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; Le Moyne 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

Olivia N. Rebeck, Miranda J. Wallace, Jerome Prusa, Jie Ning, Esse M. Evbuomwan, Sunaina Rengarajan, Le Moyne 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

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English
Pages (from-to)	98-110.e7
Journal	Cell Chemical Biology
Volume	32
Issue number	1
DOIs	https://doi.org/10.1016/j.chembiol.2024.10.013
State	Published - Jan 16 2025

Keywords

APC
PD-L1
Saccharomyces boulardii
colorectal cancer
drug delivery
immune checkpoint inhibitor
microbiome
probiotic
small bowel cancer
yeast

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10.1016/j.chembiol.2024.10.013

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Rebeck, O. N., Wallace, M. J., Prusa, J., Ning, J., Evbuomwan, E. M., Rengarajan, S., Habimana-Griffin, L. M., Kwak, S., Zahrah, D., Tung, J., Liao, J., Mahmud, B., Fishbein, S. R. S., Ramirez Tovar, E. S., Mehta, R., Wang, B., Gorelik, M. G., Helmink, B. A., & Dantas, G. (2025). A yeast-based oral therapeutic delivers immune checkpoint inhibitors to reduce intestinal tumor burden. Cell Chemical Biology, 32(1), 98-110.e7. https://doi.org/10.1016/j.chembiol.2024.10.013

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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, PD-L1, Saccharomyces boulardii, colorectal cancer, drug delivery, immune checkpoint inhibitor, microbiome, probiotic, small bowel cancer, yeast",

author = "Rebeck, {Olivia N.} and Wallace, {Miranda J.} and Jerome Prusa and Jie Ning and Evbuomwan, {Esse M.} and Sunaina Rengarajan and Habimana-Griffin, {Le Moyne} and Suryang Kwak and David Zahrah and Jason Tung and James Liao and Bejan Mahmud and Fishbein, {Skye R.S.} and {Ramirez Tovar}, {Erick S.} and Rehan Mehta and Bin Wang and Gorelik, {Mark G.} and Helmink, {Beth A.} and Gautam Dantas",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2025",

month = jan,

day = "16",

doi = "10.1016/j.chembiol.2024.10.013",

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Rebeck, ON, Wallace, MJ, Prusa, J, Ning, J, Evbuomwan, EM, Rengarajan, S, Habimana-Griffin, LM, Kwak, S, Zahrah, D, Tung, J, Liao, J, Mahmud, B, Fishbein, SRS, Ramirez Tovar, ES, Mehta, R, Wang, B, Gorelik, MG, Helmink, BA & Dantas, G 2025, 'A yeast-based oral therapeutic delivers immune checkpoint inhibitors to reduce intestinal tumor burden', Cell Chemical Biology, vol. 32, no. 1, pp. 98-110.e7. https://doi.org/10.1016/j.chembiol.2024.10.013

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AU - Wallace, Miranda J.

AU - Prusa, Jerome

AU - Ning, Jie

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AU - Rengarajan, Sunaina

AU - Habimana-Griffin, Le Moyne

AU - Kwak, Suryang

AU - Zahrah, David

AU - Tung, Jason

AU - Liao, James

AU - Mahmud, Bejan

AU - Fishbein, Skye R.S.

AU - Ramirez Tovar, Erick S.

AU - Mehta, Rehan

AU - Wang, Bin

AU - Gorelik, Mark G.

AU - Helmink, Beth A.

AU - Dantas, Gautam

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N2 - 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.

AB - 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.

KW - APC

KW - PD-L1

KW - Saccharomyces boulardii

KW - colorectal cancer

KW - drug delivery

KW - immune checkpoint inhibitor

KW - microbiome

KW - probiotic

KW - small bowel cancer

KW - yeast

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DO - 10.1016/j.chembiol.2024.10.013

M3 - Article

C2 - 39571582

AN - SCOPUS:85211349198

SN - 2451-9456

VL - 32

SP - 98-110.e7

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 1

ER -

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

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Keywords

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