The novel multi-cytokine inhibitor TO-207 specifically inhibits pro-inflammatory cytokine secretion in monocytes without affecting the killing ability of CAR T cells

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.

Effects of cytokine blocking agents on hospital mortality in patients admitted to ICU with acute respiratory distress syndrome by SARS-CoV-2 infection: retrospective cohort study

“…ANA was used intravenously at the dose of 400 mg/die for 14 days or until the patient was weaned from mechanical ventilation or adverse events related to therapy occurred. The TOCI and ANA schedules were based on dosages indicated for the treatment of cytokine release syndrome [ 18 ] and macrophage activated syndrome [ 19 , 20 ]. The standard supportive management in ICU did not change during the study period.…”

CAR-T Cell Therapy: Mechanism, Management, and Mitigation of Inflammatory Toxicities

“…Modulation of post-transcriptional processes have been also studied as a potential strategy to reduce inflammatory cytokines during CAR-T cell therapy. JTE-607 (TO-207) is a CPSF3 inhibitor that blocks pre-mRNA processing into mature mRNA and has been shown to reduce the processing and secretion of cytokines from monocytes in vitro (82). This mRNA-processing inhibitor had minimal effects on the release of soluble factors from CAR-T cells, suggesting that it selectively inhibits cytokine production in monocytes (82).…”

“…JTE-607 (TO-207) is a CPSF3 inhibitor that blocks pre-mRNA processing into mature mRNA and has been shown to reduce the processing and secretion of cytokines from monocytes in vitro (82). This mRNA-processing inhibitor had minimal effects on the release of soluble factors from CAR-T cells, suggesting that it selectively inhibits cytokine production in monocytes (82). An early clinical study found that a single dose of JTE-607 appeared to be welltolerated and reduced the severity of endotoxin-induced inflammation in healthy individuals (83).…”

Making Potent CAR T Cells Using Genetic Engineering and Synergistic Agents

“…In the case of the folate receptor, we can eliminate folate receptor-overexpressing cancer cells with folic acid linked to fluorescein isothiocyanate (FITC) and anti-FITC CAR T cells [241,242]. TO-207, an mRNA 3 -end processing antagonist, blocks the side-effects of CAR T cells by inhibiting pro-inflammatory cytokine production in monocytes [243]. Dasatinib, a multi-kinase targeted inhibitor, was introduced as an efficient agent to control CAR T-cell activity [244,245].…”