Interview with Tom Neilan, MD and Zsofia Drobni, MD: Immune Checkpoint Inhibitor Therapy From a Cardiologist's Perspective

The Severe Immunotherapy Complications (SIC) Service and Clinical-Translational Research Effort at Mass General Cancer Center is working to address the urgent need to understand how and why immune-related adverse events (irAEs) occur. SIC's multidisciplinary team comprises more than 50 individuals across 19 areas of the hospital, and this unique group of clinicians and researchers are involved in the care of every patient admitted with a suspected irAE after checkpoint blockade immunotherapy.

In this new interview series, Kerry Reynolds, MD, director of the SIC program, sits down with a SIC team member for a deeper-dive into their work. This month we meet Tomas Neilan, MD, MPH, a cardiologist at Mass General Hospital and director of the Cardio-Oncology Program, and Zsofia Drobni, MD, research fellow at the Cardiovascular Imaging Research Center.

Kerry: Tom, thank you so much for joining us today. We look forward to your talk Immune Checkpoint Inhibitor Therapy From a Cardiologist's Perspective that you will be giving with Zsofia Drobni to the Severe Immunotherapy Complications Service this month. You and your research team have been doing very interesting work. The recent paper in Circulation looking at the Association Between Immune Checkpoint Inhibitors With Cardiovascular Events and Atherosclerotic Plaque is really eye opening. Can you tell us more about it?

Tom/Zsofia: In that paper, we showed that the use of immune checkpoint inhibitors was associated with an increase in atherosclerotic plaque progression and an increase in atherosclerotic cardiovascular events, such as myocardial infarction, coronary revascularization, or stroke. To be more specific, we found a greater than 3-fold increase in the risk for atherosclerotic plaque progression after starting immune checkpoint inhibitor therapy. This increase in progression was modified by statin and corticosteroid use. Moreover, when we looked at clinical events, we found a similarly elevated risk, a 3-fold risk for cardiovascular events after starting therapy.

Kerry: How do you think this work informs the field moving forward? What should we do differently when thinking about chronic conditions after ICI?

Tom/Zsofia: Based on our findings, we know that cardiologists working with cancer patients, especially with those who received immune checkpoint inhibitor therapy, are aware of the potential for immune checkpoint inhibitor-associated myocarditis, but this paper, and several subsequent papers from other groups, highlight the need for increased awareness for other potential CV effects, such as those that may develop from atherosclerotic diseases. I believe that as the next step, we need to identify the pathological mechanisms that drive increase atherosclerosis with immune checkpoint inhibitors, and have to come up with a robust and easy way to identify those patients who are at increased risk for these cardiovascular complications of immune checkpoint inhibitor therapy.

Kerry: What is the most pressing need, in your opinion, in the field of immune-related adverse events. In short, where do we go from here?

Tom/Zsofia: We have to identify cancer patients who are about to start immune checkpoint inhibitor therapy and who may be at higher risk for cardiovascular events after therapy start. Related, we are also lacking the ability to identify those patients at risk of other cardiac complications from immune checkpoint inhibitor therapy, specifically, immune checkpoint inhibitor associated myocarditis. As you also know, using an immune checkpoint inhibitor as monotherapy is only the starting point. There are more than 4,000 ongoing active clinical trials testing the effect of immune checkpoint inhibitors, and more than 2,900 of these trials are testing the use of immune checkpoint inhibitors in combination with different cancer treatments, like radiation or traditional cytotoxic therapies. Some of these other cancer treatments also may have cardiotoxic effects, and data are lacking on what happens to atherosclerosis or to cardiovascular events if we give immune checkpoint inhibitor in combination with these other potentially cardiotoxic anti-cancer therapies.

Kerry: Is there any paper in press that we should know about? When/where will it be coming out?

Tom/Zsofia: There is another paper from our group, currently under review, in which we looked at whether the use of renin-angiotensin aldosterone system inhibitors could improve overall survival in cancer patients who receive immune checkpoint inhibitor therapy. To answer this question, we built a retrospective database of all patients treated with immune checkpoint inhibitors through the end of August 2020. This resulted in more than 10,000 patients, out of whom 5,910 were on any anti-hypertensive medication. Then, we compared those who were on any renin-angiotensin aldosterone system inhibitors at the time of immune checkpoint inhibitor start, to those taking other types of anti-hypertensive drugs. We found that patients who were concomitantly taking a renin-angiotensin aldosterone system inhibitor during immune checkpoint inhibitor therapy had better overall survival. This effect was noted especially among patients with gastrointestinal and genitourinary cancers, and, we hope, will be the basis for randomized trials in this space.

Publication:

Drobni ZD, Alvi RM, Taron J, Zafar A, Murphy SP, Rambarat PK, Mosarla RC, Lee C, Zlotoff DA, Raghu VK, Hartmann SE, Gilman HK, Gong J, Zubiri L, Sullivan RJ, Reynolds KL, Mayrhofer T, Zhang L, Hoffmann U, Neilan TG. Association Between Immune Checkpoint Inhibitors With Cardiovascular Events and Atherosclerotic Plaque. Circulation. 2020 Dec 15;142(24):2299-2311. doi: 10.1161/CIRCULATIONAHA.120.049981. Epub 2020 Oct 2.