Abstract
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.
Original language | English (US) |
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Pages (from-to) | 1423-1434 |
Number of pages | 12 |
Journal | Molecular Therapy |
Volume | 26 |
Issue number | 6 |
DOIs | |
State | Published - Jun 6 2018 |
Bibliographical note
Publisher Copyright:© 2018 The American Society of Gene and Cell Therapy
Keywords
- B cell aplasia
- CAR T cell
- CD19
- cytokine release syndrome
- mouse model
- neurologic adverse events
- toxicity