eganelisib (IPI-549)

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.

We conclude that inflammatory signaling-activated PIK3R5 is a biomarker for sensitivity to PI3Kγ inhibition via an unappreciated PI3Kγ-PAK1 axis. Synergy with cytarabine unmasked eganelisib sensitivity in additional leukemias, expanding the therapeutic potential of targeting PI3Kγ.

Herein, we investigated the potential anti-inflammatory activities of several pharmacological PI3K inhibitors, including marketed drugs idelalisib (PI3Kδ), duvelisib (PI3Kδ/γ), and copanlisib (pan-PI3K with preferential α/δ) and the clinical drug eganelisib (PI3Kγ), for treating acute lung injury (ALI). Collectively, all four representative PI3K inhibitors exerted prominent anti-inflammatory properties, indicating that PI3K δ and/or γ inhibition could be ideal targets to treat respiratory inflammatory diseases by reducing the inflammatory response. The findings of the current study provide a new basis for utilizing PI3K inhibitors to treat acute respiratory inflammatory diseases.

To address this issue, a novel size-tunable hybrid nano-micro-liposome was designed to co-deliver MDSCs inhibitor (IPI549) and αPD-L1 antibody (LPIP) for multi-pathway activation of immune responses...The combined strategy of LPIP+iRFA effectively ablated the primary tumor by activating immune responses in the transition zone while suppressing the compensatory immune evasion of surviving MDSCs. This approach avoided the relapse of the residual tumor in a post-iRFA incomplete-ablation model and appears to be a promising strategy in RFA for eradication of HCC.

P2, N=91, Active, not recruiting, Infinity Pharmaceuticals, Inc. | Trial completion date: Aug 2022 --> Aug 2023 | Trial primary completion date: Aug 2022 --> Aug 2023

Based on the observed safety profile, eganelisib doses of 30 mg and 40 mg once daily in combination with PD-1/PD-L1 inhibitors were chosen for phase 2 study.

We observed that Cuc B is a more potent molecule than a pharmacological inhibitor of PI3Kγ (IPI-549) in suppressing key signaling components of TAM and MDSCs...These results suggest that Cuc B is a novel therapeutic agent which has the potential to suppress or revert TAMs and MDSCs phenotypes. Cuc B may be used as an adjuvant drug molecule in combination with PD1 or CTLA-4 antibodies for improving immunotherapy response against less responsive tumors.

Here, we analyzed the impact of the clinically approved PI3Kδ inhibitors idelalisib and umbralisib, the PI3Kγ inhibitor eganelisib, and the dual-γ and -δ inhibitor duvelisib on the functional capacity of T cells. Extrapolation of this data to a clinical setting could provide an explanation for the observed irAEs in CLL patients undergoing treatment with PI3K inhibitors. Consequently, this highlights the need for a close monitoring of patients treated with PI3K inhibitors, and particularly duvelisib, due to their potentially increased risk of T-cell deficiencies and associated infections.

Here, we designed an albumin nanoparticle, Nano-PI, containing the immunomodulators PI3Kγ inhibitor (IPI-549) and paclitaxel (PTX). Immune cell profiling revealed that the combination of Nano-PI with α-PD1 remodeled the immune microenvironment by polarizing M2 to M1 macrophages, increasing CD4 and CD8 T cells, B cells, and dendritic cells, decreasing regulatory T cells, and preventing T cell exhaustion. Our data suggest that Nano-PI in combination with α-PD1 modulates the immune microenvironment in both lymph nodes and tumors to achieve long-term remission in mice with metastatic breast cancer, and represents a promising candidate for future clinical trials.

P1, N=219, Active, not recruiting, Infinity Pharmaceuticals, Inc. | Trial primary completion date: Oct 2021 --> Jan 2022

P2, N=91, Active, not recruiting, Infinity Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting

We developed a tumor vaccine delivery system and presented a promising personalized tumor vaccine-based therapeutic regimen in which a tumor vaccine delivery system is combined with an aPD-L1 or PI3Kγ inhibitor to improve tumor immunotherapy outcomes.

Accordingly, we develop a biohydrogel scaffold-enabled chemoimmunotherapeutic strategy by targeting myeloid cells with a phosphoinositide 3-kinase γ (PI3Kγ) inhibitor (IPI549) to synergize with immunostimulatory chemotherapy (Oxaliplatin, OX) for post-ablative cancer therapy. With several tumor mouse models, we reveal that OX&IPI549@Gel-based localized chemoimmunotherapy can substantially suppress the growth of tumor post-iMWA, simultaneously evoke robust systemic anticancer immunity to inhibit metastatic spread, and offer strong long-term immunological memory functions against tumor rechallenge. Besides, this work proposes a potential opportunity for precision medicine by utilizing a mechanism-based rationale to the adoption of our pre-existing arsenal of anticancer immunotherapeutic schedule.

P1, N=35, Completed, Arcus Biosciences, Inc. | Active, not recruiting --> Completed | N=214 --> 35 | Trial completion date: Jul 2022 --> Jul 2021 | Trial primary completion date: Feb 2022 --> Jul 2021

We compared the effects of LY294002 that inhibit with equal potency all class I isoenzymes and downstream mTOR with the action of inhibitors with higher isoform-selectivity towards PI3Kα, PI3Kβ or PI3Kγ (namely A66, TGX-221 and AS-252424). The combination of clinically approved a-selective BYL-719 with γ-selective IPI-549 was more efficient than single molecule treatment on xenograft growth. Mapping unique adaptive signaling responses to isoform-selective PI3K inhibition will help to design better combinative treatments that prevent the induction of selective compensatory signals.

P1, N=219, Active, not recruiting, Infinity Pharmaceuticals, Inc. | Trial completion date: Jun 2021 --> Oct 2022 | Trial primary completion date: Jun 2021 --> Oct 2021

HSC-2 and Cal-27 cells were cultured in the presence of the specific PI3Kγ-inhibitor (IPI-549) which significantly impaired cell vitality in a dose-dependent manner, as shown by the MTT test. Here, we highlighted two different mechanisms, namely the modulation of the tumor-infiltrating cells and the direct inhibition of cancer-cell proliferation, which might impair oral cancerogenesis in the absence/inhibition of PI3Kγ.

Moreover, the synergistic therapy increases the number of effector memory T cells (T ) in spleen, which suggests a favorable immune memory to prevent tumor recurrence and metastasis. The Ce6 and IPI-549-coloaded multifunctional nanodrug demonstrates high efficacy in colon cancer treatment.

P1, N=214, Active, not recruiting, Arcus Biosciences, Inc. | Recruiting --> Active, not recruiting

Additionally, we summarize the experimental and computational techniques utilized to identify PI3Kγ inhibitors. The insights gained so far could be used to overcome the main challenges in development and accelerate the discovery of PI3Kγ-selective inhibitors.

P1, N=219, Active, not recruiting, Infinity Pharmaceuticals, Inc. | Trial primary completion date: Dec 2020 --> Jun 2021

Of interest, although selective inhibitors of either or PI3Kδ (GSK2292767) or PI3Kγ (IPI549) had modest effects on blocking CAR-T induced IL-6 production in this in vitro model, the effect of combining both inhibitors had a more dramatic effect similar to the dual PI3K-δ,γ inhibitor, duvelisib...Our preclinical data suggest that dual PI3K-δ,γ inhibition with duvelisib may represent an attractive alternative to IL-6 receptor antagonists, such as tocilizumab, for the treatment of CAR-T-associated cytokine release syndrome in the clinic which warrants further clinical evaluation...Dose dependent effect of duvelisib on IL-6 secretion in co-culture of CART19, Ramosluc, and iDC after 48 hours (a) Dose dependent inhibition of CART19 mediated cytotoxicity using duvelisib (b) Duvelisib effectively lowers IL-6 plasma level in an immunocompetent BALB/cJ mouse model of CRS (c). (** p≤ 0.01 and ns p>0.05).

P1, N=219, Active, not recruiting, Infinity Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Apr 2020 --> Jun 2021 | Trial primary completion date: Oct 2019 --> Dec 2020

Recent studies have reported anti-cancer immunity by use of PI3K-δ inhibitor (Idelalisib), PI3K-γ inhibitor (IPI-549) and DNA-PK inhibitor (NU7441). The immunosuppressive effect of BR101801 changing the tumor microenvironment was verified without cancer cells. It is demonstrated that anticancer immunity by decreasing Tregs and increasing CD8. Anti-tumor immunity was enhanced by decreasing the expression of PD1, TIM3, LAG3 and TIGIT in CD8 + cells.

Live cell response to an S1P agonist, PI3K-α antagonist (alpelisib), PI3K-γ antagonist (IPI-549), and a pan-PI3K inhibitor (taselisib) were measured using an xCELLigence RTCA impedance biosensor. A sub-set of PIK3CA WT patient breast cancer tumors had abnormal PI3K-involved signaling comparable to levels found in PI3KCA mutated cell lines. Abnormal pan-PI3K signaling and normal PI3K-α signaling in the HCC1954 cell line correlated with xenograft results. This study thus suggests that measurement of PI3K-involvement in hyperactive S1P signaling in live patient breast cancer cells may provide a means to identify breast cancer patients who may or may not benefit from treatment with PI3K inhibitors.

Real-time live cell response to an S1P agonist, an alpha-specific PI3K antagonist (alpelisib), a gamma-specific PI3K antagonist (IPI-549), and a pan-PI3K inhibitor (taselisib) were measured using an xCELLigence RTCA impedance biosensor. The CELx PI3K test found hyperactive S1P-initiated signaling involves the PI3K node in PI3KCA mutated and WT breast tumor cells. The abnormal levels of PI3K-involved signaling in PIK3CA WT patient breast cancer tumors were comparable in magnitude to levels found in well-characterized PI3KCA mutated breast tumor cell lines. Unlike the PIK3CA mutated cells lines, the bulk of the PIK3-involved signaling in the PIK3CA WT patient tumor cells was associated with the PI3K-gamma isoform rather than the PI3K-alpha isoform.