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.
Bibliographical noteFunding Information:
The authors acknowledge the kind gifts of TG-1 mice from Dr. Thomas Tedder (Duke University) and pCL Eco DNA from Dr. Inder Verma (Salk Institute for Biological Studies) and appreciate the technical assistance provided by Anthony DeFranco, Amber McElroy, Drs. Ryan Flynn and Patricia Taylor, and the staffs of the University of Minnesota Genomics Core and University Flow Cytometry Resource. The study was supported by gifts from the Minnesota Masonic Charities and the Atwater family to the Masonic Cancer Center and grants from the Randy Shaver Cancer Research and Community Fund and the National Cancer Institute of the NIH under award numbers R01 CA72669 and 2P01 CA 065493 .
© 2018 The American Society of Gene and Cell Therapy
- B cell aplasia
- CAR T cell
- cytokine release syndrome
- mouse model
- neurologic adverse events