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

被引:16
作者
Futami, Muneyoshi [1 ]
Suzuki, Keisuke [2 ]
Kato, Satomi [1 ]
Ohmae, Saori [2 ]
Tahara, Yoshio [2 ]
Nojima, Masanori [3 ]
Imai, Yoichi [4 ]
Mimura, Takayuki [2 ]
Watanabe, Yoshihiro [2 ,5 ]
Tojo, Arinobu [1 ]
机构
[1] Univ Tokyo, Adv Clin Res Ctr, Inst Med Sci, Div Mol Therapy, Tokyo, Japan
[2] Torii Pharmaceut, Res Labs, Sakura, Japan
[3] Univ Tokyo, Inst Med Sci Hosp, Ctr Translat Res, Tokyo, Japan
[4] Univ Tokyo, Inst Med Sci, Dept Hematol Oncol, Tokyo, Japan
[5] Kanazawa Univ, Innovat Clin Res Ctr, Kanazawa, Ishikawa, Japan
关键词
IMMATURE MYELOID CELLS; SUPPRESSOR-CELLS; JTE-607; THERAPY; DIFFERENTIATION; EXPRESSION; MANAGEMENT; ENDOTOXIN; INJURY; SHOCK;
D O I
10.1371/journal.pone.0231896
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
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页数:17
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