PPRX-1701, a deliverable nanoparticle formulation of 6-bromo-acetoxime, blocks tumoral IDO1 expression and shows efficacy in immunocompetent murine glioblastoma models

Abstract Introduction: We previously showed that derivatives of the Chinese traditional medicine indirubin promote survival in murine models of the brain tumor glioblastoma. However, poor drug solubility hampered further development of this approach. Here we introduce PPRX-1701, a 6’-bromoindirubin acetoxime (BiA) containing drug/polymer nanoparticle formulation which can be injected intravenously at relatively high concentrations. Here we examine the efficacy and mechanism of PPRX-1701 in murine glioblastoma models. Methods: In vitro glioblastoma cell proliferation and migration assays were performed using standard approaches. Effects of PPRX-1701 on interferon-γ (IFN γ) signaling were determined by Western blotting. Delivery to murine GBM was assessed using a luminescent reporter assay, and survival studies were performed in immunocompetent murine glioblastoma models. Results: PPRX-1701 effects on glioblastoma cell proliferation and migration were indistinguishable from BiA alone. Our data show that intravenous administration of PPRX-1701 is well-tolerated and can reach intracranial murine glioblastoma as assessed by luminescent reporter assays. PPRX-1701 administration leads to improved survival in the GL261 glioblastoma mouse model (median survival 30 days (control), 47 days (treated), p < 0.0001). Treatment with PPRX-1701 was associated with alterations in the tumor immune microenvironment, with reduced Tregs and pro-tumor macrophages, and increased CD8+ T cells. Further mechanistic studies have shown that PPRX-1701/BiA blocks the expression of multiple immunosuppressive molecules in GBM downstream of interferon-γ (IFNγ) including PD-L1 and indoleamine 2,3-dioxygenase 1 (IDO1) - a key enzyme in the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) immunosuppressive pathway. BiA promoted more effective T-cell mediated tumor cell killing using patient derived glioblastoma ex vivo co-culture models. Conclusion: This data supports further development of PPRX-1701 as a candidate immunotherapeutic agent for glioblastoma treatment. Ongoing pre-clinical studies are investigating combination with other relevant therapies. Citation Format: Mykola Zdioruk, Michal Nowicki, Bin Wu, Paul Boucher, Yuji Takeda, Weiyi Li, E Antonio Chiocca, Sean E. Lawler. PPRX-1701, a deliverable nanoparticle formulation of 6-bromo-acetoxime, blocks tumoral IDO1 expression and shows efficacy in immunocompetent murine glioblastoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4235.