Nature: It turns out that myocarditis in cancer patients is driven by specific immune cells

Myocarditis is a possible complication
in cancer patients treated with immune checkpoint inhibitors.
Although adverse events are rare – less than 1% of patients receiving immunotherapy are affected – the mortality rate is close to 50%.

Now, researchers at Vanderbilt Ingram Cancer Center have identified the mechanism
of this deadly heart inflammation.

The researchers found that T cells that recognize cardiac antigen α-myocoagulin are the mechanism of this complication, setting the framework for identifying biomarkers so that high-risk patients can be identified and medical strategies
can be developed for them to tolerate immunotherapy.
Their findings were published Nov.
16 in
the journal Nature.

"In 2016, our research team first described the development of myocarditis in two melanoma patients receiving immunotherapy and conducted some early studies linking the activity of T cells in the heart to the condition
.
Subsequently, Dr.
James P.
Allison, a Nobel laureate from MD Anderson Cancer Center in Houston, teamed up with us to help characterize a mouse model that appears to replicate what we found
in patients.
Using the same model, together with Vanderbilt's oncologist Dr.
Douglas Johnson, we were able to pinpoint the mechanism by which it occurs — and, importantly — translate it into a patient
.
This finding represents the next important step
in making these often effective therapies safer for patients.
”

The team took heart samples and peripheral blood
from three patients who developed severe myocarditis after receiving immune checkpoint inhibitor treatment.
The team analyzed
these samples after replicating immunotherapy-associated myocarditis in a mouse model.
The researchers sequenced individual T cells that invaded the heart during myocarditis in a mouse model to reconstruct their receptors
.
These T cell receptors are then screened for peptides to determine specificity
.
After identifying specific peptides, the researchers analyzed human samples and found that all three patients had T cells that were reactive to the same antigen source — a protein called α-myosin, which is expressed
only in the heart and skeletal muscle.

"Scaling our findings from mouse models to human patients is a key part of
our work.
These results show how useful it is to have a mouse model that you can initially discover and use to understand human disease
.
Our data suggest that α-myosin is a disease-associated autoantigen
in patients with immunotherapy-associated myocarditis.
We hope that this understanding of this mechanism of this often fatal complication could pave the way for making immunotherapy safer for patients," said
Margaret Axelrod, Ph.
D.
, lead author of the study.

The cause of immunotherapy-associated myocarditis is unclear to clinicians
.
Although early treatment of steroids can improve the chances of survival, more effective treatments
are needed.
This study is the first to identify the role
of α-myosin in the mechanism of cardiac complications caused by immune checkpoint inhibitors.
The study is also one of the
first to determine candidate autoantigens for human immunotherapy toxicity.

"While self-reactive T cells are thought to be the mechanism of toxicity in many immunotherapies, tracking the condition to specific T cell receptors (often unique to each patient) and antigen sources (extracted from tens to hundreds of thousands of potential antigens in humans) is a daunting task
," Balko said.

The research was supported by a grant from the Susan and Luke Simons Trustees, the Van Stephenson Memorial Cancer Research Fund, the James C.
Bradford Jr.
Melanoma Cancer Research Fund, and grants from the National Institutes of Health
.