eganelisib (IPI-549)

UTMD mediated delivery using IPI549@αIMBs combined with anti-PD1 therapy markedly inhibited subcutaneous ATC tumor growth in mice, effectively reduced the proportion of M2-like tumor associated macrophage, and increased CD8+ T cell infiltration, which alleviated the tumor immunosuppressive state. In summary, this study explored a novel therapeutic strategy for ATC, demonstrating the efficacy of the IPI549@αIMB-based UTMD approach combined with anti-PD1 therapy and validating the underlying immunomodulatory mechanisms.

Additionally, we showed that macrophages exposed to the nanoparticles exhibited sustained antitumor activity when repeatedly put in contact with cancer cells, confirming the long-term efficacy of the treatment. This study highlights the potential of the present polymer-metal hybrid nanoparticles as a versatile platform for combined immuno- and photothermal therapy in PDAC.

P1, N=125, Recruiting, Stelexis BioSciences | Not yet recruiting --> Recruiting | Initiation date: Jan 2025 --> Apr 2025

We observed that knockout of PI3kγ in murine macrophages alongside pharmacological inhibition through IPI549 treatment in THP-1 cells led to an NF-κB-driven suppression in transcription and release of inflammatory cytokines upon infection with methicillin-resistant Staphylococcus aureus. We were also able to confirm that this suppression of NF-κB translocation and subsequent decrease in inflammatory cytokine release did not compromise and even slightly boosted the bacterial killing ability. PI3k is primarily targeted for cancer therapies, but further exploration can also be carried out on its potential roles in treating bacterial infection.

Our results demonstrated that the combination of T-DXd, anti-SIRPα, and IPI-549 significantly inhibited tumor growth compared to monotherapies, with no major weight loss, indicating a favorable tolerability profile. Importantly, previously treated mice developed durable immunological memory, completely rejecting subsequent challenges with HER2-expressing tumors. Overall, these findings highlight the therapeutic potential of combining T-DXd with macrophage-targeting strategies as a robust approach to improve the efficacy of immunotherapy in HER2-positive cancers, presenting a promising avenue for clinical development.

The therapeutic effect of various nanohybrids were validated in the mice with spontaneous tumor in the colorectal area and tumor-bearing mice, which lead to the increase of ferroptosis, the activation of STING signaling pathway, and the repolarization of macrophages. Collectively, the cGAMP and IPI-549 co-loaded nanohybrids effectively reshaped the tumor immune microenvironment, and exhibited prominent treatment effect of anti-colorectal cancer in vitro, patient-derived organoids, and in vivo.

This is the first report of translational analyses including paired tumor biopsies from a phase 2 clinical study of the first-in-class PI3K-γ inhibitor eganelisib in combination with atezolizumab and nab-paclitaxel in frontline mTNBC. These results support the mechanism of action of eganelisib as a TAM-reprogramming immunotherapy and support the rationale for combining eganelisib with ICI and chemotherapy in indications with TAM-driven resistance to ICI.

The predominant PI3Kγ inhibitors were IPI-549 and TG100-115, demonstrating favourable specificity for the gamma isoform. The combination of PI3Kγ inhibition with other therapeutic modalities demonstrated enhanced antitumour effects, suggesting a synergistic approach to overcome immune suppression. These findings support the potential of PI3Kγ-targeted therapies, particularly in combination regimens, as a promising avenue for future clinical exploration in diverse solid tumour types.

P1, N=125, Not yet recruiting, Stelexis BioSciences

In addition, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukaemia xenografts with low baseline PIK3R5 expression, as residual leukaemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Together, our study reveals a targetable dependency on PI3Kγ-PAK1 signalling that is amenable to near-term evaluation in patients with acute leukaemia.

Two PIK3CG-specific inhibitors, Eganelisib and CAY10505, were used to treat A549 and H1299 cells...Co-culture with neutrophils, soluble extracts of neutrophils and cathepsin G all promoted the migration of lung cancer cells. PIK3CG overexpression in tumor cells significantly promoted the migration and metastasis of lung cancer cell.

Finally, analyses implied Duvelisib and Eganelisib as promising dual-purposed anti-COVID and anticancer drugs, potentially targeting Mpro and PI3Kγ to stop virus replication and cytokine storms concomitantly. We also distinguished hotspot residues imparting significant interactions.