Colitis can cause severe gastrointestinal discomfort
US researchers have identified a mechanism that causes
severe gastrointestinal problems with immune-based cancer treatment.
The team from the University of Michigan Health Rogel
Cancer Center also found a way to deliver immunotherapy’s cancer-killing impact
without the unwelcome side effect.
The findings are published in Science.
“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 Gabriel Nunez, 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.
For the study, the team 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
administration of antibodies used for tumor immunotherapy.
Now, researchers could trace back the mechanism to see
what was causing this reaction.
In fact, 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 were some data that suggested the
presence of certain bacteria correlated with response to therapy. But it was
not proven that microbiota were critical to develop colitis. This work for the
first time shows that microbiota are essential to develop colitis from immune
checkpoint inhibition,” Nunez said.
To follow up what they saw in mice, researchers
reanalysed 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.
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