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, PhD , 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, PhD, and Jerome Prusa, PhD, 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.
