Targeting TGFβ-activated kinase-1 activation in microglia reduces CAR T immune effector cell-associated neurotoxicity syndrome.

in Nature cancer by Janaki Manoja Vinnakota, Francesca Biavasco, Marius Schwabenland, Chintan Chhatbar, Rachael C Adams, Daniel Erny, Sandra Duquesne, Nadia El Khawanky, Dominik Schmidt, Viktor Fetsch, Alexander Zähringer, Henrike Salié, Dimitrios Athanassopoulos, Lukas M Braun, Nora R Javorniczky, Jenny N H G Ho, Katrin Kierdorf, Reinhard Marks, Ralph Wäsch, Federico Simonetta, Geoffroy Andrieux, Dietmar Pfeifer, Gianni Monaco, Christian Capitini, Terry J Fry, Thomas Blank, Bruce R Blazar, Eva Wagner, Matthias Theobald, Clemens Sommer, Matthias Stelljes, Christian Reicherts, Astrid Jeibmann, Jens Schittenhelm, Camelia-Maria Monoranu, Andreas Rosenwald, Martin Kortüm, Leo Rasche, Hermann Einsele, Philipp T Meyer, Joachim Brumberg, Simon Völkl, Andreas Mackensen, Roland Coras, Michael von Bergwelt-Baildon, Nathalie L Albert, Laura M Bartos, Matthias Brendel, Adrien Holzgreve, Matthias Mack, Melanie Boerries, Crystal L Mackall, Justus Duyster, Philipp Henneke, Josef Priller, Natalie Köhler, Felix Strübing, Bertram Bengsch, Marco Ruella, Marion Subklewe, Louisa von Baumgarten, Saar Gill, Marco Prinz, Robert Zeiser

TLDR

  • The study found that microglia in the brain can get activated when cancer cells are killed by a type of treatment called CAR T cells. This can cause problems with thinking and memory. The study also found that a specific pathway in the brain called TAK1-NF-κB-p38 MAPK is involved in this problem. The study suggests that blocking this pathway could help prevent these problems from happening.

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 Cx3cr1:Tak1mice 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.

Overview

  • The study investigates the role of microglia in immune effector cell-associated neurotoxicity syndrome (ICANS) caused by cancer immunotherapy with chimeric antigen receptor (CAR) T cells. The study uses mouse models and cohorts of individuals with ICANS to examine the molecular mechanisms leading to ICANS. The primary objective of the study is to identify the TAK1-NF-κB-p38 MAPK pathway as a pathogenic signaling pathway in ICANS pathophysiology and to provide a rationale for testing TAK1 inhibition in a clinical trial for ICANS prevention after CAR19 T cell-based cancer immunotherapy.

Comparative Analysis & Findings

  • The study found that CD19-directed CAR (CAR19) T cell transfer in B cell lymphoma-bearing mice caused microglia activation and neurocognitive deficits. Pharmacological TAK1 inhibition or genetic Tak1 deletion in microglia using Cx3cr1:Tak1mice resulted in reduced microglia activation and improved neurocognitive activity. The TAK1-NF-κB-p38 MAPK pathway was activated in microglia after CAR19 T cell transfer. 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.

Implications and Future Directions

  • The study's findings suggest that microglia play a crucial role in ICANS pathophysiology and that the TAK1-NF-κB-p38 MAPK pathway is a pathogenic signaling pathway. The study provides a rationale for testing TAK1 inhibition in a clinical trial for ICANS prevention after CAR19 T cell-based cancer immunotherapy. Future research could further explore the role of microglia in ICANS and investigate other signaling pathways involved in ICANS pathophysiology.
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