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Published on: August 15, 2012
Targeting TGFβ-activated kinase-1 activation in microglia reduces CAR T immune effector cell-associated neurotoxicity
Janaki Manoja Vinnakota1,2, Francesca Biavasco1, Marius Schwabenland3
1Department of Medicine I, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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.
Insights
Microglia activation drives neurotoxicity in cancer immunotherapy. Targeting the TAK1-NF-κB-p38 MAPK pathway in microglia may prevent immune effector cell-associated neurotoxicity syndrome (ICANS) after CAR T cell therapy.
Area of Science:
- Immunology
- Neuroscience
- Oncology
Background:
- Cancer immunotherapy using chimeric antigen receptor (CAR) T cells can lead to immune effector cell-associated neurotoxicity syndrome (ICANS).
- The precise molecular mechanisms underlying ICANS remain incompletely understood.
Purpose of the Study:
- To investigate the role of microglia in the development of ICANS.
- To identify key molecular pathways involved in CAR T cell-induced neurotoxicity.
Main Methods:
- Utilized mouse models of B cell lymphoma treated with CD19-directed CAR (CAR19) T cells.
- Examined microglia activation and neurocognitive function in mice and in human cohorts with ICANS.
- Investigated the TGFβ-activated kinase-1 (TAK1)-NF-κB-p38 MAPK signaling pathway.
Main Results:
- CAR19 T cell transfer induced microglia activation and neurocognitive deficits in mice.
- Pharmacological TAK1 inhibition or genetic deletion in microglia reduced activation and improved neurocognitive activity.
- Human ICANS patients showed evidence of in vivo microglia activation.
Conclusions:
- Microglia play a critical role in the pathophysiology of ICANS.
- The TAK1-NF-κB-p38 MAPK pathway is identified as a key pathogenic signaling axis in ICANS.
- TAK1 inhibition presents a potential therapeutic strategy for preventing ICANS following CAR T cell immunotherapy.
