New research from physicians at the Massachusetts General Hospital (MGH) and scientists at the Broad Institute at MIT and Harvard have discovered the mechanisms that cause some cancer patients treated with immune checkpoint inhibitors (ICIs) to develop myocarditis, a dangerous and potentially fatal form of heart inflammation. The research, published today in Nature, identified specific changes that occur in immune and stromal cells in the heart that underlie the condition and also identified biomarkers in the blood that may indicate whether an individual patient’s myocarditis could lead to death.
About one percent of all patients treated with ICIs, which translates to more than 2,000 people every year in the U.S., develop myocarditis, a number that nearly doubles when patients are prescribed certain immunotherapy combination treatments. As many as one-third of patients who develop myocarditis will die from the condition.
Patients who develop this condition due to ICI treatments, referred to as checkpoint myocarditis often have their cancer therapy stopped in an attempt to mitigate the inflammation in the heart. Other methods include the administration of large doses of steroids. Both approaches have limited effects in reversing the condition and can interfere with the cancer-fighting effects of ICI treatments.
“We don’t have great solutions now to help these patients, so we try everything to shut down the immune system and reverse myocarditis, but that’s an imprecise approach that comes with its own risks,” said Alexandra-Chloé Villani, PhD, co-senior author of the study and an investigator at the Broad Institute. “Our results provide a more detailed picture of what’s happening in the heart and suggest intriguing new ways forward to improve patient care.”
The new study marks a significant step forward in understanding the immune basis of myocarditis, as the new research found that the immune reaction driving myocarditis is distinct from the anti-tumor immune response. This finding suggests that targeting the immune response in the heart separately from the tumor could allow doctors to address myocarditis more effectively while continuing cancer treatment.
“Myocarditis from immune checkpoint inhibitors is a major hurdle for us clinically,” said co-senior author Kerry Reynolds, MD, clinical director of inpatient oncology at MGH and an assistant professor of medicine at Harvard Medical School. “This study is a game-changer, paving the way to unearthing the roots of these complications.”
Importantly, the research has identified a number of potential therapeutic targets and found specific markers in the blood that could predict whether myocarditis would progress to more severe forms of the disease, potentially paving the way early intervention for patients at higher risk.
Co-senior author Tomas Neilan, MD, director of the cardio-oncology program at MGH, noted that these findings “provide a biological foundation for testing more targeted therapies for myocarditis due to an immune checkpoint inhibitor.” He added, “This paper is a major step forward as we need to improve our understanding of this toxicity, and this will lead to improved outcomes.”
The researchers are now applying their findings to ongoing clinical trials, including the ATRIUM trial, which is exploring the use of the drug abatacept, typically used to treat arthritis, to manage myocarditis. “We always want better patient outcomes, but we need hard evidence from clinical trials on how to resolve the inflammation while preserving anti-tumor responses,” said Reynolds.
By studying the immune mechanisms behind myocarditis, the researchers hope to uncover shared pathways that could apply to other organ systems affected by immunotherapy, such as the liver, lungs, and kidneys.
While the study’s findings provide hope for better management of myocarditis, they also serve as a reminder of the risks associated with immune checkpoint inhibitors. “Immunotherapy drugs are miracle life-saving medicines, and patients should not be afraid of them,” Villani said. “We just need to make them work better so that we can maximize their anti-tumor treatment benefit while minimizing the risk of adverse events.”
