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Nat Med. 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.

Author information

1
Innovative Immunotherapies Unit, San Raffaele Hospital Scientific Institute, Milano, Italy.
2
Vita-Salute San Raffaele University, Milano, Italy.
3
Genomics of the Innate Immune System Unit, San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget), Milano, Italy.
4
Pathology Unit, San Raffaele Hospital Scientific Institute, Milano, Italy.
5
San-Raffaele-Telethon Institute for Gene Therapy (SR-Tiget), Milano, Italy.
6
Molmed Spa, Milano, Italy.
7
Hematology and Bone Marrow Transplantation Unit, San Raffaele Hospital Scientific Institute, Milano, Italy.
8
Experimental Hematology Unit, San Raffaele Hospital Scientific Institute, Milano, Italy.
9
Innovative Immunotherapies Unit, San Raffaele Hospital Scientific Institute, Milano, Italy. attilio.bondanza@gmail.com.
10
Vita-Salute San Raffaele University, Milano, Italy. attilio.bondanza@gmail.com.

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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PMID:
29808007
DOI:
10.1038/s41591-018-0036-4
[Indexed for MEDLINE]

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