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Patients undergoing treatment with immune checkpoint inhibitors, a specific type of cancer immunotherapy, are at risk of developing a severe heart condition known as myocarditis. A research team associated with the Broad Institute of MIT and Harvard, along with Massachusetts General Hospital (MGH), has discovered the immune-related mechanisms behind this inflammatory condition. They have identified modifications in particular immune and stromal cell types in the heart that contribute to myocarditis and have identified blood markers that might predict the likelihood of a patient’s myocarditis resulting in death.
Published in Nature, these findings are among the earliest applications from the Severe Immunotherapy Complications (SIC) Service and Clinical-Translational Research Effort located at Mass General Cancer Center, which includes Broad researchers. Initiated in 2017, this pioneering program in North America aims to enhance the diagnosis, treatment, and understanding of severe complications arising from immunotherapy that may impact nearly all organ systems. The focus on myocarditis was chosen early in their research due to its rarity compared to other complications from immune checkpoint inhibitors (ICIs), yet it remains the most lethal.
The significance of these discoveries lies in their demonstration that the immune reaction occurring in the heart is separate from the immune response associated with tumors. This suggests the potential for targeted therapies that can address myocarditis without hindering patients’ access to vital anti-cancer immunotherapy. Moreover, the findings illuminate possible treatment targets that support an ongoing clinical trial at MGH, which is testing a medication specifically for this heart inflammation.
About 1% of patients receiving an ICI, which translates to over 2,000 individuals annually in the US, develop myocarditis. This figure increases to nearly 2% in patients undergoing certain combination immunotherapy treatments. Myocarditis can lead to serious cardiac complications such as arrhythmias and heart failure in 50% of cases, with around one-third of those affected dying from it, even with current interventions. Furthermore, traditional treatments used for other forms of myocarditis, like viral-related myocarditis, are ineffective against this condition.
“We currently lack effective solutions for these patients, so our approach typically tries to suppress the immune system to reverse myocarditis, an imprecise strategy that brings its own risks,” commented study co-senior author Alexandra-Chloé Villani, a member at the Broad Institute and an investigator at MGH. “Our findings offer a clearer insight into the heart’s condition and open up exciting new possibilities for enhancing patient care.”
“Myocarditis caused by immune checkpoint inhibitors poses a significant clinical challenge,” noted co-senior author Kerry Reynolds, clinical director of inpatient oncology at MGH and assistant professor of medicine at Harvard Medical School. “This study represents a major advancement, helping us to uncover the underlying causes of these complications. We extend our heartfelt gratitude to our patients, their clinical care teams, and the remarkable laboratory team that made this research possible.”
“This research lays a biological groundwork for exploring more targeted therapies for myocarditis related to immune checkpoint inhibitors. It is an essential step forward in enhancing our understanding of this toxicity, which should result in better patient outcomes,” added co-senior author Tomas Neilan, an associate professor of medicine at Harvard Medical School.
Benefits and risks
Roughly one-third of cancer patients in the United States qualify to receive innovative drugs known as immune checkpoint inhibitors (ICIs). These medications belong to the immunotherapy category, functioning by unleashing the immune system to combat cancer.
The risk of severe complications, along with management difficulties, is increasing as more patients receive ICI therapies each year. In 2020, over 230,000 patients in the US were treated with ICIs, a number that continues to rise with the FDA’s endorsement of more than 80 new indications. Most patients receiving one or more ICI drugs will encounter at least one type of toxicity, and anywhere from 10% to over 50% may develop serious complications. These complications can be challenging to resolve or reverse, even with discontinuation of treatment, with life-threatening organ inflammation possible after just one dose. Currently, doctors lack effective targeted treatments; as a result, they often have to cease anti-tumor therapy or administer high doses of steroids, which come with their own unwanted side effects, such as reducing the effectiveness of ICI anti-tumor treatments.
Among the more serious complications of immunotherapy, checkpoint myocarditis poses a greater risk to patients than myocarditis from other origins, though the reasons behind this distinction remain unclear. “Since we first started observing checkpoint myocarditis less than ten years ago, it’s mostly remained a mystery,” commented co-first author Daniel Zlotoff, a cardiologist at MGH. “We are just beginning to answer essential biological inquiries that we believe will illuminate the most effective treatments to make this condition more manageable and improve patient outcomes.”
In this new study, researchers gathered blood samples from individuals who developed myocarditis during ICI therapy, along with paired heart and tumor tissues from some. As patients underwent diagnostic evaluations at the SIC Service, samples were collected and sent to the lab, where the team conducted single-cell RNA sequencing, microscopy, proteomic analysis, and T-cell receptor sequencing to identify the cells involved in the inflammatory processes related to myocarditis.
In the cardiac tissue of patients, the researchers noted the activation of molecular pathways that assist in recruiting and retaining immune cells associated with inflammation. They also observed an increase in certain immune cell types and cellular groupings that included cytotoxic T cells, conventional dendritic cells (cDCs), and inflammatory fibroblasts present in the hearts of patients with the active disease. In blood samples, they detected decreases in plasmacytoid dendritic cells, cDCs, and B lineage cells, along with heightened numbers of other mononuclear phagocytes.
The team also analyzed the T-cell…
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A receptor is a specialized protein complex that attaches to and reacts to external substances called antigens. In this study, the T-cell receptors found in the damaged cardiac tissue were different from those observed in tumors, contradicting earlier studies that indicated the immune responses in both the heart and tumors were alike. Additionally, the researchers did not find any T-cell receptors that recognized the α-myosin protein, which previous studies identified as a key antigen involved in checkpoint myocarditis. These findings indicate that the most prevalent T-cell receptors in the heart tissue respond to unknown antigens. Looking ahead, the researchers aim to identify the specific antigens relevant to both the heart and tumors, determining whether they are normal proteins, mutated tumor proteins, viruses, or new substances altogether.
“Since the immune responses in the tumors and the heart differ, we are optimistic about the possibility of treating them separately one day,” stated co-first author Steven Blum, an oncologist at MGH and postdoctoral fellow in the Villani lab. “We are particularly thankful to the patients who choose to participate; their contributions are the most significant gift to research.” The research team appreciates the support from MGH and Broad members involved in the Rapid Autopsy Program, created by Dejan Juric, as well as the hospital’s pathology team, especially James Stone.
The analysis of T cell subtypes in the blood also suggested which patients might be at higher risk of severe myocarditis, indicating that blood tests could potentially help identify patients needing close monitoring or those who should avoid immunotherapy. Moreover, T cells present in the bloodstream that originated from the heart correlated with the disease’s severity. This discovery paves the way for a blood diagnostic test that could replace the need for invasive heart biopsies in patients suspected of having myocarditis.
This research also backs a current clinical trial (ATRIUM, NCT05335928) at MGH that is examining the efficacy of an arthritis medication, abatacept, in managing myocarditis in these patients. “Our goal is always to improve patient outcomes, but we require solid evidence from clinical trials to manage inflammation without compromising anti-tumor responses,” noted Reynolds. “These cellular maps are instrumental in directing our clinical trial discussions.”
By treating and researching complications across various organ systems, the experts aim to discover both unique and common mechanisms that reveal why adverse effects affect multiple body parts simultaneously in these patients. They are also collaborating with other institutions that share the mission of enhancing immunotherapy and cancer care, giving guidance for similar initiatives within the field.
“It’s crucial to remember that immunotherapy medications are remarkable, life-saving treatments, and patients should not shy away from them,” highlighted Villani. “What we need is to improve their effectiveness so we can maximize the anti-tumor benefits while reducing the chances of adverse effects.”
Other key contributors to the study include co-first authors Neal Smith, Isabela Kernin, and Swetha Ramesh, along with co-senior author Molly Thomas.
