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

doi:10.1016/j.chembiol.2024.10.013

A yeast-based oral therapeutic delivers immune checkpoint inhibitors to reduce intestinal tumor burden

Cell Chem Biol. 2024 Nov 16:S2451-9456(24)00452-5. doi: 10.1016/j.chembiol.2024.10.013. Online ahead of print.

Authors

Olivia N Rebeck¹, Miranda J Wallace¹, Jerome Prusa¹, Jie Ning¹, Esse M Evbuomwan², Sunaina Rengarajan³, LeMoyne Habimana-Griffin⁴, Suryang Kwak¹, David Zahrah⁵, Jason Tung⁵, James Liao¹, Bejan Mahmud¹, Skye R S Fishbein¹, Erick S Ramirez Tovar¹, Rehan Mehta¹, Bin Wang¹, Mark G Gorelik¹, Beth A Helmink⁶, Gautam Dantas⁷

Affiliations

¹ The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
² The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA.
³ The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Dermatology, John T. Milliken Department of Internal Medicine, Washington University School of Medicine, St. Louis MO 63110, USA.
⁴ The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁵ The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁶ Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: dantas@wustl.edu.

PMID: 39571582
DOI: 10.1016/j.chembiol.2024.10.013

Abstract

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.

Keywords: APC(min); PD-L1; Saccharomyces boulardii; colorectal cancer; drug delivery; immune checkpoint inhibitor; microbiome; probiotic; small bowel cancer; yeast.