Targeting Indoleamine 2,3-Dioxygenase in Cancer Models Using the Novel Small Molecule Inhibitor NTRC 3883-0

Abstract

Indoleamine 2,3-dioxygenase (IDO1) is a key regulator of immune suppression by catalyzing the oxidation of L-tryptophan. IDO1 expression has been related to poor prognosis in several cancers and to resistance to checkpoint immunotherapies. We describe the characterization of a novel small molecule IDO1 inhibitor, NTRC 3883-0, in a panel of biochemical and cell-based assays, and various cancer models. NTRC 3883-0 released the inhibitory effect of IDO1 on CD8-positive T cell proliferation in co-cultures of IDO1-overexpressing cells with healthy donor lymphocytes, demonstrating its immune modulatory activity. In a syngeneic mouse model using IDO1-overexpressing B16F10 melanoma cells, NTRC 3883-0 effectively counteracted the IDO1-induced modulation of L-tryptophan and L-kynurenine levels, demonstrating its in vivo target modulation. Finally, we studied the expression and activity of IDO1 in primary cell cultures established from the malignant ascites of ovarian cancer patients. In these cultures, IDO1 expression was induced upon stimulation with IFNγ, and its activity could be inhibited by NTRC 3883-0. Based on these results, we propose the use of ascites cell-based functional assays for future patient stratification. Our results are discussed in light of the recent discontinuation of clinical trials of more advanced IDO1 inhibitors and the reconsideration of IDO1 as a valid drug target.

Plasmacytoid Dendritic Cells, a Novel Target in Myeloid Neoplasms

“…Targeting those immune checkpoint molecules is a common anti-tumor strategy currently used in cancers. Other strategies are also proposed as TNF superfamily modulation [ 92 ], vaccination and adoptive DC transfer therapy [ 93 , 94 ], and IDO1 blockade [ 82 , 83 ] with or without immune checkpoint molecule inhibitors association [ 95 , 96 , 97 ]. Finally, targeting CD8 + regulatory T-cells has also been proposed [ 98 ].…”

CD34 + progenitor-derived NK cell and gemcitabine combination therapy increases killing of ovarian cancer cells in NOD/SCID/IL2Rg null mice

“…SKOV-3 and K562 were purchased from the ATCC, and IGROV-1 and OVCAR-3 were kindly provided by Prof. Dr. OC Boerman, Department of Nuclear Medicine, Radboud University Medical Center, Nijmegen, the Netherlands. Primary patient-derived OC cell line ASC 009 was generated from ascites material obtained from the Gynecologic Oncology Biobank of the Radboud University Medical Center by NTRC in Oss, the Netherlands as described, 17 and kindly provided by Guido Zaman. This study was approved by the Radboudumc Committee for Medical Research Ethics (CMO 2018/4845), and written informed consent was obtained.…”

Kynurenines as a Novel Target for the Treatment of Malignancies

“…Preclinical research showed that the combination of melatonin and 1-MT has a synergistic effect combined with tumor-specific immunotherapy and seems to be a new and promising method of growth control of HPV-associated tumors [ 93 ]. Also, novel IDO inhibitors, LW106 and NTRC 3883-0 inhibit tumor outgrowth in-vivo, limiting IDO-dependent stroma immune resistance and proliferation of cancer stem cells within the tumor microenvironment ( Table 1 ) [ 94 , 95 ].…”

“…Its administration inhibits tumor growth in a B16-F10 melanoma mouse model [ 153 ]. Likewise, LW-106 demonstrated a potent antitumor activity based on a similar mechanism in the IDO-overexpressing melanoma mouse model, while NTRC 3883-0 in ovarian cancer cell culture and melanoma mouse model ( Table 1 ) [ 94 , 95 ].…”