Why Do Cancer Immunotherapy Side Effects Differ Among Patients?
Immune checkpoint inhibitors have become a central part of melanoma treatment. Doctors now use them for many patients, from those with high risk melanoma after surgery to people whose cancer has spread to other organs. Drugs such as pembrolizumab, nivolumab, ipilimumab and nivolumab-relatlimab work by helping the immune system recognize and attack melanoma cells after blocking signals that normally keep immune responses in check. For many patients, these therapies have changed how melanoma gets treated and have allowed long term cancer control, survival and even cure in cases that once had few options. Because of this success, checkpoint inhibitors now play a central role in care across many stages of the disease.
At the same time, these powerful drugs carry real risks. When the immune system turns fully on to fight cancer, it can also damage healthy tissue. One of the most common and serious side effects affects the colon and causes immune-mediated colitis. Patients can develop diarrhea, abdominal pain and even bleeding. In the most serious cases, the condition can become life threatening. Doctors may have to pause or stop melanoma treatment so they can treat the inflammation with steroids or other immune suppressing medicines.
Ahmad Tarhini, MD, PhD
“This is a challenging condition in the clinic that requires close attention and careful monitoring,” said Ahmad Tarhini, MD, PhD, a medical oncologist in the Cutaneous Oncology Department and lead investigator of the study. "While immunotherapy demonstrates exceptional efficacy in managing melanoma, it can incite an overactive immune response, leading to significant adverse events that cannot be overlooked.”
Analyzing Genetic Markers
New research presented at the American Association for Cancer Research Annual Meeting suggests that inherited genetics may help explain why some patients develop this complication while others do not. Tarhini and his fellow researchers studied samples from 744 patients enrolled in a large melanoma trial. All patients received immunotherapy. Using genome-wide testing, investigators examined hundreds of thousands of inherited genetic markers to see whether certain patterns are linked to colitis after treatment. The analysis accounted for differences in genetic ancestry to help isolate true genetic risk factors.
The team also examined existing genetic risk scores for inflammatory bowel disease, a condition that shares similarities with immunotherapy-triggered colitis. While these scores did not align with milder side effects, one stood out in patients who developed the most severe and life-threatening forms of colitis. Patients with that inherited profile faced a much higher risk of developing serious colon inflammation. Separately, these researchers identified a novel biomarker signature comprising 10 specific genetic markers, which showed a strong association with colitis risk. When combined into a single score, those markers closely tracked the severity of a patient’s risk of developing colitis and were associated with survival outcomes.
“Our findings suggest that a patient’s inherited genetics play an important role in how their immune system reacts to immunotherapy,” Tarhini said. “This may allow us to identify patients at higher risk for colitis earlier, in order to tailor treatment plans or monitoring in a way that keeps patients safer.”
Tarhini says the findings suggest that a patient’s genetics may influence their response to immunotherapy for melanoma. The research indicates that being able to identify patients at higher risk of serious immune related side effects could help doctors better plan treatment and monitor more closely for early warning signs. While larger studies are still needed before genetic testing becomes part of routine care, the results add new insights into how melanoma treatment could be made safer and more personalized for patients.
