Understanding the Link: Researchers Uncover the Reason Behind Cancer Immunotherapy’s Association with Colitis
“Understanding the Mechanism Behind Colitis Induced by Cancer Immunotherapy and Its Solution”
A breakthrough study conducted at the University of Michigan Health Rogel Cancer Center delved into the root cause of severe gastrointestinal issues triggered by immune-based cancer treatment. The team not only pinpointed the mechanism behind this problem but also devised a strategy to retain the cancer-fighting benefits of immunotherapy while sidestepping the adverse side effects.
Published in Science, the study led by senior author Gabriel Nunez, M.D., highlighted how comprehending the underlying mechanism facilitated the development of an alternative therapy. Nunez, the Paul de Kruif Professor of Pathology at Michigan Medicine, emphasized, “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.”
Immunotherapy, heralded as a promising cancer treatment, has demonstrated efficacy against various cancer types. However, immune checkpoint inhibitors used in this therapy sometimes trigger severe side effects, notably colitis, characterized by inflammation in the digestive tract.
The challenge for researchers arose from the discrepancy: while patients experienced colitis, laboratory mice did not display similar symptoms, hindering the investigation into the cause of this side effect.
To bridge this gap, the Rogel team, under the leadership of first author Bernard C. Lo, Ph.D., devised a novel mouse model. This model involved transferring microbiota from wild-caught mice into the traditional mouse model, resulting in the development of colitis in response to tumor immunotherapy antibodies. This breakthrough allowed researchers to trace the precise mechanism triggering the reaction.
The study revealed that colitis stemmed from the composition of the gut microbiota, leading to hyper-activated immune T cells while simultaneously eliminating regulatory T cells that control T cell activation within the gut.
The critical insight was that this phenomenon occurred within a specific domain of the immune checkpoint antibodies.
Subsequently, researchers removed this domain, which, remarkably, maintained a potent anti-tumor response without inducing colitis.
Nunez highlighted the significance of their findings: “This work for the first time shows that microbiota are essential to develop colitis from immune checkpoint inhibition.”
Moreover, researchers reanalyzed data from prior studies involving human cells from patients treated with immune checkpoint antibodies, reinforcing the role of regulatory T cells in colitis induction.
The antibody devised to counteract colitis originated from Takeda Pharmaceuticals. The Rogel team plans further studies to deepen their understanding of the mechanisms underlying colitis and seeks clinical collaborations to advance this knowledge into potential clinical trials.
The study included contributions from various authors, reflecting the collaborative effort involved in this breakthrough research.
source: University of Michigan
