UF Health Cancer Institute researchers have discovered a small compound produced naturally by gut bacteria that doubled the response to lung cancer immunotherapy treatment in mice and can now be made into a drug for testing in humans.
The findings, published Dec. 19 in Cell Reports Medicine, could have widespread clinical impact as a combination therapy with commonly used immunotherapy treatments like immune checkpoint inhibitors, which release the brakes on a patient's own immune system to target their cancer.
"Across all cancers, only about 20% of patients who receive immune checkpoint inhibitors respond to them — 80% do not — so anything that could boost responsiveness is a blockbuster drug," said Rachel Newsome , Ph.D., a postdoctoral associate in the lab of Christian Jobin , Ph.D., and the study's first author. "We envision this small molecule drug could be given at the same time or before immune checkpoint therapy and boost patient responsiveness by 50% without adding any invasive treatment. Our goal is to naturally boost the activity of immunotherapy, so more people have a positive effect from treatment. We want to empty those cancer center parking lots that are so full right now."
The study builds on years of work in Jobin's lab looking at the complex relationship between the collection of microorganisms, including bacteria, that live in the gut — known as the gut microbiota — and our health and immune system. The new findings that a drug can be made from a natural molecule in the microbiome represent a groundbreaking expansion of the field of microbiome science.
"We created a pipeline to harvest the therapeutic potential of the microbiota through specific steps to get to an active molecule," said Jobin, the Gatorade Distinguished Professor of Medicine in the UF College of Medicine and co-leader of the UF Health Cancer Institute's Immuno-Oncology and Microbiome research program.
In 2018, funding from the Florida Academic Cancer Center Alliance and a collaboration with Moffitt Cancer Center gave Jobin's lab access to feces from patients enrolled in a clinical trial testing immune checkpoint inhibitors. Feces enable researchers to study the composition of the gut microbiota. The clinical trial collected feces from patients using a preservative that enabled the storage of live bacteria. When researchers transplanted feces from humans who responded to immunotherapy into mice that did not, the mice responded to the treatment.
The discovery was pivotal: It showed that the gut microbiota plays a key role in determining responses to immunotherapy.
The team then reverse-engineered the complex microbiota into single bacteria. Newsome identified six bacterial strains out of more than 180 that, when given to mice with lung tumors, boosted their response to immunotherapy.
But fecal transplants or oral bacteria administration are difficult to implement on a large scale as therapeutics in humans. Researchers needed to identify how the six bacteria promoted the anti-tumor response. From these bacteria, researchers identified a single metabolite, called Bac429, that stimulated an immune response like the six bacteria.
"When we injected Bac429 into the tumors of mice with highly nonresponsive lung cancer, they had 50% less tumor growth after immunotherapy," Newsome said. "It's a stark difference."
Newsome and Jobin are developing drug derivatives of the natural Bac429. They're also working to uncover the exact mechanism. They believe the interaction of the naturally produced molecule with immune cells may occur in the gut, with immune cells then migrating to tumors.
The new study focused on lung cancer, the deadliest cancer that's one of the least responsive to immune checkpoint inhibitors. But the researchers believe the molecule could work in other cancers.
"Combination therapy is being used more and more in cancer," Jobin said. "One could envision having this molecule attached to an antibody or a lipid nanoparticle like those being pioneered at UF."
Jobin's lab is also researching how diet, and specifically carbohydrate intake, might affect the molecule's function. That could lead to precise diet interventions to boost cancer treatment responses.
UF is pursuing multiple patent applications related to Newsome and Jobin's work on these microbial-derived molecules. Newsome and Jobin have also formed Bebi Therapeutics Inc., a biotech company born as a "spinout" from UF in which Jobin and Newsome hold interest. Funding from Gatorade royalties was critical for the work, which was also funded by the National Cancer Institute, the UF Health Cancer Institute and the UF College of Medicine.
