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Researchers identify why cancer immunotherapy causes gastro problems

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Researchers in the US have identified a mechanism that causes severe gastrointestinal problems with immune-based cancer treatment.

The team at 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 the journal Science.

Senior study author, Gabriel Nunez, M.D., Paul de Kruif Professor of Pathology at Michigan Medicine, said: “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-tumour effect.”

Immunotherapy has become a promising treatment for several types of cancer.

However, immune checkpoint inhibitors can also cause severe side effects, including ulcerative colitis, which is inflammation in the digestive tract.

The condition 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 ulcerative colitis, the laboratory mice were not, so researchers couldn’t study what was causing this side effect.

To get past this, the researchers, led by first author Bernard C. Lo, Ph.D., created a new mouse model, injecting microbiota from wild-caught mice into the traditional mouse model.

In this model, the rodents did develop ulcerative colitis after administration of antibodies used for tumour immunotherapy.

Now, scientists could trace back the mechanism to see what was causing this reaction.

In fact, ulcerative colitis developed due to 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 occurring within a specific domain of the immune checkpoint antibodies.

Scientists then removed that domain, which they found still resulted in a strong anti-tumour response but without inducing ulcerative colitis.

Nunez said: “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.”

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 ulcerative colitis.

The Rogel has planned additional studies to further understand the mechanisms causing the condition and seeks clinical partners to move this knowledge to a clinical trial.

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