Researchers may have uncovered the immune basis for the development of myocarditis in patients with cancer receiving immune checkpoint inhibitors, according to a recent study published by Blum et al in Nature. The findings revealed 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.
Background
More than 230,000 patients in the United States were treated with immune checkpoint inhibitors in 2020, a number that has likely grown since the U.S. Food and Drug Administration approved more than 80 indications for these drugs. However, as more patients undergo this type of therapy each year, the threat of serious immune checkpoint inhibitor–related complications is growing. Most patients receiving one or more immune checkpoint inhibitor will develop at least one type of toxicity, and—depending upon the drug given—10% to more than 50% of them may develop a severe complication. These complications can be difficult to halt or reverse, even with treatment discontinuation, and patients can develop life-threatening organ inflammation following a single dose. In the absence of effective targeted treatments, physicians often have to stop the antitumor therapy or give large amounts of steroids, which can decrease the efficacy of the immune checkpoint inhibitor therapy.
Roughly 1% of patients treated with an immune checkpoint inhibitor—over 2,000 patients per year in the United States—will develop myocarditis, and this number increases to nearly 2% among patients treated with certain combinations of immunotherapy drugs. Myocarditis leads to dangerous cardiac events such as arrhythmia and heart failure in 50% of cases, and about 33% of those who develop the condition will die from it, regardless of current treatments. In addition, treatments and supportive care approaches used for other types of myocarditis such as viral myocarditis have proven ineffective for this type.
“Myocarditis from immune checkpoint inhibitors is a major hurdle for us clinically,” detailed co–senior study author Kerry Reynolds, MD, Assistant Professor of Medicine at Harvard Medical School, Clinical Director of Inpatient Oncology at the Massachusetts General Hospital, and Director of the Severe Immunotherapy Complications Service. “This study is a game-changer, paving the way to unearthing the roots of these complications. We are incredibly grateful to each and every patient who partnered with us, all those involved in their clinical care, and the exceptional team in our lab[oratory] who made this research possible,” she highlighted.
Myocarditis related to the use of immune checkpoint inhibitors is significantly more dangerous compared with myocarditis from other causes; however, there is little understanding of the reasons why.
“Since we first started seeing [immune] checkpoint [inhibitor–related] myocarditis less than a decade ago, it’s largely been a black box,” noted co–lead study author Daniel Zlotoff, MD, PhD, a postdoctoral fellow in the Villani Laboratory, a cardiologist, and an assistant in Medicine at the Massachusetts General Hospital. “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,” he added.
“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,” explained co–senior study author Alexandra-Chloé Villani, PhD, Assistant Professor of Medicine at Harvard Medical School, an institute member at the Broad Institute, as well as an investigator in the Krantz Family for Cancer Research and the Center for Immunology and Inflammatory Diseases at the Massachusetts General Hospital. “Our results provide a more detailed picture of what’s happening in the heart and suggest intriguing new ways forward to improve patient care,” she emphasized.
The results of the study are among the earliest translational findings to come from the Severe Immunotherapy Complications Service and Clinical-Translational Research Effort. Launched in 2017, the initiative was 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.
Study Methods and Results
In the study, the researchers collected blood from patients who developed myocarditis while receiving immune checkpoint inhibitor therapy as well as from paired heart and tumor tissue from some of the patients. As the patients underwent diagnostic procedures at the Severe Immunotherapy Complications Service, or after they died from the disease, samples were taken and rapidly sent to the laboratory—where the researchers 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.
In the heart tissue of the patients, the researchers observed the upregulation of molecular pathways that help recruit and retain immune cells involved in inflammation. They also observed an increase in abundance of several immune cell subsets as well as an increase in abundances of certain cellular groupings composed of specific cytotoxic T cells, conventional dendritic cells, and inflammatory fibroblasts that were found together in the hearts of patients with active disease. In the blood, they found reductions in plasmacytoid dendritic cells, conventional dendritic cells, and B-lineage cells along with increased numbers of other mononuclear phagocytes.
On further analysis, the researchers found that T-cell receptors abundant in the affected heart tissue were distinct from those seen in tumors, in contrast to previous findings suggesting that the immune responses in a patient’s heart and tumor were the same. The researchers also found no evidence of T-cell receptors recognizing the alpha-myosin protein, which was previously reported to be a pivotal antigen driving immune checkpoint inhibitor–related myocarditis. The researchers suggested that the T-cell receptors most abundant in affected heart tissue recognize undetermined antigens.
The pattern of T-cell subtypes in the blood also indicated which individuals were more likely to die from myocarditis, suggesting that a blood-based measurement could one day be used to identify patients who are at increased risk and should be monitored closely or avoid immunotherapy altogether. They found T cells in the peripheral blood that originated in the heart and correlated with severity of disease. The findings could lead to the development of a diagnostic blood test that could replace invasive heart biopsies in patients suspected of having myocarditis.
Conclusions
“This work provides a biological foundation for testing more targeted therapies for myocarditis [caused by] an immune checkpoint inhibitor. This paper is a major step forward as we need to improve our understanding of this toxicity, and ... [may] lead to improved outcomes,” underscored co–senior study author Tomas Neilan, MD, MPH, Associate Professor of Medicine at Harvard Medical School, Director of ther Cardio-Oncology Program and Co-Director of the Cardiovascular Imaging Research Center at Massachusetts General Hospital.
Notably, the findings provided the first evidence for an immune reaction in the heart that is distinct from the immune response at the tumor, suggesting that targeted treatments might be able to address myocarditis while allowing patients to continue receiving potentially life-saving antitumor immunotherapy. The results also identified possible therapeutic targets that bolster the rationale behind an ongoing clinical trial that is currently testing a drug for this kind of heart inflammation.
In future studies, the researchers hope to identify the particular antigens at play in the heart and the tumor and discern whether they are normal proteins, mutated tumor proteins, foreign particles like viruses, or something novel.
“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,” underscored co–lead study author Steven Blum, MD, a postdoctoral fellow in the Villani Laboratory and an oncologist at the Massachusetts General Hospital. “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 research also lent support to the ongoing ATRIUM clinical trial (Clinicaltrials.gov identifier NCT05335928) based at the Massachusetts General Hospital 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 antitumor responses. These cell maps help guide us to what we should be studying in clinical trials,” stated Dr. Reynolds.
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 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. We just need to make them work better so that we can maximize their antitumor treatment benefit while minimizing the risk of adverse events,” concluded Dr. Villani.
Disclosure: The research in this study was supported in part by the National Institutes of Health, the Damon Runyon Cancer Research Foundation, the Melanoma Research Alliance, the Mass General Hospital Transformative Scholar in Medicine Award, and the Howard M. Goodman Fellowship. For full disclosures of the study authors, visit nature.com.
