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Sphingomyelin-derived epacadostat nanovesicle enhances IDO1 inhibition for improved melanoma combination immunotherapy

Genes & Immunity (2024)Cite this article

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Epacadostat (EPA), the most advanced inhibitor targeting the indoleamine 2,3-dioxygenase 1 (IDO1), is a critical endogenous metabolic immune regulator. In preclinical melanoma models [1], EPA potentiated the antitumor efficacy of immune checkpoint blockers (ICB) in comparison to ICB monotherapy. Phase I/II clinical trials proved the excellent safety and significant IDO1 targeting ability of EPA [2]. Much to the disappointment, combing EPA with Keytruda (anti-PD-1 inhibitor) exerted zero numerical progression-free survival benefit versus Keytruda alone in a subsequent Phase III randomized clinical study (NCT02752074) in unresectable or metastatic melanoma patients [3]. Despite many reasons were blamed for this blockbuster failure such as dosing regimen and experimental designs, the poor pharmacokinetics of EPA is neglected [1].

Piggybacked by our previous success using sphingomyelin (SM)-derived drug nanotherapeutic strategy [4], recently, we developed a SM-derived EPA nanovesicle. The SM-EPA conjugate was bridged by an oxime-ester bond that is highly responsive to hydrolase cleavage in tumors [5]. Following the spontaneous self-assembly into liposomal nanovesicle (Epacasome), EPA was securely packaged in the lipid bilayer. We showed that Epacasome strengthened IDO1 suppression by reducing the production of kynurenine, and promoted T cell proliferation in a co-culture setting. Also, it markedly increased the intracellular uptake via clathrin-mediated endocytosis with highly efficient drug release inside cancer cells. Systematic pharmacokinetic and biodistribution studies demonstrated that free EPA was eliminated from the blood rapidly with a T1/2 = 0.15 h. However, Epacasome significantly extended the circulation T1/2 to ~4.72 h, drastically increasing area under curve (AUC: 1196.55 vs 7.81 μg/ml*h), mean residence time (MRT, 6.82 vs 0.22 h), and dramatically decreased volume of distribution (1.1 vs 5.97 μg/(μg/ml)). The improved pharmacokinetics allowed Epacasome a higher chance for tumor uptake based on the enhanced permeability and retention effect, resulting in 46.3-fold more EPA delivery to tumors compared to free EPA. More strikingly, Epacasome deepened tumor penetration and distribution, which are vital for improved IDO1 inhibition in tumors. Epacasome was superior to free EPA in reducing the tumor growth and prolonging mouse survival. It also synergized with anti-PD-1 inhibitor to further fortify the IFN-γ and granzyme-B-mediated cytotoxic T lymphocytes (CTLs) immunity. Meanwhile, this combination regimen repolarized macrophage to inflammatory M1 phenotype, attenuated granulocyte myeloid-derived suppressor cells and the Foxp3+ Tregs, and enhanced CD80+/CD86+ and CD103+ dendritic cells in B16-F10 melanoma model. These improved anti-melanoma efficacy and immune responses were found to be CD8 T cell dependent and attributed to the boosted IDO1 inhibition as reflected by the greatly increased tryptophan/kynurenine ratios in both plasma and tumor.

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Fig. 1: The development of DTIC laden SM-derived EPA liposomal nanovesicles (DTIC/Epacasome) and the mediated immune antitumor effects.

References

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Acknowledgements

This study was supported in part by a Startup Fund from the R. Ken Coit College of Pharmacy at The University of Arizona (UArizona) and a PhRMA Foundation for Research Starter Grant in Drug Delivery, and by National Institutes of Health (NIH) grants (R35GM147002, R01CA272487, and P30CA023074).

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  1. Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, AZ, 85721, USA

    Zhiren Wang, Wenpan Li & Jianqin Lu

  2. NCI-designated University of Arizona Comprehensive Cancer Center, Tucson, AZ, 85721, USA

    Jianqin Lu

  3. BIO5 Institute, The University of Arizona, Tucson, AZ, 85721, USA

    Jianqin Lu

  4. Southwest Environmental Health Sciences Center, The University of Arizona, Tucson, AZ, 85721, USA

    Jianqin Lu

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JL and ZW conceptualized and wrote this manuscript. WL reviewed and revised the manuscript. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Jianqin Lu.

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JL has applied for patents related to this technology (patent title: Immunogenic nanovesicles for cancer immunotherapy, patent number: WO2022115488). The other authors have no competing interests.

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Wang, Z., Li, W. & Lu, J. Sphingomyelin-derived epacadostat nanovesicle enhances IDO1 inhibition for improved melanoma combination immunotherapy. Genes Immun (2024). https://doi.org/10.1038/s41435-024-00281-8

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