‘Potential gamechanger’: Researchers discover basis for immunotherapy-induced myocarditis
Key takeaways:
- T-cell receptors in the hearts of patients with immunotherapy-induced myocarditis differed from those in their tumors.
- Patients who died of ICI-induced myocarditis also had a specific T-cell profile in blood circulation.
Clinicians may one day be able to treat immune checkpoint inhibitor-related myocarditis without disrupting cancer therapy, findings from a cellular investigation showed.
Individuals who die of immune checkpoint inhibitor-related myocarditis also have a specific T-cell profile in blood circulation.
“The most critical takeaway is the potential — though it needs to be validated — to decouple toxicity from the anti-tumor response,” Kerry L. Reynolds, MD, clinical director of inpatient oncology units and director of the Severe Immunotherapy Complications (SIC) Service and Clinical-Translation Research Effort at Massachusetts General Hospital, told Healio.
“This discovery is a potential gamechanger for patients, as it opens the door to further research and developing targeted therapies that may alleviate life-threatening toxicities while preserving the critical therapeutic efficacy of immune checkpoint inhibitors,” Reynolds added. “In addition, the identification of cardiac-expanded T-cell receptors as a biomarker could enable early detection of high-risk patients, allowing for timely intervention before the toxicity escalates. This is a major step forward for the field, sparking further research and paving the way for rigorous validation and clinical trials to fully realize the potential.”
A ‘dark side’
More than 230,000 individuals with cancer received immune checkpoint inhibitor (ICI) therapy in 2020, according to study background.
That number likely has increased sharply, as the FDA has approved agents in that therapeutic class for more than 100 indications.
In the U.S., about 40% of patients with cancer are eligible for ICIs, Alexandra-Chloé Villani, PhD, assistant professor of medicine at Harvard Medical School and principal investigator at the Krantz Family for Cancer Research and the Center for Immunology and Inflammatory Diseases at Massachusetts General Hospital, told Healio.
“[ICIs] are a good-news story,” Reynolds said. “They have revolutionized cancer care, offering hope and extending survival for patients with advanced malignancies. However, these therapies come with a dark side — immune-related adverse events that can severely impact quality of life and, in some cases, prove fatal.”
Up to 90% of individuals who receive ICIs as part of combination therapy develop toxicities, and anywhere from 14% to 55% develop “severe toxicity,” Villani said.
Of those, 1% to 2% develop myocarditis, and the mortality rate for patients with that condition can approach 40%, Villani added.
In the monotherapy setting, up to 74% of patients develop any toxicity and up to 14% develop severe toxicities.
Mechanistic investigation
Both Villani and Reynolds have personal connections to this problem.
A patient of Reynolds died in 2016 due to ICI complications, and Villani has a family member who has suffered from these toxicities.
“This drove me and my colleagues to commit to understanding the underlying mechanisms of toxicity, uncovering predictors and, ultimately, finding ways to ensure patients receive these life-saving [ICIs] without undue harm,” Reynolds said.
Currently, clinicians do not have many options for treating these toxicities.
“We know so little about the mechanisms of these toxicities that one of the only main solutions we have is to give patients with cancer heavy-dose steroids, which basically shut down your immune system,” Villani said. “It also shuts down your ability to attack the tumor. The other commonly used solutions in the case of severe toxicities are to stop or withhold therapy.
“If you have myocarditis and we save you, we’re not technically allowed to rechallenge you with [ICIs],” she added. “Even if the drug was working for your cancer, you cannot be rechallenged at this point, because we don't know how this works and if rechallenging you would put you at risk again for re-developing myocarditis.”
Villani, Reynolds and colleagues investigated ICI-related myocarditis with blood samples from 28 patients with the disease and 41 controls to determine a connection.
‘Deeply insightful’ findings
In the heart, researchers found an increased number of cytotoxic T cells, conventional dendritic cells and fibroblasts.
“When you have heart inflammation with myocarditis, it tends to be very patchy,” Villani said. “It was interesting to see that you had enrichment and co-localization of specific T cells with the dendritic cells, which instruct the T cells on what to do, and that these cells co-localized with inflammatory fibroblasts as a cellular niche, suggesting that fibroblasts may play an important role in recruiting and retaining immune cells from the blood.”
When researchers compared these T cell, dendritic cell and inflammatory fibroblast populations from the heart and blood between cases and controls, they found that the shift in their abundance associated with myocarditis disease also correlated with troponin levels.
“Troponin is measured in the blood in the clinic to try to assess if you have cardiac damage,” Villani said. “The more troponin you have in the blood, the more you have cardiac damage. When we modeled the abundance of these cell subsets with troponin, we saw that they were correlated, which further supported that there’s a tie with the presence of these cells and disease, as well as with disease severity.”
Additionally, blood levels of patients with ICI-related myocarditis had decreased dendritic cell levels, which may suggest that they got trafficked to the heart, Villani said.
Patients who died of myocarditis also had a specific T-cell profile in blood circulation.
“We identified a type of T cell that had shared expanded T-cell receptors between the heart and the blood that was specifically enriched in patients who died of myocarditis,” Villani said. “It’s an important advance as a proof of principle, and it needs to be validated in a bigger cohort to know whether measuring this cell population in circulation could help predict patients at risk for fatal myocarditis.”
When researchers compared the heart and tumor, they discovered the most expanded T-cell receptors differed between tissues.
“We had very few T-cell receptors that were shared between both the tumor and the heart, and they were not very abundant in terms of copy,” Villani said.
“The results were deeply insightful, and both confirmed and surprised us,” Reynolds said. “We expected to see immune dysregulation in affected tissues, but we were struck by the distinct T-cell responses between the heart and tumor. This finding challenges the conventional assumption that toxicity and anti-tumor responses are inseparably linked. In addition, the discovery of circulating, cardiac-expanded T-cell receptors as a potential biomarker of fatality was particularly important for me, given that I struggle to understand why some survive serious toxicity and others succumb to it, and offers a glimmer of hope if it could be validated.”
‘Hope’ for the future
Villani said the results provide even stronger support for the randomized phase 3 ATRIUM trial, which is evaluating abatacept (Orencia, Bristol Myers Squibb) as treatment for ICI-associated myocarditis
“Much more work” is needed to validate these data in larger, more diverse populations, Reynolds said.
Researchers are trying to find more biomarkers in the blood that could be measured easily to predict outcomes.
“We recently received a transformative Quantum Krantz Award at the Mass General Krantz Family Center for Cancer Research that will empower our work to identify biomarkers in the blood that can predict the development of immune related adverse events across organ systems, including myocarditis,” Villani said. “This award also helps support the use of new cutting -edge spatial transcriptomics to analyze in the same patient tissues affected by toxicities and tumors with the goal of elucidating the relationship between the cellular and molecular determinants of response to ICIs and toxicities. This work will propel the foundations to tackle the next phase of immune-oncology, allowing to develop new cancer treatments that minimize adverse reactions and maximize the immune system’s response against cancer,” Villani said.
It also will be important to investigate therapeutic strategies that can target proinflammatory pathways without compromising anti-tumor immunity, Reynolds said.
“Ultimately, our goal is to eventually translate these insights into clinical trials that redefine how we manage and prevent immune-related toxicities,” Reynolds said.
Villani emphasized clinicians should continue to promote ICIs as the research continues.
“Patients should not be afraid of these lifesaving therapies because of the toxicity, but we need to be mindful of them,” Villani said. “It’s important that patients tell their care provider if they have any symptoms. Often, if patients are responding to treatment, they’re afraid that their care provider will stop the treatment [due to toxicities]. They may be less inclined to share early symptoms. My messaging is to tell patients it’s OK to tell your symptoms. The sooner you tell your care provider, the easier they are to handle.”
“What I want to emphasize most is that this work is about hope — hope that we can offer patients life-saving treatments without the fear of severe complications someday,” Reynolds added. “We have a long road to truly understand, but it’s about recognizing that [ICIs], while powerful, come with profound responsibilities to understand and mitigate these risks. Our group is unwavering in our commitment to understand this, and it is just the beginning.”
For more information:
Alexandra-Chloé Villani, PhD, can be reached at avillani@mgh.harvard.edu.
Kerry L. Reynolds, MD, can be reached at kreynolds7@partners.org.
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