Abstract 1787: YH29407, a novel IDO1 inhibitor, enhances the anti-tumor effects through increased tumor-reactive T cell functions in solid tumor

Abstract

Abstract Background: The indoleamine 2,3-dioxygenase (IDO), is an enzyme responsible for catabolizing tryptophan (Trp) to kynurenine (Kyn). The depletion of tryptophan and the increase in kynurenine exert important immunosuppressive functions by activating T regulatory cells and myeloid-derived suppressor cells. Therefore, overexpression of IDO is associated with poor clinical outcome. In this study, we evaluated pharmacokinetic and pharmacodynamic profiles and anti-cancer immune responses of YH29407, a novel IDO1 inhibitor. Methods: MC38 murine tumor models were established for pharmacokinetic and pharmacodynamic profiling. The kynurenine levels in plasma and tumor of YH29407, epacadostat and BMS-986205 following 3 day treatment were detected. The antitumor effects of YH29407 100 mg/kg QD/BID, epacadostat 100 mg/kg BID and BMS-986205 100 mg/kg QD for 10 day administration were evaluated in MC38 models. Various immunologic profiles were evaluated after 5 day treatment of individual inhibitors. Results: The AUC of kynurenine in plasma was decreased by 81.4% with YH29407 100 mg/kg BID, 62.7% with epacadostat 100 mg/kg BID, and 19.8% with BMS-986205 100 mg/kg QD treatment, respectively, compared to control group. The intratumoral concentration of kynurenine was also reduced by 99.4%, 89.9% and 1.1% with 3 day treatment of YH29407 100 mg/kg BID, epacadostat 100 mg/kg BID, and BMS-986205 100 mg/kg QD treatment, respectively, compared to control group. The intratumoral concentration of YH29407 BID, epacadostat BID and BMS-986205 QD at 24 hours after 3 day treatment was 9.697 µg/g, 5.478 µg/g and 0.025 µg/g, respectively. These results indicate favorable pharmacokinetic property of YH29407. Compared to epacadostat and BMS-986205, YH29407 100 mg/kg BID treatment exhibited significant proliferative response of splenocytes (P <0.05). IFN-γ secretion levels were also significantly increased by YH29407 treatment, compared to epacadostat and BMS-986205 treatment (P <0.05). Profiling of serum cytokine levels revealed significant increase of Granzyme B, IFN-γ, IL-12, and MMP2 and decrease of FASL, compared to the vehicle group. Upregulation of IFN-γ in CD3+ tumor-infiltrating lymphocytes was significantly induced in the YH29407 treated group compared to epacadostat and BMS-986205 treated groups (P <0.05). Treatment with YH29407 100 mg/kg BID induced significant tumor growth inhibition, compared to epacadostat 100 mg/kg BID and BMS-986205 100 mg/kg QD. Conclusion: The novel IDO1 inhibitor, YH29407, with improved pharmacokinetic and pharmacodynamic profiles, showed antitumor inflammatory reprogramming leading to enhanced antitumor efficacy. Citation Format: Kyoung-Ho Pyo, Ho-Woong Kang, Sun Min Lim, Do Hee Kim, Dong Kwon Kim, Gyu-Jin Lee, Jong-Suk Park, Se-Woong Oh, Byoung Chul Cho. YH29407, a novel IDO1 inhibitor, enhances the anti-tumor effects through increased tumor-reactive T cell functions in solid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1787.