Therapeutic Targeting Of Monokine Production Is A Promising Strategy To Attenuate Cytokine-Release Syndrome In Car-T Cell Therapy

Cancer immunotherapy using chimeric antigen receptor-armed T cells (CAR-T cells) have shown excellent outcomes in hematological malignancies. However, cytokine release syndrome (CRS), characterized by excessive activation of CAR-T cells and macrophages remains to be overcome. Steroid administration usually resolves signs and symptoms of CRS but abrogates CAR-T cell expansion and persistence. Tocilizumab, a humanized monoclonal antibody against interleukin-6 receptor (IL-6R), attenuates CRS without significant loss of CAR-T cell activities, while perfect rescue of CRS symptoms cannot be achieved by IL-6/IL-6R blockade. There is actual need for novel strategies to prevent or cure CRS. TO-207, an N-benzoyl-L-phenylalanine derivative compound, significantly inhibits inflammatory cytokine production in a human monocyte/macrophage-specific manner. Here we tested TO-207 for its ability to inhibit cytokine production without impaired CAR-T cell function in a CRS-simulating co-culture system consisting of CAR-T cells, target leukemic cells and monocytes.