Oral microbiome drug boosts cancer immunotherapy in mice

A mouse with melanoma, colorectal or breast cancer received an oral compound derived from the gut. Combined with immune checkpoint blockade — treatment that releases the immune system’s natural brakes — the formulation eradicated tumors in the University of Michigan researchers’ models and left behind long-term immune memory.

The compound is 3,4-dihydroxybenzoic acid, or DHB, a metabolite made by gut bacteria as they break down dietary fiber. The team found that DHB trains T cells to become memory T cells: cells that multiply quickly and help sustain an attack on cancer. That matters because checkpoint immunotherapy can fail when T cells progressively lose their ability to kill and stop dividing.

DHB’s natural origin did not make it an easy medicine. It is poorly absorbed and rapidly cleared from the body. The researchers addressed that limitation by creating a prodrug, an inactive precursor that becomes active in target tissues, and enclosing it in a protective nanoemulsion shell for oral delivery.

The study, published in Nature Nanotechnology, tested the treatment in mouse models of melanoma, colorectal cancer and breast cancer. The researchers also found that DHB improved CAR T-cell therapy — a treatment that reengineers a patient’s own immune cells to recognize cancer. James Moon, a University of Michigan pharmaceutical sciences professor and Rogel Cancer Center member, said the team hopes the mouse results will hold in human clinical trials.

So what changes in practice? If the effect survives human testing, an oral formulation could give existing checkpoint and CAR T-cell therapies an additional way to keep immune cells effective. For now, that possibility remains ahead of the evidence: the reported results come from mice, and no human trial result is described. The researchers are continuing to screen other compounds that may improve immune-system activity, and hope their nanomedicine-formulation methods could prove useful for treating autoimmune diseases.