JAN 11, 2024 8:30 AM PST

Adverse Effects Minimized for Immunotherapy Treatment

Immunotherapy has transformed the way we treat cancer patients. An alternative approach to chemotherapy, immunotherapy enhances the immune system to target cancer. One type of immunotherapy is a category known as immune checkpoint inhibitors (ICIs). Immune checkpoint inhibitors block the binding between two cells that prevent the activation or the function of T cells. T cells are a critical immune cell population responsible for targeting and killing pathogens and infected cells.

Two types of immune checkpoint inhibitors include anti-CTLA-4 and anti-PD-1. Both therapies target T cells, but at different stages of the immune response. Anti-CTLA-4 targets the interaction between antigen presenting cells (APC) and T cells. An antigen presenting cell is a general term that defines the antigen presenting function of various immune cells including dendritic cells, macrophages, and B-cells. CTLA4 is a marker on T cells, and it can bind to a ligand, known as B7, on an APC. This interaction prevents the T cell from becoming activated and travel to the point of inflammation (i.e., cancer) and target the infected cells. Anti-PD-1 blocks the interaction between the PD-1 on the T cell and another cell (including cancer cells), which express PD-L1. In this case the surface marker interaction prevents T cell function. The use of both these ICIs have significantly reduced solid tumor growth and in some cases cured patients without an incident of recurrence. However, it has become widely known that immune checkpoint inhibitors can cause colitis or inflammation of the intestinal tract. A side effect of colitis can cause extreme pain and lead to patients discontinuing cancer treatment.

A group from the Rogel Cancer Center at the University of Michigan led by Dr. Gabriel Nunez, investigated this phenomenon to determine why this adverse side effects occurs. The report published in Science identified a key mechanism responsible for severe gastrointestinal (GI) problems related to anti-CTLA4. In addition, Nunez’s group discovered a way to administer the drug and not cause colitis.

To uncover this mechanism Nunez’s group used mouse models to study the gut microbiota. Interestingly, mice previously did not get colitis, so the team had to take microbiota from wild mice and inject into the lab mice. In the mouse models used, tumor-bearing mice developed colitis after treatment with anti-CTLA-4. Nunez and others speculated that the gut microbiota composition caused the colitis. According to the report, the microbiota caused T cells to become extremely active, which allowed the chronic inflammation of the intestines. Additionally, researchers found that this was also caused by the specific T cell subtype defined by a receptor or domain referred to as Fc gamma (Fcγ). Once the Fcγ domain was removed, anti-CTLA4 induced a strong immunological response absent from the colitis side effect. This report for the first time demonstrated the critical role of microbiota in immune checkpoint therapy.

Nunez and others analyzed patient data and further confirmed the relationship between Fcγ domain T cells, microbiota, and colitis. This work is critical for the improvement of treatment for patients. Nunez and his team identified the underlying mechanism of a common ICI adverse effect. Overall, this work can better inform physicians on how to better treat patients and be aware of the immune system-gut relationship that can dictate treatment efficacy.

Report, Rogel Cancer Center, University of Michigan, Gabriel Nunez, Science

About the Author
Master's (MA/MS/Other)
Greetings! I am a predoctoral trainee in the Department of Immunology at Roswell Park Comprehensive Cancer Center. I am passionate about tumor immunology, and hope to one day become an independent principal investigator.
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