Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells

M Norelli, B Camisa, G Barbiera, L Falcone, A Purevdorj, M Genua, F Sanvito, M Ponzoni, C Doglioni, P Cristofori, C Traversari, C Bordignon, F Ciceri, R Ostuni, C Bonini, M Casucci, A Bondanza

Research output: Contribution to journalArticle

Abstract

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. © 2018 The Author(s).
Original languageEnglish
Pages (from-to)739-748
Number of pages10
JournalNature Medicine
Volume24
Issue number6
DOIs
Publication statusPublished - 2018

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