Immune checkpoint inhibitors, which work by blocking checkpoint proteins from binding with their partner proteins, can stimulate antitumor immunity, have significantly changed clinical practice and the treatment of cancer. Immunotherapy has resulted in durable responses for patients and positive treatment response across several tumor types. [1]

However, immune checkpoint inhibitors can also induce certain toxicities known as immune-related adverse events (irAEs). These toxicities are autoimmune conditions that, after the administration of immune checkpoint inhibitors therapy, can affect any organ in the body. In clinical practice, these toxicities are challenging oncologists, requiring a steep learning curve to diagnose and manage as well as a new approach to balancing the risk of these adverse events with the real benefits of immunotherapy.

Colitis is among the most common and severe irAE that can lead to treatment discontinuation.

Now, for the first time, researchers at the University of Michigan Health Rogel Cancer Center have identified a mechanism that causes severe gastrointestinal problems with immune-based cancer treatment.  They also found a way to deliver immunotherapy’s cancer-killing impact without the unwelcome side effect.

Their findings of their study, which was, in part, funded National Institutes of Health (NIH),  Takeda Millennium Pharmaceuticals, Canadian Institutes of Health, Crohn’s and Colitis Foundation, National Science Foundation and supported by the Rogel Cancer Center Shared Resources of Single Cell Spatial Analysis, Tissue and Molecular Pathology, were published on January 4, 2024 in Science. [2]

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“[The outcome of this study 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,” noted senior study author Gabriel Nunez, M.D., Paul de Kruif 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, laboratory mice were not. So researchers couldn’t study what was causing this adverse event.

A new mouse model
To get past this, the Rogel team, 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 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 explained.

To follow up what they saw in mice, researchers reanalyzed 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.

The antibody they used to stop the colitis was developed by Takeda Pharmaceuticals.

The Rogel team plans additional studies to further understand the mechanisms causing colitis and seeks clinical partners to move this knowledge to a clinical trial.

[1] Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-1492. doi: 10.1016/S1470-2045(18)30700-9. Epub 2018 Oct 22. Erratum in: Lancet Oncol. 2018 Dec;19(12):e668. Erratum in: Lancet Oncol. 2018 Nov;19(11):e581. PMID: 30361170.
[2] Lo BC, Kryczek I, Yu J, Vatan L, Caruso R, Matsumoto M, Sato Y, Shaw MH, Inohara N, Xie Y, Lei YL, Zou W, Núñez G. Microbiota-dependent activation of CD4+ T cells induces CTLA-4 blockade-associated colitis via Fcγ receptors. Science. 2024 Jan 5;383(6678):62-70. DOI: 10.1126/science.adh8342. Epub 2024 Jan 4. PMID: 38175892.

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