Corticosteroids ameliorate CAR T-cell-induced cytokine-release syndrome without inhibiting multiple myeloma treatment.

BACKGROUND

Cytokine-release syndrome (CRS) is a common toxicity of chimeric antigen receptor (CAR) T cells. CRS is often treated with corticosteroids such as dexamethasone. Dexamethasone is also used to treat multiple myeloma. To model CRS after CAR T-cell treatment of multiple myeloma (MM), three cell types are required: monocyte-lineage cells, CAR T cells, and MM cells. Some cytokines important in CRS, including interleukin (IL)-6, are released mainly by monocyte-lineage cells.

METHODS

We added cells of an acute monocytic leukemia cell line (THP-1) to co-cultures of anti-B-cell maturation antigen (BCMA) CAR T cells (CAR-BCMA) and BCMA+ target cells. Addition of THP-1 cells to the co-cultures led to increased levels of IL-6 and monocyte chemoattractant protein-1 (MCP-1) in culture supernatants. We developed a murine CRS model. This model included engraftment of THP-1 into NOD-scid common γ-chain-deficient mice to provide a source of some cytokines associated with CRS, including IL-6 and MCP-1. The murine model also included engraftment of the bioluminescent BCMA+ MM cell line MM.1S-veff-Luc and an infusion of CAR-BCMA. We treated CRS with dexamethasone or vehicle control.

RESULTS

With this model, mice exhibited signs of CRS and had elevated serum cytokine levels after CAR T-cell infusion, and CAR-BCMA eliminated large burdens of MM.1S-veff-Luc. Dexamethasone administered 1, 3, and 5 days after CAR-BCMA ameliorated CRS. Dexamethasone was associated with faster elimination of MM burdens when either a dexamethasone-sensitive cell line (MM.1S-veff-Luc) or a dexamethasone-resistant cell line (MM.1R-veff-Luc) was used as the malignancy burden. Importantly, mice that received CAR-BCMA plus dexamethasone had higher levels of splenic CAR T cells when compared with mice that received CAR-BCMA without dexamethasone. When MM.1S-veff-Luc was treated, the median splenic CD3+CAR+ cell count for mice that received CAR-BCMA plus dexamethasone was 764 473 vs 327 888 for mice that received CAR-BCMA without dexamethasone (p=0.0021).Among four patients who received anti-BCMA CAR T cells and corticosteroids on a clinical trial, CAR+ cell levels continued to increase after initiation of corticosteroids in all patients.

CONCLUSIONS

In summary, our results should encourage further clinical research to design corticosteroid regimens that optimize treatment of CAR T-cell toxicities while maintaining anti-malignancy activity.

TRIAL REGISTRATION NUMBER: NCT03602612.