YH25248, a selective PI3K delta inhibitor, shows synergistic effect with an anti-PD-L1 antibody

Phosphatidylinositol 3-kinase (PI3K) plays critical roles in numerous intracellular processes. Of the four known subtypes, PI3Kδ subtype is primarily expressed in immune cells and has been reported to promote B cell differentiation and regulatory T (Treg) cell activation. Treg cell-mediated immunosuppression is thought to be a major resistance mechanism for immune checkpoint inhibitors. We therefore hypothesized that an effective PI3Kδ inhibitor could enhance anti-cancer immunity when combined with immune checkpoint inhibitors. Through recent efforts, we have discovered YH25248, an oral PI3Kδ-specific inhibitor. YH25248 effectively inhibits PI3Kδ (IC50 = 10nM) showing more than 100-fold selectivity over α, β, and γ subtypes, and exhibited favorable kinase selectivity in 463 kinase panels. In cellular experiments, phospho-AKT was effectively blocked (IC50 = 7 nM), with basophil activation, a known PI3Kδ specific signal, was also inhibited. YH25248 reduced the activity of Treg cells (CD4+/CD25+) isolated from the splenocytes of CT26 tumor-bearing mice, while sparing conventional T cells (CD4+/CD25-). When YH25248 was orally administered (10 mg/kg) to mice, drug exposure in plasma was reasonable, with a half-life of 4.3 hours, while once-daily oral administration of YH25248 (10 ~ 60 mg/kg) significantly inhibited tumor growth of CT26 colon carcinomas in mouse. When the immune cells of tumors were analyzed by flow cytometry, the number of Treg cells was reduced, CD8 + T cells increased. In this model, YH25248 (30 mg/kg, QD) showed synergistic efficacy when combined with an anti-PD-L1 antibody (200 μg/mice, 10F.9G2 clone). In other syngeneic models using 4T1 or MC38 cells, YH25248 (30 mg/kg, QD) also exhibited similar synergistic efficacy in combination with the anti-PD-L1 antibody. In conclusion, YH25248 is a potent, selective, oral inhibitor of PI3Kδ that reduces tumor growth in syngeneic mouse tumor models by increasing the ratio of CD8+ to Treg cells. The combination of YH25248 and anti-PD-L1 antibody resulted in substantially greater tumor growth inhibition in several syngeneic models. These data support the promising potential of YH25248 for combination therapy with immune checkpoint inhibitors to increase therapeutic response rates. Citation Format: Jinhwi Park, Ho-Woong Kang, Hyun-Mo Koo, Jongsuk Park, Tae-Wang Kim, Se-Woong Oh, Soongyu Choi. YH25248, a selective PI3K delta inhibitor, shows synergistic effect with an anti-PD-L1 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3915.