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Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells
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Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells
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Journal Article
Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells
2018
Overview
In the clinic, chimeric antigen receptor–modified T (CAR T) cell therapy is frequently associated with life-threatening cytokine-release syndrome (CRS) and neurotoxicity. Understanding the nature of these pathologies and developing treatments for them are hampered by the lack of appropriate animal models. Herein, we describe a mouse model recapitulating key features of CRS and neurotoxicity. In humanized mice with high leukemia burden, CAR T cell–mediated clearance of cancer triggered high fever and elevated IL-6 levels, which are hallmarks of CRS. Human monocytes were the major source of IL-1 and IL-6 during CRS. Accordingly, the syndrome was prevented by monocyte depletion or by blocking IL-6 receptor with tocilizumab. Nonetheless, tocilizumab failed to protect mice from delayed lethal neurotoxicity, characterized by meningeal inflammation. Instead, the IL-1 receptor antagonist anakinra abolished both CRS and neurotoxicity, resulting in substantially extended leukemia-free survival. These findings offer a therapeutic strategy to tackle neurotoxicity and open new avenues to safer CAR T cell therapies.
IL-1 blockade prevents cytokine-release syndrome and neurotoxicity by CAR T cells.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Animals
/ Antibodies, Monoclonal, Humanized - pharmacology
/ Antibodies, Monoclonal, Humanized - therapeutic use
/ Antigens
/ B cells
/ Biomedical and Life Sciences
/ Cancer
/ Fever
/ Hematopoietic Stem Cells - metabolism
/ Humans
/ Immunotherapy, Adoptive - adverse effects
/ Interleukin 1 receptor antagonist
/ Interleukin 1 Receptor Antagonist Protein - pharmacology
/ Interleukin 1 Receptor Antagonist Protein - therapeutic use
/ Leukemia
/ Mice
/ Receptors, Chimeric Antigen - metabolism
/ Syndrome
/ T cells
