Jacob Dwyer, Michigan Medicine
Researchers at the University of Michigan Health Rogel Cancer Center have identified a mechanism that causes serious gastrointestinal problems associated with immune-based cancer treatments.
In addition, they found a way to achieve the anti-cancer effects of immunotherapy without side effects.
The results are published in Science.
Gabriel Nunez, MD
“This is a good example of understanding a mechanism that will help develop a more effective alternative therapy. “Once we identify the cause of colitis, we could develop strategies to overcome and prevent it while maintaining antitumor effects,” said study senior author Gabriel Nuñez, MD, Paul de Kruif Professor of Pathology at Michigan Medicine.
Immunotherapy has shown promise as a treatment for several types of cancer. But immune checkpoint inhibitors can also cause serious side effects, including colitis, an inflammation of the digestive tract.
Colitis can cause severe gastrointestinal distress, which in some cases leads patients to stop their cancer treatment for this reason.
The challenge for researchers is that although patients develop colitis, mice in the laboratory do not. This prevented researchers from investigating the cause of this side effect.
To overcome this obstacle, Rogel's team, led by first author Bernard C. Lo, Phd., developed a new mouse model. This model consisted of injecting the microbiota of wild-caught mice into the traditional mouse model.
In this model, mice developed colitis after administration of tumor immunotherapy antibodies. Now researchers could trace the mechanism to find out what caused this reaction.
In fact, colitis developed due to the composition of the intestinal microbiota, which caused immune T cells to become hyperactively activated, while regulatory T cells that inhibit T cell activation were eliminated in the intestine.
This occurred within a specific domain of immune checkpoint antibodies.
The researchers removed this domain and found that it still resulted in a strong antitumor response, but without triggering colitis.
“There was previously some data suggesting that the presence of certain bacteria might be related to response to therapy. However, it has not yet been proven that the microbiota is crucial for the development of colitis. “This work shows for the first time that the microbiota is essential for the development of colitis through inhibition of the immune checkpoint,” said Nunez.
To build on their observations in mice, the researchers examined previously published data from studies using human cells from patients treated with immune checkpoint antibodies. This review reinforced the view that regulatory T cells play a critical role in the initiation of colitis.
The antibody that allowed them to stop colitis was developed by Takeda Pharmaceuticals.
Rogel's team plans to conduct additional studies to better understand the mechanisms that cause colitis. In addition, they aim to build alliances with clinical partners to translate this knowledge into a clinical trial.
Additional authors include Ilona Kryczek, Jiali Yu, Linda Vatan, Roberta Caruso, Masanori Matsumoto, Yosuke Sato, Michael H. Shaw, Naohiro Inohara, Yuying Xie, Yu Leo Lei and Weiping Zou.
Funding for this work was provided by grants from the National Institutes of Health (R01 DK121504, R01 DK095782, R01 DE026728, R01 DE030691, P30 CA046592); Takeda Millennium Pharmaceuticals, Canadian Institutes of Health, Crohn's and Colitis Foundation, National Science Foundation grant IOS-2107215.
This work was supported by the following shared resources at the Rogel Cancer Center: single cell spatial analysis, tissue pathology, and molecular analysis.
Written by Nicole Fawcett of Michigan Medicine, adapted into Spanish by Juan Ochoa of Michigan News.