Abstract
Cancer immunotherapy using chimeric antigen receptor–armed T (CAR T) cells have been shown to improve outcomes significantly in patients with hematological malignancies. However, cytokine release syndrome (CRS) remains a risk. CRS is characterized by the excessive activation of CAR T cells and macrophages. Signs and symptoms of CRS are usually resolved after steroid administration, but steroids abrogate the expansion and persistence of CAR T cell populations. Tocilizumab is a humanized monoclonal antibody (mAb) that attenuates CRS without significant loss of CAR T cell activity. However, interleukin-6 (IL-6)/IL-6 receptor (IL-6R) blockade alone cannot relieve CRS symptoms fully, and novel treatments are needed to prevent or cure CRS. TO-207 is an N-benzoyl-L-phenylalanine derivative that significantly inhibits inflammatory cytokine production in human monocyte and macrophage-specific manner. We investigated whether TO-207 could inhibit cytokine production without impairing CAR T cell function in a CRS-simulating co-culture system.
Highlights
Treatment with chimeric antigen receptor (CAR)-T cells has emerged as a promising therapeutic approach for cancer therapy
A clear dose-dependent cytotoxic effect of 19-28z chimeric antigen receptor–armed T (CAR T) cells was validated by a 72h co-culture, in which target cells (NALM-6, K562/CD19) and CAR T cells were mixed at the effector to target ratio (E/T) of 0~10 (Fig 1D)
Teachey et al [9] compared cytokine profiles in patients who underwent CD19 CAR T therapy, and reported higher levels of IFN-γ, IL-6, IL-8, sIL2Rα, sgp130, soluble IL-6 receptor (sIL-6R), monocyte chemotactic protein-1 (MCP-1), MIP-1α, MIP-1β, and granulocyte macrophage-colony stimulating factor (GM-CSF) were associated with grade 4–5 cytokine release syndrome (CRS)
Summary
Treatment with chimeric antigen receptor (CAR)-T cells has emerged as a promising therapeutic approach for cancer therapy. Binding of CARs to cognate antigens expressed on the surface of tumor cells induces T cell activation and subsequent release of various cytokines, including interleukin-2 (IL-2), interferon-γ (IFN-γ), IL-6, and granulocyte macrophage-colony stimulating factor (GM-CSF). The cytokine profile of patients undergoing CD19 CAR T-cell therapy has been associated with the severity of CRS; higher levels of IFN-γ, IL-6, IL-8, sIL-2Rα, sgp130, sIL-6R, MCP-1, MIP-1α, MIP-1β, and GM-CSF have been reported in patients with grade 4–5 CRS [9]. We developed an in vitro co-culture model that accurately recapitulates CAR T-related CRS, in which activated CAR T cells released IFN-γ, activating monocytes and cytokine release such as TNF-α, MIP-1α, M-CSF, IL-6, MCP-1, IL-1β, and IL-8. Since the cytotoxicity is largely dependent on CAR T cells, selective inhibition of monocyte-derived cytokines by TO-207 would be an ideal treatment for CAR T–related CRS
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