New Oral Nanomedicine Boosts Effectiveness of Cancer Immunotherapies

Immune checkpoint blockade is a form of cancer treatment that works by releasing the natural brakes in the immune system, allowing T cells to find and destroy cancer cells.

Although they have transformed cancer immunotherapy, patients usually have low response rates.

In a new study published in Nature Nanotechnology, University of Michigan researchers developed an oral drug that can increase the ability of T cells to attack tumors.

To do so, they used 3,4-dihydroxybenzoic acid, or DHB, that is produced by gut bacteria.

“Our gut microbiome produces many beneficial compounds that can be used for new drug development,” said James Moon, Ph.D., John G. Searle Professor of Pharmaceutical Sciences and a member of 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.”

Normally, checkpoint immunotherapy fails because the T cells progressively lose their killing capacity and stop dividing.

In the study, the researchers screened several metabolites from the gut microbes and identified DHB as a potential drug candidate.

DHB is normally produced in the gut during the breakdown of dietary fiber.

The team found that DHB trains T cells to become memory T cells, which are the engines of cancer immunotherapy.

They multiply quickly and drive anti-tumor immune responses.

The problem with using naturally existing compounds like DHB is that they are not absorbed well and are rapidly cleared from the body.

To prevent this from occurring, the researchers created a prodrug with DHB—in addition to enclosing DHB in a nanoemulsion protective shell, they converted it into an inactive precursor that transforms into an active drug after it reaches the target tissues.

They tested the oral prodrug formulation in mouse models for several tumor types, including melanoma, colorectal cancer and breast cancer.

When mice were given the prodrug in combination with immune checkpoint blockade therapy, their tumors were eradicated.

Their immune systems developed long-term memory that could prevent tumor recurrence.

“We found that DHB also improved the efficacy of CAR T-cell therapies, which is widely used to re-engineer a patient’s own immune cells to target cancer,” Moon said.

“We hope that our results from mouse tumor models will also hold true in human clinical trials.”

The researchers are continuing to screen other compounds that can improve the activity of the immune system.

They are hopeful that their methods for formulating nanomedicines will be useful in treating autoimmune diseases.

(Newswise/HG)