Abstract 2200: Dual pocket binding novel tankyrase inhibitor, K-476, enhances the efficacy of immune checkpoint inhibitor by attracting CD8+ T cells into tumor
Authors: Kinosada Haruka , Kunieda Kana , Okada Ryoko , Suzuki-Imaizumi Minami , Mie Motoya , Ishii Toshihiko , Nakai Ryuichiro 
Published: September 2020

Introduction:

Wnt/β-catenin pathway regulates many biological processes such as cell proliferation, stem cell renewal and tissue differentiation. Activation of Wnt/β-catenin pathway has been reported in many cancers. Tankyrase, one of the positive regulators of Wnt/β-catenin pathway, induces degradation of Axin, a negative regulator of Wnt/β-catenin pathway. Therefore, tankyrase inhibition stabilizes Axin protein and inhibits Wnt/β-catenin pathway, leading to exert antitumor effect. Recently, the role of Wnt/β-catenin pathway in immunotherapy has also gained attention; aberrant activation of Wnt/β-catenin pathway causes inactivation of dendritic cells and suppresses chemokine production resulting in paucity of CD8 T+ cells in tumor tissue. Although immune checkpoint inhibitors (ICIs), such as anti-CTLA-4 and anti-PD-1/PD-L1 antibodies have been successfully approved in some cancer therapies, some patients are still resistant to ICIs. One of the main causes is considered to be immune-desert tumor microenvironment, characterized by the absence of infiltrating lymphocytes including CD8+ T cells, cytotoxic effector cells for immunotherapy. Thus, Wnt/β-catenin pathway inhibition may overcome the resistance of anti-PD-1/PD-L1 therapy by attracting CD8+ T cells into tumor. K-476 is a highly potent and selective tankyrase inhibitor synthesized in house. In this study, we investigated whether K-476 enhanced the antitumor effect of anti-PD-L1 antibody. Furthermore, since tankyrase inhibitors are reported to have a potential gastrointestinal toxicity, we also evaluated the toxicity in mice administrated with K-476.

Methods and results:

Antitumor effect of K-476 combined with anti-PD-L1 antibody was evaluated in B16-derived melanoma bearing mice. Although K-476 monotherapy did not show antitumor effect, a combination with anti-PD-L1 antibody demonstrated a significant antitumor effect at doses from 50 to 200 mg/kg compared to anti-PD-L1 antibody alone, and the magnitude of the effect was comparable among the doses tested. Axin stabilization was observed in tumors after administration of K-476, suggesting that the effect was exerted through inhibition of Wnt/β-catenin pathway. The expression of chemokines, Ccl3 and Ccl4 which attract CD8+ T cells, was also upregulated. In addition, significant increase of CD8+ T cells was observed in the tumor. Gastrointestinal toxicity was not observed up to 200 mg/kg of K-476 in C57BL/6J mice. These results suggested that K-476 enhanced antitumor effect of anti-PD-L1 antibody through upregulation of Ccl3 and Ccl4 production and induction of CD8+ T cells without obvious toxicity.

Conclusion:

K-476 could be an attractive therapeutic agent that enhances the efficacy of anti-PD-L1 antibody.

Citation Format: Haruka Kinosada, Kana Kunieda, Ryoko Okada, Minami Suzuki-Imaizumi, Motoya Mie, Toshihiko Ishii, Ryuichiro Nakai. Dual pocket binding novel tankyrase inhibitor, K-476, enhances the efficacy of immune checkpoint inhibitor by attracting CD8+ T cells into tumor [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2200.