Why some cancer treatments are harming the heart – and what researchers are doing about it

Why some cancer treatments are harming the heart – and what researchers are doing about it

It’s no secret that scientific breakthroughs can have unintended consequences. Take man-made pesticides like DDT. Initially celebrated for controlling insect-borne diseases, they eventually led to the decline of bird populations due to their harmful effects on the eggshells of some species. The medical research field is hardly exempt from such challenges, and a new class of cancer drugs known as immune checkpoint inhibitors, or ICIs, present a case in point. ICIs have been praised for their effectiveness against previously untreatable cancers, but recent research has highlighted their unintended effects on the heart and other organs. NHLBI-funded researchers are now using innovations in technologies – and a lot of creativity – to figure out ways to address some these emerging harms.

Harnessing the body’s immune system to fight cancer

When cancer develops, abnormal cells grow and form tumors that spread uncontrollably in the body. Normally, the immune system works by recognizing, then attacking, foreign invaders like these.  

“But tumor cells have become adaptive to this by using a mask that’s expressed on the cell surface that allows them to continue to invade without being detected, effectively deactivating the immune system,” said Jue Chen, Ph.D., chief of the atherothrombosis and coronary artery disease branch in NHLBI’s Division of Cardiovascular Sciences. “It’s like an invisibility cloak for the tumor cells, and it’s known as an immune checkpoint.”

ICIs were designed to remove that cloak so that the immune system is then reactivated to fight the tumor cells, Chen explained. Because the ICIs have been so successful at doing that, they have been lauded as the next big thing in cancer treatment.

Hijacking the immune system

Yet this success, especially for hard-to-treat cancers such as advanced metastatic melanoma and certain types of lung cancer, has come at a cost: while helping clear out the tumors, the ICIs are also inadvertently harming healthy tissues in the body. “That’s because they’re triggering an overreaction of the immune system,” explained Chen. 

And that’s a problem. Research has found that this kind of overactivity can stimulate plaque buildup in the arteries, a hallmark of atherosclerosis, which can lead to heart attacks and stroke. One NHLBI-funded study found, for example, that the risk of cardiovascular events due to atherosclerosis was three times higher among patients who received an ICI for cancer treatment, compared with cancer patients not treated with an ICI. In rare cases, ICI treatment can also trigger an abnormal heart rhythm, known as an arrythmia, or even induce myocarditis, an inflammation of the heart muscle that can be fatal. 

The harmful impacts of ICIs can extend to other organs of the body, too. The most common adverse effects are found in the gastrointestinal tract, endocrine system, and skin. For 10-40% of patients, these problems are so acute that the treatment must be stopped. 

Designing a more personalized ICI

Now, researchers at New York University are working to design potentially better therapies – ICIs that treat cancer without the harmful risks to the heart. In a new study using samples from human carotid and coronary atherosclerotic plaques, they created an extensive map of all the immune checkpoints in plaque cells, revealing a network in arteries that ICI treatments can target, potentially causing adverse reactions. They also completed a similar map using atherosclerotic plaques from mice to see how the mouse immune checkpoint map compared.

“Because of the new information provided in these maps, we think we can predict exactly how the body’s immune system will react – whether it enhances plaque formation or not,” said Kathryn Moore, Ph.D., professor in the departments of medicine and cell biology at NYU. “Then as new ICIs are developed, we can test them in mice to confirm if our predictions are correct.” 

Because they incorporated into their maps samples of plaque from people with a variety of different conditions and who use different medications, the researchers are already gaining useful insights. If a person has, say, diabetes or takes statins – often prescribed to treat existing atherosclerosis – they’ve found the ICIs can have varied effects. For example, statin use profoundly influences immune checkpoint expression in the plaques. Similarly, having diabetes affects the expression of immune checkpoints in the plaques, but in a different way. The clinical implications of these findings require more studies, the researchers note, but the results could well inform how new cancer therapies are developed.  

“We are now in an era where we can leverage new technologies to expand on what we already know and also predict how other parts of the body beyond the heart could be affected by ICIs,” said Chiara Giannarelli, M.D., Ph.D., associate professor in the departments of medicine and pathology at NYU who co-led the study with Moore. “It’s all getting us closer the goal of designing new, more precise drugs that treat cancer, without some of the very real side effects.”