Dexamethasone Treats CAR T-Cell CRS Without Impairing Multiple Myeloma Efficacy
New research demonstrates that dexamethasone effectively ameliorates cytokine-release syndrome in CAR T-cell therapy for multiple myeloma while maintaining or enhancing anti-tumor activity and increasing CAR T-cell levels.
Corticosteroids can effectively treat cytokine-release syndrome (CRS) induced by chimeric antigen receptor (CAR) T-cell therapy without inhibiting treatment efficacy in multiple myeloma, according to research published in the Journal for ImmunoTherapy of Cancer. The study found that dexamethasone administration was associated with faster elimination of multiple myeloma burdens and higher levels of CAR T cells in treated mice.
CRS is a common toxicity of CAR T cells, often treated with corticosteroids such as dexamethasone. To model CRS after CAR T-cell treatment of multiple myeloma, three cell types are required: monocyte-lineage cells, CAR T cells, and multiple myeloma cells. Some cytokines important in CRS, including interleukin-6, are released mainly by monocyte-lineage cells.
Researchers developed a murine CRS model that included engraftment of THP-1 cells into NOD-scid common γ-chain-deficient mice to provide a source of cytokines associated with CRS, including IL-6 and monocyte chemoattractant protein-1. The model also included engraftment of the bioluminescent BCMA+ multiple myeloma cell line MM.1S-veff-Luc and an infusion of anti-B-cell maturation antigen (BCMA) CAR T cells. Addition of THP-1 cells to co-cultures of anti-BCMA CAR T cells and BCMA+ target cells led to increased levels of IL-6 and MCP-1 in culture supernatants.
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 multiple myeloma 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 versus 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 (NCT03602612), CAR+ cell levels continued to increase after initiation of corticosteroids in all patients. The results should encourage further clinical research to design corticosteroid regimens that optimize treatment of CAR T-cell toxicities while maintaining anti-malignancy activity.
Cardiovascular events occur in up to 20% of patients experiencing severe CRS. The hyperactivation of T cells leads to a surge in circulating cytokines, particularly interleukin-6, which exerts pleiotropic effects on endothelial cells, cardiac myocytes, and the coagulation system. Prompt recognition of CRS and initiation of targeted interventions such as IL-6 receptor antagonists (e.g., tocilizumab) and corticosteroids have revolutionized symptom control and improved cardiac outcomes.