An oral drug developed from a compound produced by gut bacteria helped eradicate tumors in mice when combined with existing immunotherapy and produced a long-lasting immune response that prevented tumors from regrowing in one mouse model, University of Michigan researchers reported Tuesday, Aug. 25.

The drug is based on a metabolite called 3,4-dihydroxybenzoic acid, or DHB, which gut bacteria produce when breaking down dietary fiber. The treatment improved anti-tumor responses in mouse models of melanoma, colorectal cancer and breast cancer when paired with immune checkpoint therapy, according to Michigan Medicine.

“Our gut microbiome produces many beneficial compounds that can be used for new drug development,” said James Moon, the John G. Searle Professor of Pharmaceutical Sciences at U-M and a member of the Rogel Cancer Center. “This is the first time anyone has shown that natural microbial metabolites can be developed as a new oral formulation for immunotherapy.”

The findings, published in Nature Nanotechnology, address a challenge in cancer treatment. Immune checkpoint drugs release the brakes on the immune system so T cells can attack tumors, but those cells can lose their ability to kill cancer cells over time.

Moon’s team screened metabolites produced by gut microbes and found that DHB helped T cells develop characteristics of memory cells, allowing them to multiply quickly and sustain anti-tumor responses.

DHB in its natural form is poorly absorbed and is cleared from the body quickly. To address that, researchers enclosed it in a nanoemulsion shell and converted it into an inactive precursor, called a prodrug, that becomes active after reaching target tissues.

In mouse studies, the oral prodrug combined with checkpoint therapy eliminated tumors in some models and produced long-term immune memory. In a colorectal cancer model, mice that had successfully responded to treatment resisted tumor growth when researchers later exposed them to the cancer again.

The researchers also found that DHB improved the effectiveness of CAR T-cell therapies, which re-engineer a patient’s own immune cells to target cancer.

Moon said the team hopes the results seen in mouse tumor models will eventually hold true in human clinical trials. The study does not identify a timeline for testing the treatment in people.

Moon and co-inventors Kai Han, Deepak Nagrath, Kim Hutchings and Martin Clasby have filed patent applications related to the formulation. Moon also disclosed financial interests in EVOQ Therapeutics and Saros Therapeutics.

The study was funded by multiple National Institutes of Health grants, the Rogel Cancer Center and other sources.

Researchers are continuing to screen additional compounds that could improve immune activity and are exploring whether similar nanomedicine approaches could be useful in treating autoimmune diseases.