Abstract LB-085: RG70099: A novel, highly potent dual IDO1TDO inhibitor to reverse metabolic suppression of immune cells in the tumor micro-environment

• Published in: Cancer research (Chicago, Ill.) Vol. 76; no. 14_Supplement; pp. LB - 085-LB-085
• Main Authors: Gyulveszi, Gabor, Fischer, Christine, Mirolo, Massimiliano, Stern, Martin, Green, Luke, Ceppi, Maurizio, Wang, Haiyan, Brgi, Beatrice, Staempfli, Andreas, Muster, Wolfgang, van Waterschoot, Robert, Gloge, Andreas, Sade, Hadassah, Klaman, Irina, Hoelzlvimmer, Gabriele, Surya, Arjun, Banerjee, Monali, Shrivastava, Ritesh, Middya, Sandip, Yadav, Dharmendra, Basu, Sourav, Acuna, Gonzalo
• Format: Journal Article
• Language: English
• Published: 15.07.2016
• DOI: 10.1158/1538-7445.AM2016-LB-085
• ISSN: 0008-5472

IDO1TDO mediate substantial immunosuppressive effects through the metabolism of tryptophan (Trp) to kynurenine (Kyn). The consequent decrease in Trp suppresses T cell activity by multiple mechanisms, including the activation of GCN2 and mTOR pathways. Additionally, increased levels of Kyn further enhance the effect of Trp metabolism by engagement of aryl hydrocarbon receptor and potentially enhancing the number and activity of regulatory T cells. Taken together, expression of IDO1 and TDO in the tumor micro-environment dampens tumor-specific effector T cell response, and elevated expression of IDO1TDO correlates with reduced survival of cancer patients. IDO1 selective inhibitors have already demonstrated clinical anti-tumor activity for certain tumor types. Therefore, targeting the TrpKyn pathway via simultaneous inhibition of IDO1 and TDO enzymes has the potential to bring enhanced benefit to cancer patients by relieving immunosuppression in a wide variety of tumor types.