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.

Developing the first microbiome-based oral nanomedicine

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.

Our gut microbiome produces many beneficial compounds that can be used for new drug development. This is the first time anyone has shown that natural microbial metabolites can be developed as a new oral formulation for immunotherapy.” ”

-James Moon, Ph.D., John G. Searle Professor of Pharmaceutical Sciences and a member of Rogel Cancer Center

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.

Additional authors: Kai Han, Young Seok Cho, Mariko Takahashi, Xingwu Zhou, Hannah E. Dobson, Kim Hutchings, Yuesong Wu, Youngseo Na, Fang Xie, Julia Crowther, Jinmei Wu, Jin Xu, Chuan Lee, Himani Jasewicz, Yujin Kim, Minal Nenwani, Olamide Animasahun, Fulei Wuchu, Anthony Andren, Harrison Wong, Emma Camp, Ziye Wan, Qi Wu, Li Zhang, Cheng Xu, Katherine Dong, Yao Xu, Anna Schwendeman, Grace Y. Chen, Yuying Xie, Costas A. Lyssiotis, Martin Clasby, Deepak Nagrath and Yu Leo Lei

Funding/disclosures: This work was supported by NIH (R01DE030691, R01CA271799, R01NS122536, R01DE031951, P30CA046592, R01DE026728 and R01CA271369); National Natural Science Fund for Excellent Young Scientists Fund Program (Overseas) of China; National Natural Science Foundation of China (52473160); Project Program of Jiangsu Key Laboratory of Drug Design and Optimization; China Pharmaceutical University (DDOZZ202301); Rogel Cancer Center; Forbes Scholar Award and NIH T32 training grant (T32GM145304)

Tech transfer(s)/Conflict(s) of interest: Patent applications for microbial metabolite prodrug-based oral formulation to improve the efficacy of ICB have been filed with Moon, Han, Nagrath, Hutchings and Clasby as inventors. Moon declares financial interests for board membership, as a paid consultant, for research funding, and/or as an equity holder in EVOQ Therapeutics, and Saros Therapeutics. Lyssiotis has consulted for Astellas Pharmaceuticals, Odyssey Therapeutics, Third Rock Ventures and T-Knife Therapeutics and is an inventor on patents pertaining to Kras-regulated metabolic pathways, redox control pathways in pancreatic cancer and targeting the GOT1-ME1 pathway as a therapeutic approach (US patent number 2015126580-A1, 05/07/2015; US patent number 20190136238, 05/09/2019; international patent number WO2013177426-A2, 04/23/2015)

Michigan Research Core(s): Pharmacokinetic and Mass Spectrometry Core and Advanced Genomics Core

Paper cited: “Oral nano-delivery of a gut microbial metabolite enhances T cell stemness for cancer immunotherapy,” Nature Nanotechnology. DOI: 10.1038/s41565-026-02235-9

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