How Cancer Immunotherapy Fuels Heart Inflammation in Some Patients

Importantly, the findings provide the first evidence for an immune reaction in the heart that is distinct from the immune response aimed at the tumor. This suggests that the use of targeted treatments to address myocarditis might allow patients to continue receiving life-saving anti-tumor immunotherapy.

A recently launched clinical trial at Mass General is testing an arthritis medication as a possible treatment for immunotherapy-associated heart inflammation.

“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, HMS associate professor of medicine, director of the Cardio-Oncology Program, and co-director of the Cardiovascular Imaging Research Center at Mass General.

The research is part of the Severe Immunotherapy Complications (SIC) Service and Clinical-Translational Research Effort, which is focused on improving the diagnosis, treatment, and understanding of serious immunotherapy complications, which can affect nearly every organ system.

“Myocarditis from immune checkpoint inhibitors is a major hurdle for us clinically,” said co-senior author Kerry Reynolds, HMS assistant professor of medicine, clinical director of inpatient oncology, and director of the SIC Service at Mass General. “This study is a game changer, paving the way to unearthing the roots of these complications.”

A rare but devastating complication

Nearly one-third of patients with cancer in the United States have tumors that can benefit from treatment with immune checkpoint inhibitors, or ICIs — part of the immunotherapy class of medicines that take the brakes off the body’s immune system so that it can fight cancer.

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 United States were treated with ICIs in 2020.

Most patients taking one or more ICI drugs will develop at least one form of toxicity, and between 10 percent and 50 percent will have a severe complication. These 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.

Roughly 1 percent of patients treated with an ICI — more than 2,000 individuals a year in the United States — will develop myocarditis. The number goes up to nearly 2 percent in patients treated with certain immunotherapy drugs in combination.

ICI-related myocarditis can lead to serious cardiac problems, such as arrhythmia and heart failure in 50 percent of cases. About a third of those who develop this form of myocarditis die from it, despite current therapies.

Notably, treatments and supportive care used for other forms of myocarditis, such as those caused by a virus, don’t work for the immunotherapy-induced form.

“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, HMS assistant professor of medicine, an institute member at the Broad, and an investigator in the Krantz Family Center for Cancer Research and the Center for Immunology and Inflammatory Diseases at Mass General.

“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 said.

Identifying the molecular fingerprints of myocarditis

The new findings are based on analysis of blood, heart, and tumor tissue samples from patients who developed myocarditis while on ICI therapy.

The heart tissue showed upregulation of molecular pathways that help recruit and retain immune cells involved in inflammation. Patients with active disease also had greater abundance of clusters of cytotoxic T cells, dendritic cells, and inflammatory fibroblasts.

In the blood, the team found fewer immune cells called plasmacytoid dendritic cells, dendritic cells, and B cells, which help fight infections. Other immune cells known as mononuclear phagocytes were present in higher numbers.

The team also analyzed the T-cell receptor, a unique protein complex that binds and responds to foreign particles called antigens. T-cell receptors in tissue from affected hearts were distinct from those seen in tumors.

There was also no evidence that T-cell receptors recognized a heart-muscle protein involved in contraction called α-myosin, previously reported to be a pivotal antigen driving immune checkpoint therapy-induced myocarditis. These results suggest that the T-cell receptors most abundant in affected heart tissue recognize undetermined antigens.

The researchers hope to identify the antigens at play in the heart and in the tumor and discern whether they are normal proteins, mutated tumor proteins, foreign particles such as viruses, or something else.

“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, HMS instructor in medicine at Mass General and postdoctoral fellow in the Villani lab.

The pattern of T-cell subtypes in the blood indicated which individuals were more likely to succumb to myocarditis, suggesting that a blood test could one day be used to flag patients at increased risk who should be monitored closely or avoid immunotherapy altogether.

The team also found T cells in the peripheral blood that originated in the heart and correlated with severity of disease. Those findings open the door to developing a diagnostic blood test that could replace invasive heart biopsies for patients suspected of having myocarditis.

“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.”

Adapted from a Broad Institute news release.