Researchers at the University of Michigan Rogel Health Cancer Center have identified a mechanism that causes severe gastrointestinal problems with immune-based cancer therapy.
They also found a way to deliver the cancer-killing effect of immunotherapy without the unwanted side effects.
The findings are published in Science.
This is a good example of how understanding a mechanism helps you develop an alternative treatment that is more beneficial. “Once we identify the mechanism that causes colitis, we could then develop ways to overcome this problem and prevent colitis while maintaining the antitumor effect.”
Gabriel Nunez, MD, Senior Study Author, Paul de Kruif Professor of Pathology at Michigan Medicine
Immunotherapy has emerged as a promising treatment for various types of cancer. But immune checkpoint inhibitors can also cause serious side effects, including colitis, which is inflammation in the digestive tract.
Colitis can cause severe gastrointestinal distress, and some patients will stop cancer treatment because of it.
The problem the researchers faced was that while the patients developed colitis, the lab mice did not. So the researchers couldn’t study what was causing this side effect.
To overcome this, the Rogel team, led by first author Bernard C. Lo, Ph.D., created a new mouse model by injecting microbiota from wild mice into the traditional mouse model.
In this model, mice developed colitis after being given antibodies used for tumor immunotherapy. Now, the researchers could trace the mechanism to see what was causing this reaction.
In fact, colitis developed due to the composition of the gut microbiota, which caused the over-activation of immune T cells, while the regulatory T cells that put the brakes on T cell activation were deleted in the gut.
This was happening in a specific region of the immune checkpoint antibodies.
The researchers then removed this domain, which they found still led to a strong anti-tumor response but without causing colitis.
“Previously, there was some data that suggested the presence of certain bacteria correlated with treatment response. But it hadn’t been shown that the microbiota was critical for the development of colitis. This work for the first time shows that the microbiota is essential for the development of colitis from immune checkpoint inhibition,” Nunez said.
To follow up on what they saw in the mice, the researchers reanalyzed previously reported data from studies of human cells from patients treated with immune checkpoint antibodies, which boosted the role of regulatory T cells in causing colitis.
The antibody they used to stop the colitis was developed by Takeda Pharmaceuticals.
Rogel’s team is planning additional studies to further understand the mechanisms that cause colitis and is seeking clinical collaborators to take 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 came from National Institutes of Health grants 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 these Rogel Cancer Center Shared Resources: Single Cell Spatial Analysis, Tissue and Molecular Pathology.
Source:
Journal Reference:
Well, BC et al. (2024). Microbial-dependent activation of CD4 + T cells induces colitis associated with CTLA-4 blockade through Fcγ receptors. Science. doi.org/10.1126/science.adh8342.
