Immunotherapy is a promising treatment that recruits the immune system to help fight cancer, but it has had limited success in gastrointestinal cancers. Now, researchers at Washington University School of Medicine in St. Louis have engineered a probiotic that delivers immunotherapy directly to the gut to shrink tumors in mice, offering a potentially promising oral drug for hard-to-reach cancers.
The probiotic cancer treatment, described Nov. 20 in the journal Cell Chemical Biology, establishes a customizable drug delivery system that can be modified to potentially treat other gut diseases.
"Gastrointestinal cancers are difficult to treat, in part because of their location," said Gautam Dantas, the study's senior author and the Conan Professor of Laboratory and Genomic Medicine in the Department of Pathology & Immunology at WashU Medicine. "We have engineered a yeast-based probiotic that delivers immunotherapy directly to the tumor site. Our hope is that one day the probiotic could be added to the arsenal of therapies to help shrink tumors in people."
Gastrointestinal cancers, including stomach, liver, esophageal, pancreatic and colorectal cancers, represent more than one-quarter of all cancers. More than 5 million people are living with such cancers - a number that is growing - and 3.7 million die worldwide each year. Late-stage detection, due in part by anatomical challenges that hinder imaging and sampling of the long and complex gastrointestinal system composed of various organs and tissues, has contributed to the high mortality rate. Patients may require a combination therapy regime, including surgery, chemotherapy, radiation therapy and immunotherapy, among others.
Although immunotherapy drugs for gastrointestinal cancers are available, they are delivered intravenously and often exhibit limited effectiveness. Safe doses of immunotherapy may not be sufficient to reach the tumor site and be effective, Dantas explained. Oral immunotherapy drugs could directly target hard-to-reach gastrointestinal cancers, but such protein-based treatments degrade in the gut's harsh environment before reaching the tumors. Probiotics - bacteria and yeast - can withstand stomach acid and digesting enzymes, offering a potentially promising strategy for safely transporting protein-based drugs that otherwise would get chewed up.
Co-first author Olivia Rebeck, who conducted the experiments when she was a graduate student in the Dantas lab with postdoctoral scholars Miranda Wallace and Jerome Prusa, used a yeast strain to deliver immunotherapy to the gut. The yeast - Saccharomyces cerevisiae var. boulardii - is a commonly used and safe probiotic. Unlike bacteria, the microorganism is less likely to exchange genetic material with other microbes and doesn't take up residence in the gastrointestinal tract where it could potentially disrupt microbial communities. Its natural anticancer properties, found to inhibit some types of cancer cells in a dish, potentially offer an additional benefit.
The researchers engineered yeast to act as single-celled drug factories and produce immune checkpoint inhibitors - anticancer drugs that alert immune cells to the presence of cancer cells. Tumors sabotage the process that the body's healthy cells use to avoid immune recognition and subsequent attack, allowing cancer to hide from the immune system. The researchers found the yeast-based probiotic made and secreted the drug that releases the brake on the immune system, allowing it to fight tumors.
The researchers gave mice with colorectal cancer the drug-making probiotic or an intravenous injection of the immunotherapy drug. They found fewer tumors in mice receiving the probiotic compared with mice given immunotherapy drugs systemically.
The researchers have filed two patents - with help from the Office of Technology Management at WashU - related to the engineered probiotic.
Using yeast as a delivery system can be adapted for other gastrointestinal diseases. The researchers are currently working on modifying the system to help combat Clostridioides difficile, commonly referred to as C. diff, a bacterium that can cause diarrhea and colitis, among other symptoms. Delivering therapies that directly target the bug or its toxins could potentially replace the need for antibiotics that also harm beneficial gut microbes.
Rebeck ON, WallaceMJ, Prusa J, Ning J, Evbuomwan EM, Rengarajan S, Habimana-Griffin L, 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. A yeast-based oral therapeutic platform for delivery of immune checkpoint inhibitors reduces intestinal tumor burden. Cell Chemical Biology. Nov 20, 2024. DOI: 10.1016/j.chembiol.2024.10.013
This study was funded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH), grant numbers R01AI155893 and K99AI17674; the National Center for Complementary and Integrative Health of the NIH, grant numbers R01AT00974 and K99AT012651; the National Institute of General Medical Sciences of the NIH, grant numbers T32GM007067, R25GM103757 and 5T34GM141639; the National Cancer Institute of the NIH, grant number T32CA11327; the National Institute of Child Health and Human Development of the NIH, grant number T32HD004010; the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH, grant number T32DK077653. Radiological Society of North America, grant number RR2336; the Washington University/Mallinckrodt/Siteman Kornfeld PSTP Post-Bac Scholars Program. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
Dantas G, Helmink BA, Rebeck ON, WallaceMJ, Prusa J, and Kwak S are inventors on a patent application related to the yeast-based ICI delivery system. Dantas G and Kwak S are inventors on another patent related to the use of engineered microbes as therapeutic agents (Publication #: WO/2020/061389, filed 20 Sept. 2019).
About Washington University School of Medicine
WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,900 faculty. Its National Institutes of Health (NIH) research funding portfolio is the second largest among U.S. medical schools and has grown 56% in the last seven years. Together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,900 faculty physicians practicing at 130 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Children's hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.
Originally published on the WashU Medicine website
