• Christopher A Pennell, Jessie L Barnum, Cameron S McDonald-Hyman, Angela Panoskaltsis-Mortari, Megan J Riddle, Zhengming Xiong, Michael Loschi, Govindarajan Thangavelu, Heather M Campbell, Meghan D Storlie, Yosef Refaeli, Scott N Furlan, Michael C Jensen, Leslie S Kean, Jeffrey S Miller, Jakub Tolar, Mark J Osborn, and Bruce R Blazar.
• Department of Laboratory Medicine and Pathology, Masonic Cancer Center, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: penne001@umn.edu.
• Mol. Ther. 2018 Jun 6; 26 (6): 1423-1434.

AbstractThe clinical success of chimeric antigen receptor (CAR) T cell therapy for CD19+ B cell malignancies can be limited by acute toxicities and immunoglobulin replacement needs due to B cell aplasia from persistent CAR T cells. Life-threatening complications include cytokine release syndrome and neurologic adverse events, the exact etiologies of which are unclear. To elucidate the underlying toxicity mechanisms and test potentially safer CAR T cells, we developed a mouse model in which human CD19 (hCD19)-specific mouse CAR T cells were adoptively transferred into mice whose normal B cells express a hCD19 transgene at hemizygous levels. Compared to homozygous hCD19 transgenic mice that have ∼75% fewer circulating B cells, hemizygous mice had hCD19 frequencies and antigen density more closely simulating human B cells. Hemizygous mice given a lethal dose of hCD19 transgene-expressing lymphoma cells and treated with CAR T cells had undetectable tumor levels. Recipients experienced B cell aplasia and antigen- and dose-dependent acute toxicities mirroring patient complications. Interleukin-6 (IL-6), interferon γ (IFN-γ), and inflammatory pathway transcripts were enriched in affected tissues. As in patients, antibody-mediated neutralization of IL-6 (and IFN-γ) blunted toxicity. Apparent behavioral abnormalities associated with decreased microglial cells point to CAR-T-cell-induced neurotoxicity. This model will prove useful in testing strategies designed to improve hCD19-specific CAR T cell safety.Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

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