Abstract 5481: Combination therapy with anti-PD-1 and YH29407, a novel IDO1 inhibitor, enhances T cell-mediated antitumor immunity in MC38 tumor-bearing mice
Authors: Pyo Kyoung-Ho , Kim Dong Kwon , Oh Se-Woong , Lee Gyu-Jin , Kang Ho-Woong , Kim Jae Hwan , Byeon Youngseon , Kim Young Seob , Synn Chun-Bong , Lee Wongeun , Lee Su Hwan , Lee Seul , Yang Seung Min , Lee Soyeon , Joo Yunjoo , Lee Eun Ji , Lim Sun Min , Cho Byoung Chul 
Published: June 2022

Background: The IDO is an enzyme responsible for catabolizing tryptophan (Trp) to kynurenine (Kyn). The kynurenine exert important immunosuppressive functions by activating Treg cells and myeloid-derived suppressor cells. YH29407 is a novel IDO1 inhibitor, improved the pharmacodynamics compared to previous IDO inhibitors.

Methods: To evaluate antitumor effects and immune profiles of YH29407, YH29407 was dosed at 50 or 100 mg/kg twice daily (B.I.D.) alone or in combination with anti-PD-1 (10 mg/kg, B.I.W., i.p.) and BMS-986205 was dosed at 125 mg/kg once daily (Q.D.) alone or in combination with anti-PD-1 in a MC38 syngeneic tumor model. The antitumor effects during 11 days of administration of YH29407 alone or combinations and BMS-986205 alone or combination in the MC38 model were measured. Measurements were carried out up to day 50 for survival testing. After 3 days of treatment for each condition, immune cell profiles were evaluated by flow cytometry.

Results: The YH29407 at dose of 100 mg/kg B.I.D combination treatment group showed the best effects on tumor size reduction. The group constituting &gt;TGI:70% contained 100% (15/15) of the combination treatment group, whereas 15% (2/13) of competitor BMS-986205 combination group were contained. In addition, in the combination treatment group, most tumors showed an aspect of decrease including complete responses of 5 mice. Moreover, there was a complete response in YH29407 alone group but, not observed in BMS-986205 group. According to flow cytometry analysis, the combination treatment group showed higher CD3+ total T cells compared to the vehicle group (*p&lt;0.05). Also, the effector T cells were respectively increased in the combination treatment group than BMS-986205 alone group. Significantly, helper T cells were increased in the combination treatment group against vehicle group (***p&lt;0.001) and BMS-986205 combination group (*p&lt;0.05). In addition, total macrophages were increased in the combination treatment group than BMS-986205 alone group (*p&lt;0.05). On the other hand, M-MDSC were significantly decreased in the combination treatment group than BMS-986205 combination group (*p&lt;0.05). We evaluated the tumor-infiltrating immune cells by immunohistochemistry, infiltrated CD3+ T cells were increased in the tumor of the combination treatment group than the vehicle group and BMS-986205 combination group (both *p&lt;0.05). Likewise, tumor infiltrated CD8+ T cells were increased in the combination treatment group than vehicle group (**p&lt;0.01) and BMS-986205 combination group (*p&lt;0.05). However, dose-response effect or synergistic effect on immune cell profiles between YH29407 50 mg/kg alone or combination and YH29407 100 mg/kg alone or combination were not observed.

Conclusion: Taken together, we suggest that YH29407 is the best combination partner with immune checkpoint inhibitors for solid tumor.

Citation Format: Kyoung-Ho Pyo, Dong Kwon Kim, Se-Woong Oh, Gyu-Jin Lee, Ho-Woong Kang, Jae Hwan Kim, Youngseon Byeon, Young Seob Kim, Chun-Bong Synn, Wongeun Lee, Su Hwan Lee, Seul Lee, Seung Min Yang, Soyeon Lee, Yunjoo Joo, Eun Ji Lee, Sun Min Lim, Byoung Chul Cho. Combination therapy with anti-PD-1 and YH29407, a novel IDO1 inhibitor, enhances T cell-mediated antitumor immunity in MC38 tumor-bearing mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5481.