Researchers at the Health Rogel Cancer Center at the University of Michigan have identified a mechanism that causes severe gastrointestinal problems during immunotherapy cancer treatment.
They also found a way to achieve the cancer-killing effect of immunotherapy without unwanted side effects.
The results are published in Science.
This is a great example of how understanding a mechanism helps you develop an alternative therapy that is more beneficial. Once we identified the mechanism causing colitis, we could develop ways to overcome this problem and prevent colitis while maintaining the anti-tumor effect,“ said Gabriel Nunez, MD, senior author of the study, Paul de Kruif Professor of Pathology at Michigan Medicine.
Gabriel Nunez, M.D., lead study author, Paul de Kruif Professor of Pathology at Michigan Medicine.
Immunotherapy has proven to be a promising treatment for several types of cancer. However, immunotherapy checkpoint inhibitors can cause severe side effects, including colitis, inflammation in the digestive tract.
Colitis can cause severe gastrointestinal discomfort, and some patients discontinue their cancer treatment as a result.
The problem for the researchers was that while patients developed colitis, lab mice did not. Therefore, the researchers could not investigate what caused this side effect.
To overcome this, the Rogel team, led by lead author Bernard C. Lo, Ph.D., developed a new mouse model by injecting microbiota from wild mice into the traditional mouse model.
In this model, the mice developed colitis after receiving antibodies for tumor immunotherapy. Now researchers could trace back the mechanism to find out what caused this reaction.
Indeed, colitis developed due to the composition of the gut microbiota, which led to the overactivation of immune T cells, while regulatory T cells that dampen T cell activation were depleted in the gut.
This occurred within a specific domain of the immunotherapy checkpoint antibodies.
The researchers then removed this domain, which, in their opinion, still led to a strong anti-tumor response without triggering colitis.
„Previously, there were some data suggesting that the presence of certain bacteria is associated with therapy response. However, it was not proven that gut microbiota are essential for the development of colitis. This work demonstrates for the first time that gut microbiota are essential for the development of colitis upon immunotherapy checkpoint inhibition,“ Nunez said.
To follow up on what they saw in mice, the researchers analyzed previously published data from studies on human cells from patients treated with immunotherapy checkpoint antibodies, further strengthening the role of regulatory T cells in triggering colitis.
The antibody that they used to stop colitis was developed by Takeda Pharmaceuticals.
The Rogel team plans further studies to better understand the mechanisms that cause colitis and is seeking clinical partners to translate this knowledge into a clinical trial.
Other 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.
This work was funded 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 grants IOS-2107215.
This work was supported by the following shared resources of the Rogel Cancer Center: single-cell spatial analysis, tissue and molecular pathology.
Michigan Medicine – University of Michigan
Lo, BC, et al. (2024). Microbiota-Dependent Activation of CD4+ T Cells Induces CTLA-4 Blockade-Associated Colitis. Science. doi.org/10.1126/science.adh8342.