2024-11-20 ワシントン大学セントルイス校
<関連情報>
- https://source.washu.edu/2024/11/probiotic-delivers-anticancer-drug-to-the-gut/
- https://medicine.washu.edu/news/probiotic-delivers-anticancer-drug-to-the-gut/
- https://www.sciencedirect.com/science/article/pii/S2451945624004525
酵母ベースの経口治療薬が免疫チェックポイント阻害剤を投与し腸腫瘍の負担を軽減 A yeast-based oral therapeutic delivers immune checkpoint inhibitors to reduce intestinal tumor burden
Olivia N. Rebeck, Miranda J. Wallace, Jerome Prusa, Jie Ning , Esse M. Evbuomwan , Sunaina Rengarajan, LeMoyne Habimana-Griffin, Suryang Kwak, David Zahrah, Jason Tung, James Liao, Bejan Mahmud, Skye R.S. Fishbein, Erick S. Ramirez Tovar, Rehan Mehta, Bin Wang, Mark G. Gorelik, Beth A. Helmink, Gautam Dantas
Cell Chemical Biology Published: 20 November 2024
DOI:https://doi.org/10.1016/j.chembiol.2024.10.013
Graphical abstract
Highlights
- Engineered yeast, Sb_haPD-1, secretes “miniature” immune checkpoint inhibitors
- Orally administered Sb_haPD-1 is viable, stable, and well tolerated in mice
- Sb_haPD-1 reduces intestinal tumors that are resistant to standard αPD-L1 therapy
- Tumor reduction is accompanied by immune and microbiome signatures
Significance
We developed an ICI delivery system in Sb, expanding the arsenal of available microbial chassis to carry anticancer therapies, which has historically been dominated by bacterial probiotics. We believe this orally administered, yeast-based therapy prototype provides compelling evidence that supports the utility of engineered yeasts as remediators of intestinal cancers. Whether this platform can be repurposed to treat other GI malignancies, such as gastric or pancreatic cancers, is yet to be determined. Although the effects we observed in tumor reduction and immune modulation were statistically significant, their modest effect sizes leave much room for improvement in future designs. Beyond cancer, we believe this platform could also be adapted to treat other GI diseases, including IBD and metabolic disorders.
Summary
Engineered probiotics are an emerging platform for in situ delivery of therapeutics to the gut. Herein, we developed an orally administered, yeast-based therapeutic delivery system to deliver next-generation immune checkpoint inhibitor (ICI) proteins directly to gastrointestinal tumors. We engineered Saccharomyces cerevisiae var. boulardii (Sb), a probiotic yeast with high genetic tractability and innate anticancer activity, to secrete “miniature” antibody variants that target programmed death ligand 1 (Sb_haPD-1). When tested in an ICI-refractory colorectal cancer (CRC) mouse model, Sb_haPD-1 significantly reduced intestinal tumor burden and resulted in significant shifts to the immune cell profile and microbiome composition. This oral therapeutic platform is modular and highly customizable, opening new avenues of targeted drug delivery that can be applied to treat a myriad of gastrointestinal malignancies.
