Abstract 5107: A novel AhR inhibitor ‘DA-4505’ improved the anti-cancer efficacy of surgical and chemotherapy via synergistic anti-tumor effects of aPD-1

Abstract

Abstract Background: The Aryl hydrocarbon receptor (AhR) is one of the most predominant regulators of cancer metabolism. The AhR exerts important immunosuppressive functions by activating Treg cells and myeloid-derived suppressor cells and repressing CD8+ effector T cells. Here, we propose that a best-in-class AhR inhibitor, DA-4505, improves anti-tumor efficacy via modulation of tumor immune surveillance compared to BAY2416964, an AHR antagonist drug candidate being studied in the clinical phase. Methods: To evaluate anti-tumor effects of DA-4505 and BAY2416964, the two AhR inhibitors were dosed at 10 mg/kg once daily alone or in combination with aPD-1 (10 mg/kg) in surgical and chemotherapy models, and a PDX model (YHIM2004). Tumor volume, relapse, and survival were evaluated, and immune profiles were analyzed with IHC, flow cytometry, and scRNAseq. Results: A significant tumor reduction appeared in the CT26 and 4T1 tumor models after the DA-4505 treatment compared to vehicle group (P<0.05). In contrast, DA-4505 treatment did not induce significant tumor regression compared to vehicle group in tumor-bearing NOG mice, suggesting that anti-tumor effects of DA-4505 were driven by immunologic mechanisms. To evaluate the role of DA-4505 in conjunction with surgery, DA-4505 alone or in combination with anti-PD-1 was given prior to and following resection of the tumors in 4T1 tumor-bearing mice. Survival of mice treated with DA-4505 alone or DA-4505 combined with anti-PD-1 was significantly prolonged after resection compared to aPD-1 treatment group (P<0.05). In addition, there were four mice that did not have a relapse by treating DA-4505 with or without aPD-1 after surgery (4/5). A tumor regression also appeared in the YHIM2004-engrafted humanized mouse study. A tumor reduction was shown by treating DA-4505 alone or in combination with pembrolizumab compared to vehicle group (P<0.05). Next, we co-administered an AhR inhibitor and aPD-1 as a partner to improve the antitumor effects of chemotherapy. The DA-4505 add-on group showed tumor regression when compared with the combination therapy group treated with aPD-1 and chemotherapy (P<0.0001). In addition, a significant increase in survival rate was shown in the group treated with a DA-4505 add-on compared to vehicle group (P<0.001). Analysis of scRNAseq showed that M1 macrophage expressing CCL7 and CCL8 were increased in DA-4505 treated group compared to the vehicle and aPD-1 groups. This suggests that immune modulatory effect of DA-4505 may be due to enhanced recruitment of immune cells into the tumor site by macrophages with high chemotactic activity. Conclusion: The AhR inhibitor DA-4505 demonstrated an improvement in anti-tumor efficacy. In addition, it has shown a synergistic effect when combined with aPD-1. Discoveries from this study provide a preclinical rationale for future clinical implications in solid tumor. Citation Format: DongKwon Kim, Sujeong Baek, Seung Min Yang, Yu Jin Han, Seong-san Kang, Chun-Bong Synn, Mi Hyun Kim, Heekyung Han, Kwangmin Na, Young Taek Kim, Sungwoo Lee, Taedong Han, Hyounmie Doh, Jongho Cho, Dajeong Kim, Daewon Cha, Jae Hwan Kim, Youngseon Byeon, Young Seob Kim, Mi Ran Yun, Ji Yun Lee, Jii Bum Lee, Chang Gon Kim, Min Hee Hong, Sun Min Lim, Byoung Chul Cho, Kyoung-Ho Pyo. A novel AhR inhibitor ‘DA-4505’ improved the anti-cancer efficacy of surgical and chemotherapy via synergistic anti-tumor effects of aPD-1. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5107.