Abstract 1383: A next-generation PI3Kδ/γ inhibitor, ZX-101A inhibiting solid tumor growth by enhancing anti-tumor immunity
Authors: Hao Xiaolin , Peng Zhiyuan , Guo Kun , Li Ying-Ying , Kong Deming , Yang Jinfu , Qin Xiaoli (Shelley) 
Published: July 2021

Abstract
PI3K signaling cascade plays a central role in the regulation of key cellular pathways including growth, proliferation, differentiation, migration and survival. Previous studies suggested that both PI3Kδ and γ activities exert immunosuppression by targeting regulatory T cells (Treg) and myeloid cells. ZX-101A is an inhibitor of PI3K with predominant activity against the PI3Kδ and PI3Kγ isoforms, whose expressions are largely restricted to hematopoietic cells. Dual inhibition of PI3Kδ and PI3Kγ by ZX-101A may potentially restore the immune surveillance to limit tumor growth.The inhibitory effect of ZX-101A on PI3K activity was evaluated by blocking of AKT phosphorylation at T308 and S473 in human B-cell lymphoma DOHH2 cells and stimulated THP1 monocyte cells. ZX-101A significantly decreased the phosphorylation of AKT at S473 site in comparison to DMSO treated DOHH2 cells, but no difference on p-AKT level between the two concentrations of ZX-101A and the three treatment time points. In contrast, ZX-101A blocked the p-AKT on S473 in LPS-stimulated THP-1 cell line in both dose- and time-dependent manner. In vitro cell proliferation assay demonstrated ZX-101A potently inhibited cell proliferation of B-cell and T-cell lymphoma cell lines, but without potent effect on cells (e.g. 4T1 and CT26) derived from solid tumors. In contrast, ZX-101A inhibited tumor growth in CT26 syngeneic mouse model after 21-day treatment with TGI at 76.9% (1mg/kg QD), 79.5% (3mg/kg QD) and 90.0% (12mg/kg), which was attributed to enhanced anti-tumor immunity by ZX-101A treatment. Flow cytometry study on CT 26 tumors demonstrated that ZX-101A decreased Treg and increased M1/M2 macrophage polarization in the tumor microenvironment. Ex vivo T-cell differentiation assay using mouse spleen T cells and M1/M2 polarization assay using human PBMC cells confirmed the effect of ZX-101A on decreasing Treg differentiation and enhancing M1 macrophage function. Similarly, in vivo anti-tumor growth was observed in 4T1 and A20 syngeneic models. In A20 syngeneic model, ZX-101A in combination of anti-PD1 antibody achieved 99.7% TGI after 18 days of treatment, while anti-PD1 antibody alone only had TGI at 11.7%. Safety assessment on the mouse spleen, thymus and colon organs indicated minimal side effects by the treatment of the ZX-101A alone and in combination with anti-PD1. Its absorption, distribution, metabolism, and excretion (ADME) and safety profile, through a series of preclinical in vitro and in vivo studies, supported the ZX-101A clinical development. These results suggested ZX-101A as a potential immunotherapeutic agent to appropriate solid tumor types.
Citation Format: Xiaolin Hao, Zhiyuan Peng, Kun Guo, Ying-Ying Li, Deming Kong, Jinfu Yang, Xiaoli (Shelley) Qin. A next-generation PI3Kδ/γ inhibitor, ZX-101A inhibiting solid tumor growth by enhancing anti-tumor immunity [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 1383.