ANN ARBOR, Mich. — Immune-based treatments have been very effective for many people dealing with cancer, but these approaches to destroying tumors may also cause severe gastrointestinal issues, a new study reveals. The factors driving these side-effects have remained a mystery, until now. Researchers from the University of Michigan Health Rogel Cancer Center have discovered the specific mechanism causing these intestinal problems.
Even better, researchers add they’ve also uncovered a new way to deliver cancer-killing immunotherapy without causing any extra gastrointestinal symptoms.
“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,” says senior study author Gabriel Nunez, M.D., the Paul de Kruif Professor of Pathology at Michigan Medicine, in a media release.
Immunotherapy has emerged in recent years as one of the top new treatments for numerous varieties of cancer. Unfortunately, many patients treated in this manner have reported developing severe side-effects, including colitis, which typically causes inflammation in the digestive tract. Colitis can also cause seriously severe gastrointestinal discomfort and some cancer patients choose to stop their immunotherapies over the unbearable side-effects.
Researchers noticed that while human patients were developing colitis in response to such treatments, lab mice were not displaying the same side-effects. So, they set out to better understand what is causing these issues in humans.
The research team, led by first author Bernard C. Lo, Ph.D., put together a new experiment by injecting microbiota from wild-caught mice into the traditional mouse model. While observing this new model, study authors saw that the mice did indeed develop colitis after receiving tumor immunotherapy antibodies. With that information in hand, they could then trace back the mechanism to see what was driving this reaction.
This experiment revealed that colitis was developing due to the composition of the gut microbiota. The bacteria in the intestines were causing immune T-cells to hyper-activate. Meanwhile, this process also deleted regulatory T cells intended to impede T cell activation from the gut. This was all occurring within a very specific domain of the immune checkpoint antibodies. Crucially, when study authors removed that domain, they discovered a strong anti-tumor response remained while colitis never developed.
“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,” Prof. Nunez concludes.
After this experiment with mice, study authors reassessed a set of previously reported data taken from studies of human cells gathered from patients treated using immune checkpoint antibodies. This strategy further validated the role of regulatory T cells in the development of colitis. The specific antibody chosen to stop colitis was developed by Takeda Pharmaceuticals.
The study is published in the journal Science.
While it’s only anecdotal evidence, it may be helpful to someone. I had Large B Cell Lymphoma. I was placed on a trial of Lenalitaminde, an immune booster. I experienced intestinal distress, so I began to take four tablets of Lactinex ™, a probiotic, with each dose of Lenalitaminde. The intestinal distress went away. That was eight years ago and I am still cancer-free without chemotherapy. I am pleased to see the medical profession is finally catching up.