• Mcdonald-Hyman, Cameron S.
• Xiong, Zhengming
• Pennell, Christopher A.
• Barnum, Jessie L.
• Jensen, Michael C.
• Miller, Jeffrey S.
• Kean, Leslie S.
• Refaeli, Yosef
• Osborn, Mark
• Blazar, Bruce R.
• Furlan, Scott N.
• Panoskaltsis-Mortari, Angela
• Loschi, Michael
• Thangavelu, Govindarajan
• Campbell, Heather M.
• Riddle, Megan J.
• Storlie, Meghan D.

Abstract

<p>The 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. Pennell et al. describe a human CD19 transgenic mouse model that mirrors the tumor efficacy and morbidities associated with CAR T cell therapy for human B cell malignancies. This model should allow approaches designed to reduce toxicity while preserving anti-tumor effects to be explored prior to testing in the clinic.</p>

Topics

• density
• toxicity