Sphingomyelin-derived nanovesicles for the delivery of the IDO1 inhibitor epacadostat enhance metastatic and post-surgical melanoma immunotherapy

Zhiren Wang, Wenpan Li, Yanhao Jiang, Tuyen Ba Tran, Leyla Estrella Cordova, Jinha Chung, Minhyeok Kim, Georg Wondrak, Jennifer Erdrich and Jianqin Lu ()
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Zhiren Wang: The University of Arizona
Wenpan Li: The University of Arizona
Yanhao Jiang: The University of Arizona
Tuyen Ba Tran: The University of Arizona
Leyla Estrella Cordova: The University of Arizona
Jinha Chung: The University of Arizona
Minhyeok Kim: The University of Arizona
Georg Wondrak: The University of Arizona
Jennifer Erdrich: The University of Arizona College of Medicine
Jianqin Lu: The University of Arizona

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Epacadostat (EPA), the most advanced IDO1 inhibitor, in combination with PD-1 checkpoint inhibitor, has failed in a recent Phase III clinical trial for treating metastatic melanoma. Here we report an EPA nanovesicle therapeutic platform (Epacasome) based on chemically attaching EPA to sphingomyelin via an oxime-ester bond highly responsive to hydrolase cleavage. Via clathrin-mediated endocytosis, Epacasome displays higher cellular uptake and enhances IDO1 inhibition and T cell proliferation compared to free EPA. Epacasome shows improved pharmacokinetics and tumour accumulation with efficient intratumoural drug release and deep tumour penetration. Additionally, it outperforms free EPA for anticancer efficacy, potentiating PD-1 blockade with boosted cytotoxic T lymphocytes (CTLs) and reduced regulatory T cells and myeloid-derived suppressor cells responses in a B16-F10 melanoma model in female mice. By co-encapsulating immunogenic dacarbazine, Epacasome further enhances anti-tumor effects and immune responses through the upregulation of NKG2D-mediated CTLs and natural killer cells responses particularly when combined with the PD-1 inhibitor in the late-stage metastatic B16-F10-Luc2 model in female mice. Furthermore, this combination prevents tumour recurrence and prolongs mouse survival in a clinically relevant, post-surgical melanoma model in female mice. Epacasome demonstrates potential to synergize with PD-1 blockade for improved response to melanoma immunotherapy.

Date: 2023
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DOI: 10.1038/s41467-023-43079-4

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