce and Wagner, Eva and Theobald, Matthias and Sommer, Clemens and Stelljes, Matthias and Reicherts, Christian and Jeibmann, Astrid and Schittenhelm, Jens and Monoranu, Camelia-Maria and Rosenwald, Andreas and Kortuem, Martin and Rasche, Leo and Einsele, Hermann and Meyer, Philipp and Brumberg, Joachim and Voelkl, Simon and Mackensen, Andreas and Coras, Roland and von Bergwelt-Baildon, Michael and Albert, Nathalie and Bartos, Laura and Brendel, Matthias and Holzgreve, Adrien and Mack, Matthias and Boerries, Melanie and Mackall, Crystal and Duyster, Justus and Henneke, Philipp and Priller, Josef and Koehler, Natalie and Struebing, Felix and Bengsch, Bertram and Ruella, Marco and Subklewe, Marion and von Baumgarten, Louisa and Gill, Saar and Prinz, Marco and Zeiser, Robert (2024) Targeting TGFβ-activated kinase-1 activation in microglia reduces CAR T immune effector cell-associated neurotoxicity syndrome. NATURE CANCER, 5 (8). ISSN , 2662-1347
Full text not available from this repository. (Request a copy)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 TGF beta-activated kinase-1 (TAK1)-NF-kappa B-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-kappa B-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. Zeiser and colleagues show that CAR T cell therapy results in upregulation of the TGF beta-activated kinase-1 (TAK1)-NF-kappa B-p38 MAPK pathway in microglia, causing neurocognitive defects, and find that TAK1 inhibition can reduce immune effector cell-associated neurotoxicity syndrome.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CHIMERIC ANTIGEN RECEPTOR; PERIPHERAL BENZODIAZEPINE-RECEPTORS; CYTOKINE RELEASE SYNDROME; VERSUS-HOST-DISEASE; TRANSLOCATOR PROTEIN; HUMAN BRAIN; TAK1; ALPHA; CD19; EXPRESSION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Abteilung für Nephrologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 Jul 2025 09:19 |
| Last Modified: | 24 Jul 2025 09:19 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65732 |
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