Researchers at the University of Michigan Health Rogel Cancer Center, studying the effects ofimmunotherapy, have identified a mechanism that causes severe gastrointestinal problems with immune-based cancer treatment. They also found a way to provide the anti-tumor effect of the treatment without the unwanted side effects.
The results of the study were published in Science.
Immunotherapy: how to counteract side effects
“This is a good example of how understanding a mechanism helps develop a more beneficial alternative therapy. Once we identify the mechanism that causes colitis, we may develop ways to overcome this problem and prevent colitis while preserving the antitumor effect,” said senior study author Gabriel Nunez, MD, Paul de Kruif Professor of Pathology at Michigan Medicines.
Immunotherapy has emerged as a promising treatment for several types of cancer. But immune checkpoint inhibitors can also cause serious side effects, including colitis, which is an inflammation of the digestive tract.
Colitis can cause serious gastrointestinal distress, and some patients will stop cancer treatment because of this. The problem the researchers faced was that while the patients developed colitis, the laboratory mice did not. So the researchers couldn't study what caused this side effect.
To overcome the discomfort of immunotherapy side effects, the Rogel team, led by first author Bernard C. Lo, Ph.D., created a new mouse model, injecting the microbiota of wild-caught mice into the traditional mouse model .
In this model, mice developed colitis after administration of antibodies used for tumor immunotherapy. Now, researchers could trace back the mechanism to see what was causing this reaction.
Indeed, colitis developed due to the composition of the gut microbiota, which caused hyperactivation of immune T cells while regulatory T cells that restrain T cell activation were eliminated in the intestine.
This was happening within a specific domain of immune checkpoint antibodies. The researchers then removed that domain, which they found still caused a strong anti-tumor response but without inducing colitis.
“Previously, there was some data suggesting the presence of certain bacteria related to response to immunotherapy. But it had not been proven that the microbiota was essential for developing colitis. This work shows for the first time that the microbiota is essential for developing colitis by immune checkpoint inhibition,” Nunez said.
To follow up on what they saw in mice, the researchers reanalyzed previously reported data from studies in human cells from patients treated with immune checkpoint antibodies, which enhanced the role of regulatory T cells in inducing colitis.
The antibody used to stop colitis was developed by Takeda Pharmaceuticals. Rogel's team plans further studies to better understand the mechanisms that cause colitis and seeks clinical partners to transfer this knowledge into a clinical trial.
Taking vitamin D supplements can help prevent a potentially serious side effect of cancer immunotherapy.
Immune checkpoint inhibitors help the immune system recognize and fight cancer cells, and while these treatments have helped many patients and prolonged their lives, they can cause side effects such as colitis, an inflammatory reaction in the colon.
“Immune checkpoint inhibitor-induced colitis may limit the use of such life-saving drugs leading to treatment interruption. Although it is one of the most common and serious adverse events of immunotherapy, there is a lack of understanding of risk factors that could be modified to prevent colitis,” said Osama Rahma, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.
Dr. Rahma and his colleagues conducted a study that examined whether taking vitamin D supplements could reduce the risk of colitis in patients receiving immunotherapy to treat cancer.
The team chose this strategy because previous studies have found that vitamin D can affect the immune system in autoimmune disorders and inflammatory bowel disease.
The study included information on 213 patients with melanoma who received immune checkpoint inhibitors between 2011 and 2017. Thirty-seven (17%) of these patients developed colitis. Sixty-six patients in the study (31%) took vitamin D supplements before starting treatment with immunotherapy.
Patients taking vitamin D were 65% less likely to develop colitis, after adjusting for confounding factors. These findings were validated in another group of 169 patients, of whom 49 (29%) developed colitis. In this validation group receiving immunotherapy, vitamin D use was linked to a 54% lower chance of developing colitis.
“Our findings of a link between vitamin D intake and colitis risk reduction could potentially impact practice if validated in future prospective studies,” Dr. Rahma said. “Vitamin D supplementation should be further tested to determine whether it may be a safe, easily accessible, and cost-effective approach to prevent the gastrointestinal toxicity of immunotherapy and to extend the efficacy of immune checkpoint inhibitor treatment in patients with cancer”.
Computed tomography (CT) scans are a reliable tool for establishing a diagnosis of immune-related colitis, a potentially life-threatening adverse event in patients with advanced melanoma receiving ipilimumab immunotherapy, and this noninvasive approach could provide a safer tool An alternative to colonoscopy and biopsy to confirm colitis.
“Immune checkpoint inhibitors, such as ipilimumab and nivolumab, can lead to colon inflammation, and up to 15% of patients receiving ipilimumab alone or in combination with antibodies targeting the PD-1 pathway experience significant immune-related effects colitis,” said senior author Patrick Ott, MD, PhD, clinical director of the Center for Immuno-Oncology and Melanoma Center at Dana-Farber Cancer Institute (DFCI) in Boston.
“Immunotherapy-related colitis can be a life-threatening adverse event for patients receiving immune checkpoint inhibitors. However, there are no clear guidelines on how to best establish the diagnosis,” Ott added. Colonoscopy is certainly the gold standard for diagnosing colitis, however it is an invasive and expensive procedure that carries some risk of intestinal perforation, he explained .
“Our study demonstrates that CT scans are a good means of establishing a diagnosis of immunotherapy-related colitis,” Ott said.
To evaluate whether CT scans can provide a safer, faster, and more cost-effective alternative to reliably diagnose colitis, Ott and colleagues retrospectively evaluated 303 patients with metastatic melanoma who had been treated with ipilimumab at the DFCI between 2008 and 2015.
Thirty-three percent of patients (99) who received ipilimumab experienced diarrhea and other gastrointestinal (GI) symptoms related to colitis; Forty-six of these patients were diagnosed with immunotherapy colitis based on direct visualization and biopsy of the colonic mucosa or the need for corticosteroids for resolution of gastrointestinal symptoms. Thirty of the 46 patients with colitis had undergone both colonoscopy/biopsy and CT.
The researchers correlated the CT scans with biopsy results when both were performed and with the need for corticosteroids for resolution of colitis (suggesting that patients most likely had colitis) and found that the CT scans had predictive value 96% positive, meaning they predicted colitis correctly 96 times out of 100.
Scans commonly showed thickening of the bowel wall and problematic air/fluid levels. Only 3% of colitis patients had no CT findings. The team also found that age, the number of doses of ipilimumab, and shorter intervals between doses increased the risk of immunotherapy colitis. The method's strong predictive value could help doctors avoid riskier colonoscopies, Ott noted.
“Immunotherapy, particularly the use of immune checkpoint inhibitors, is a rapidly evolving field, and many oncologists have yet to learn how to best address these toxicities; therefore, given that colitis is one of the most dangerous diseases, better diagnostic guidance should be helpful,” Ott said.
While CT scans had a positive predictive value of 96%, their ability to predict the absence of colitis was only 42.9%, indicating that CT scans may be much less accurate in ruling out immunotherapy colitis.
The study's retrospective design and single-institution design are both potentially limiting factors, Ott said. Additionally, ipilimumab monotherapy is only used in patients with melanoma. However, he added, promising data on the efficacy of ipilimumab in combination with nivolumab in several malignancies suggests that these combined treatments will be used more frequently in the future, potentially leading to many more cases of immunotherapy colitis.
Because the mechanisms causing immune-related colitis are considered similar between different checkpoint inhibitors, the findings can likely be extrapolated to combination regimens, Ott said. Although a prospective study would be needed to validate the study findings, the authors they believe this research provides valuable information that can advance treatment.
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