Researchers at the University of Michigan Health Rogel Cancer Centre discovered a mechanism connected to serious gastrointestinal problems following immune-based cancer treatment. Additionally, they discovered a technique to deliver the cancer-killing effects of immunotherapy without the unwanted side effect. Science has published the results.
“This is a good example of how understanding a mechanism helps you to develop an alternative therapy that’s more beneficial. Once we identified the mechanism causing the colitis, we could then develop ways to overcome this problem and prevent colitis while preserving the anti-tumor effect,” said senior study author Gabriel Nunez, M.D., Paul de Kruif Professor of Pathology at Michigan Medicine.
Immunotherapy has emerged as a promising treatment for several types of cancer.
But immune checkpoint inhibitors can also cause severe side effects, including colitis, which is inflammation in the digestive tract. Colitis can cause severe gastrointestinal discomfort, and some patients will discontinue their cancer treatment because of it.
The problem facing researchers was that while patients were developing colitis, the laboratory mice were not. So researchers couldn’t study what was causing this side effect. To get past this, the Rogel team, led by first author Bernard C Lo, PhD, created a new mouse model, injecting microbiota from wild-caught mice into the traditional mouse model.
In this model, the mice did develop colitis after the administration of antibodies used for tumor immunotherapy. Now, researchers could trace back the mechanism to see what was causing this reaction. Colitis developed because of the composition of the gut microbiota, which caused immune T cells to be hyper-activated while regulatory T cells that put the brakes on T cell activation were deleted in the gut.
This was happening within a specific domain of the immune checkpoint antibodies. Researchers then removed that domain, which they found still resulted in a strong anti-tumor response but without inducing colitis. “Previously, there was some data that suggested the presence of certain bacteria correlated with response to therapy. However, it was not proven that microbiota was critical to developing colitis. This work for the first time shows that microbiota is essential to developing colitis from immune checkpoint inhibition,” Nunez said.
To follow up on what they saw in mice, researchers reanalyzed previously reported data from studies of human cells from patients treated with immune checkpoint antibodies, which reinforced the role of regulatory T cells in inducing colitis. The antibody they used to stop the colitis was developed by Takeda Pharmaceuticals. The Rogel team plans additional studies to further understand the mechanisms causing colitis and seeks clinical partners to move this knowledge to a clinical trial.
Additional authors are 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.
