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Cancer Discov. 2018 Jun;8(6):750-763. doi: 10.1158/2159-8290.CD-17-1368. Epub 2018 Mar 21.

Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates.

Author information

1
The Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington.
2
The Fred Hutchinson Cancer Research Center, Seattle, Washington.
3
Department of Pediatrics, University of Washington, Seattle, Washington.
4
Juno Therapeutics, Seattle, Washington.
5
Deparment of Comparative Medicine, University of Washington, Seattle, Washington.
6
Department of Pathology, University of Washington, Seattle, Washington.
7
Washington National Primate Research Center, University of Washington, Seattle, Washington.
8
Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
9
The Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington. michael.jensen@seattlechildrens.org Leslie.kean@seattlechildrens.org.

Abstract

Chimeric antigen receptor (CAR) T-cell immunotherapy has revolutionized the treatment of refractory leukemias and lymphomas, but is associated with significant toxicities, namely cytokine release syndrome (CRS) and neurotoxicity. A major barrier to developing therapeutics to prevent CAR T cell-mediated neurotoxicity is the lack of clinically relevant models. Accordingly, we developed a rhesus macaque (RM) model of neurotoxicity via adoptive transfer of autologous CD20-specific CAR T cells. Following cyclophosphamide lymphodepletion, CD20 CAR T cells expand to 272 to 4,450 cells/μL after 7 to 8 days and elicit CRS and neurotoxicity. Toxicities are associated with elevated serum IL6, IL8, IL1RA, MIG, and I-TAC levels, and disproportionately high cerebrospinal fluid (CSF) IL6, IL2, GM-CSF, and VEGF levels. During neurotoxicity, both CD20 CAR and non-CAR T cells accumulate in the CSF and in the brain parenchyma. This RM model demonstrates that CAR T cell-mediated neurotoxicity is associated with proinflammatory CSF cytokines and a pan-T cell encephalitis.Significance: We provide the first immunologically relevant, nonhuman primate model of B cell-directed CAR T-cell therapy-mediated CRS and neurotoxicity. We demonstrate CAR and non-CAR T-cell infiltration in the CSF and in the brain during neurotoxicity resulting in pan-encephalitis, accompanied by increased levels of proinflammatory cytokines in the CSF. Cancer Discov; 8(6); 750-63. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 663.

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