Researchers uncover immune mechanism behind myocarditis from cancer immunotherapy

· News-Medical

Some patients being treated with immune checkpoint inhibitors, a type of cancer immunotherapy, develop a dangerous form of heart inflammation called myocarditis. Researchers led by physicians and scientists at the Broad Institute of MIT and Harvard and Massachusetts General Hospital (MGH), a founding member of the Mass General Brigham healthcare system, have now uncovered the immune basis of this inflammation. The team identified changes in specific types of immune and stromal cells in the heart that underlie myocarditis and pinpointed factors in the blood that may indicate whether a patient's myocarditis is likely to lead to death.

Appearing in Nature, the results are among the earliest translational findings to come from the Severe Immunotherapy Complications (SIC) Service and Clinical-Translational Research Effort, which is based at Mass General Cancer Center and includes Broad researchers. Launched in 2017, this is a first-of-its-kind program in North America focused on improving the diagnosis, treatment, and understanding of serious immunotherapy complications, which can affect nearly every organ system. The team focused on myocarditis as one of their first research projects because despite being one of the rarer complications from immune checkpoint inhibitors (ICIs), it is the most deadly.

Roughly 1 percent of patients treated with an ICI -; more than 2,000 individuals a year in the US -; will develop myocarditis, and this number goes up to nearly 2 percent among patients treated with certain immunotherapy drugs in combination. Myocarditis leads to dangerous cardiac events such as arrhythmia and heart failure in 50 percent of cases, and about a third who develop the condition will die from it, despite current treatments. In addition, treatments and supportive care approaches used for other forms of myocarditis, such as viral myocarditis, don't work for this type.

"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 study co-senior author Alexandra-Chloé Villani, an institute member at the Broad, an investigator in the Krantz Family for Cancer Research and the Center for Immunology and Inflammatory Diseases at MGH, and an assistant professor of Medicine at Harvard Medical School who leads the translational research endeavors related to the SIC Service at MGH. "Our results provide a more detailed picture of what's happening in the heart and suggest intriguing new ways forward to improve patient care."

"This work provides a biological foundation for testing more targeted therapies for myocarditis due to an immune checkpoint inhibitor. This paper is a major step forward as we need to improve our understanding of this toxicity, and this will lead to improved outcomes," said co-senior author Tomas Neilan, an associate professor of medicine at Harvard Medical School and director of the Cardio-Oncology Program and co-director of the Cardiovascular Imaging Research Center at Mass General.

Benefits and risks

The threat of serious complications and the challenge of how to manage them is growing as more patients undergo ICI treatment each year. More than 230,000 patients in the US were treated with ICIs in 2020, and that number has likely grown since then as the FDA has approved more than 80 indications for these medicines. Most patients taking one or more ICI drugs will develop at least one form of toxicity and, depending upon the drug given, ten percent to more than 50 percent will develop a severe complication. The complications can be difficult to halt or reverse, even if the treatment is stopped, and patients can develop life-threatening organ inflammation after a single dose. Doctors currently don't have effective targeted treatments, so they often have to stop the anti-tumor therapy or give large amounts of steroids, which have their own undesired side effects such as lowering the efficacy of the ICI anti-tumor treatment.

One of the more feared complications of immunotherapy, checkpoint myocarditis is significantly more dangerous for patients than myocarditis from other causes and it's unclear why. "Since we first started seeing checkpoint myocarditis less than a decade ago, it's largely been a black box," said co-first author Daniel Zlotoff, a cardiologist and assistant in medicine at MGH and postdoctoral fellow in the Villani lab. "Only now are we starting to answer the fundamental biological questions, which we hope will shed light on the optimal treatments to make it more tolerable and improve outcomes for patients."

In the new study, the researchers collected blood from individuals who developed myocarditis while on ICI therapy and consented to be part of the study, along with paired heart and tumor tissue from some. As patients underwent diagnostic procedures at the SIC Service, or after they succumbed to the illness, samples were taken and rapidly sent to the lab, where the research team performed single-cell RNA sequencing analysis along with microscopy, proteomic analysis, and T-cell receptor sequencing to identify cells involved in driving and sustaining the inflammatory processes associated with myocarditis.

"Because the responses in the tumor and the heart are different, it makes us hopeful that we can someday disentangle the two and treat them separately," said co-first author Steven Blum, an oncologist at MGH and postdoctoral fellow in the Villani lab. "We're especially grateful to the patients who are willing to participate. Ultimately, it's the biggest gift that a patient can give to research." The researchers acknowledge that the result was only possible with crucial contributions from MGH and Broad members who lead the Rapid Autopsy Program, developed by Dejan Juric, and the hospital's pathology team, notably James Stone.

The work also lends support to an ongoing clinical trial (ATRIUM, NCT05335928) based at MGH exploring the use of an arthritis drug, abatacept, to control myocarditis in these patients. "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. "These cell maps help guide us to what we should be studying in clinical trials."

By treating and studying complications across different organ systems, the researchers hope to find both distinct and shared mechanisms that can shed light on adverse events that affect diverse parts of the body in these patients, often simultaneously. The researchers are also working to bring together other institutions that share the goal of improving immunotherapy and cancer patient care, and are providing guidance for similar efforts elsewhere.

"It's important to remember that immunotherapy drugs are miracle life-saving medicines, and patients should not be afraid of them," said Villani. "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."

Source:

Broad Institute of MIT and Harvard

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