Study Uncovers Reason Behind Colitis Issues in Chemotherapy

Researchers from the University of Michigan Health Rogel Cancer Center have made a significant breakthrough in understanding and mitigating severe gastrointestinal problems associated with immune-based cancer treatment. The study, published in Science, reveals a mechanism causing colitis, inflammation in the digestive tract, linked to immune checkpoint inhibitors, a type of immunotherapy. 

Immunotherapy has shown promise in treating various cancers, but immune checkpoint inhibitors, a specific class of immunotherapy, can lead to severe side effects, including colitis. Colitis often results in gastrointestinal discomfort, causing some patients to discontinue their cancer treatment. 

The challenge for researchers was the absence of colitis development in laboratory mice, hindering their ability to study the side effect. To address this, the Rogel team, led by first author Bernard C. Lo, Ph.D., developed a new mouse model. They injected microbiota from wild-caught mice into the traditional mouse model, resulting in colitis development after administering antibodies used in tumor immunotherapy. This breakthrough allowed researchers to identify the mechanism causing the reaction. 

The study revealed that colitis was triggered by the composition of the gut microbiota, leading to hyper-activation of immune T cells and the deletion of regulatory T cells, which normally control T cell activation in the gut. This effect was localized within a specific domain of the immune checkpoint antibodies. By removing this domain, researchers achieved a potent anti-tumor response without inducing colitis. 

Senior study author Gabriel Nunez, M.D., Paul de Kruif Professor of Pathology at Michigan Medicine, emphasized the importance of understanding the mechanism, stating, “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.” 

The researchers’ findings have implications for microbiota’s essential role in developing colitis from immune checkpoint inhibition, a revelation that was not definitively proven before. This breakthrough challenges previous notions and highlights the critical link between gut microbiota and the side effects of immunotherapy. 

In a significant move towards clinical application, the team removed the problematic domain from the antibodies, resulting in a robust anti-tumor response without inducing colitis. The antibody used for this purpose was developed by Takeda Pharmaceuticals. 

Reanalyzing previously reported data from studies on human cells treated with immune checkpoint antibodies reinforced the role of regulatory T cells in inducing colitis. The researchers plan to conduct further studies to deepen their understanding of the mechanisms behind colitis and are actively seeking clinical partners to move this knowledge into a clinical trial. 

The study marks a pivotal advancement in cancer immunotherapy, offering a potential solution to a debilitating side effect. By unraveling the intricate relationship between gut microbiota and colitis in response to immune checkpoint inhibitors, the researchers have laid the foundation for future clinical interventions that preserve the anti-tumor effects while minimizing adverse gastrointestinal effects. The prospect of clinical trials opens new avenues for improving cancer treatment outcomes and patient quality of life. 

Journal Reference  

Bernard C. Lo et al, Microbiota-dependent activation of CD4 + T cells induces CTLA-4 blockade–associated colitis via Fcγ receptors, Science (2024). DOI: 10.1126/science.adh8342.