Abstract 1800: An oral triple inhibitor of PI3Kδ/γ and DNA-PK elicits anticancer immunity and potentiates therapeutic efficacy of immune checkpoint blockade

Abstract

Abstract Background: PI3Kδ and PI3Kγ are mainly expressed in leukocytes, indicating that they are involved in immune modulation of the tumor microenvironment (TME). Additionally, DNA-dependent protein kinase (DNA-PK) plays a pivotal role as a mediator in repairing DNA damage in cancer cells. Here, we developed a triple inhibitor of PI3Kδ/γ and DNA-PK, BR101801, to promote antitumor immune responses and thereby enhance therapeutic efficacy of the PD-1 immune checkpoint inhibitor. Methods: CT26 and MC38 colon tumor-bearing immunocompetent mice were treated with BR101801 (50 mg/kg, PO) daily and/or anti-PD-1 (8 mg/kg, IP) twice a week. The tumors were comprehensively analyzed using flow cytometry, multiplex tissue imaging, and NanoString profiling methods. Results: Oral administration of BR101801 suppressed tumor growth without significant toxicities. The optimal schedule for BR101801 was determined by activation of T cell immunity in the TME. BR101801 monotherapy significantly increased CD8+ cytotoxic T cells and decreased CD4+CD25+Foxp3+ regulatory T cells, while no changes were observed in tumor-associated macrophages. Moreover, BR101801 increased AH-1+ tumor-specific CD8+ T cells within BR101801-treated CT26 tumors. BR101801 induced extensive immune remodeling of the TME by altering immune-related genes. Notably, gene signatures related to DNA damage and inflammatory responses were more enriched in BR101801-treated tumors. Furthermore, the combination immunotherapy of BR101801 and anti-PD-1 antibody strongly suppressed tumor growth and improved antitumor immunity within the TME, leading to complete tumor regression. Conclusion: Our study demonstrates that BR101801, an oral triple inhibitor of PI3Kδ/γ and DNA-PK, effectively elicited anticancer immune responses within the TME and potently inhibited tumor progression in combination with immune checkpoint blockade. Citation Format: Seung Joon Lee, Won Suk Lee, Eun-Jin Go, Hannah Yang, Hong Ro Kim, Bong-Seog Kim, Chan Kim, Hong Jae Chon. An oral triple inhibitor of PI3Kδ/γ and DNA-PK elicits anticancer immunity and potentiates therapeutic efficacy of immune checkpoint blockade [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 1800.