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

PLoS One. 2020 Apr 22;15(4):e0231896. doi: 10.1371/journal.pone.0231896. eCollection 2020.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytokines / antagonists & inhibitors*
  • Cytokines / biosynthesis
  • Cytokines / metabolism*
  • Humans
  • Inflammation / metabolism
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Prednisolone / pharmacology
  • Receptors, Chimeric Antigen / metabolism*
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*

Substances

  • Cytokines
  • Receptors, Chimeric Antigen
  • Prednisolone

Grants and funding

M.F., S.K., and A.T. received a research grant from Torii Pharmaceutical. K.S., S.O., Y.T., T.M., and Y.W. are employed by Torii Pharmaceutical. The funder provided support in the form of salaries for authors K.S., S.O., Y.T., T.M., and Y.W., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.