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. 2018 Jun;24(6):739-748.
doi: 10.1038/s41591-018-0036-4. Epub 2018 May 28.

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

Margherita Norelli  1   2 , Barbara Camisa  1 , Giulia Barbiera  3 , Laura Falcone  1 , Ayurzana Purevdorj  1 , Marco Genua  3 , Francesca Sanvito  4 , Maurilio Ponzoni  4 , Claudio Doglioni  4 , Patrizia Cristofori  5 , Catia Traversari  6 , Claudio Bordignon  2   6 , Fabio Ciceri  2   7 , Renato Ostuni  3 , Chiara Bonini  2   8 , Monica Casucci  1 , Attilio Bondanza  9   10
Affiliations

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

Margherita Norelli et al. Nat Med. 2018 Jun.

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.

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Comment in

  • Modeling cytokine release syndrome.
    Rooney C, Sauer T. Rooney C, et al. Nat Med. 2018 Jun;24(6):705-706. doi: 10.1038/s41591-018-0068-9. Nat Med. 2018. PMID: 29808004 No abstract available.
  • Calming the cytokine storm.
    Bird L. Bird L. Nat Rev Immunol. 2018 Jul;18(7):417. doi: 10.1038/s41577-018-0030-6. Nat Rev Immunol. 2018. PMID: 29899366 No abstract available.

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