Corticosteroids ameliorate CAR T-cell-induced cytokine-release syndrome without inhibiting multiple myeloma treatment.
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.
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.
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.
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.
NCT03602612.
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.
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.
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.
NCT03602612.
Authors
Amatya Amatya, Weissler Weissler, Lam Lam, Natrakul Natrakul, Brudno Brudno, Cutmore Cutmore, Mikkilineni Mikkilineni, Kochenderfer Kochenderfer
View on Pubmed