Abstract IA26: Reprogramming tumor-associated macrophages by targeting PI3K-gamma with IPI-549

Abstract

Abstract The PI3 kinases (PI3K) belong to a family of signal-transducing enzymes that mediate key cellular functions in cancer and immunity. The PI3K-gamma (γ) isoform is highly expressed in myeloid cells/macrophages and plays an important role in M2 macrophage polarization (Kaneda, Nature 2016). PI3K-γ knockout mice also demonstrated the role for PI3K-γ in tumor growth and immune tolerance (Gunderson, Cancer Discovery 2015; Kaneda, 2016). IPI-549 is an oral, potent, and selective inhibitor of PI3K-γ that shows single-agent antitumor activity in multiple murine tumor models (Kaneda, 2016) and enhanced antitumor activity and improved survival when combined with immune-checkpoint blockade (ICB) (De Henau, Nature 2016). This antitumor activity is dependent on the presence of both immune-suppressive tumor-associated CD11b+ myeloid cells and CD8+ cytotoxic T cells. IPI-549 can reduce the suppression of T-cell activity by both murine and human myeloid-derived suppressor cells in vitro and in vivo. IPI 549 treatment of tumor-bearing mice leads to a shift in tumor-associated myeloid cells from an immunosuppressive M2 phenotype to a proinflammatory M1 phenotype and an increased frequency of circulating tumor-specific T cells and tumor-infiltrating CD8+ T cells. In addition, preclinical tumor model systems show that resistance to ICB is directly mediated by the suppressive activity of infiltrating myeloid cells (De Henau, Nature 2016). Treatment of ICB-resistant 4T1 and B16GMCSF tumor-bearing mice with IPI-549 and anti-PD1 for 14 days led to a significant antitumor activity and an increased CD8+/T-reg cell ratio, confirming that selective pharmacologic targeting PI3K-γ by IPI-549 restores sensitivity to ICB. We are conducting a Ph 1/1b study IPI-549-01 (ClinicalTrials.gov NCT02637531) evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunomodulatory activity of IPI-549 to determine its recommended phase 2 dose and preliminary clinical activity, as both a monotherapy and in combination with nivolumab, in patients with advanced solid tumors. Citation Format: Jeffery L. Kutok. Reprogramming tumor-associated macrophages by targeting PI3K-gamma with IPI-549 [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr IA26.