Q&A: How a partnership between physicians and researchers aims to make cancer drugs safer
ӳý and Mass General researcher Alexandra-Chloé Villani and Mass General oncologist Kerry Reynolds describe their pioneering effort to better understand, diagnose, and manage dangerous complications from cancer immunotherapy.
In the mid-2010s, oncologist Kerry Reynolds and colleagues at Mass General Hospital noticed an alarming pattern: more and more patients undergoing cancer treatment were coming to the hospital gravely ill, not from the cancer but from the medicine itself. These patients had been given the revolutionary immunotherapy drugs known as immune checkpoint inhibitors (ICIs), which take the brakes off the body’s immune system so that it can fight cancer. For some patients, this treatment results in striking and long-lasting remission — but for a subset, it triggers complications ranging from mild rash to potentially deadly brain and heart inflammation.
Motivated to make immunotherapy safer, Reynolds teamed up with researcher Alexandra-Chloé Villani to launch the in 2017. Based at Mass General Cancer Center and including researchers at the ӳý of MIT and Harvard, the group aims to reveal the biological roots of these dangerous complications and to discover new ways to improve patient care.
Earlier this year, the researchers shared their first translational results, describing the . Now, they’ve uncovered the immune basis of checkpoint myocarditis, a severe form of heart inflammation that afflicts one percent of patients on an ICI therapy and up to 2 percent with certain combination therapy. Despite being one of the rarer complications of ICI therapy, this form of myocarditis leads to dangerous cardiac events such as arrhythmia and heart failure in 50 percent of cases, and about a third who develop the condition will die from it, despite current treatments.
To learn more about their work, we talked with Villani, an institute member at the ӳý, an investigator in the Krantz Family for Cancer Research and the Center for Immunology and Inflammatory Diseases at Massachusetts General Hospital (MGH), and an assistant professor of Medicine at Harvard Medical School (HMS), and Reynolds, the clinical director of inpatient oncology at MGH, director of the SIC Service, and an assistant professor of medicine at HMS.
How big of a problem are these complications from cancer immunotherapy?
Kerry Reynolds: The first immune checkpoint inhibitor was FDA-approved in 2011 to treat melanoma, with nearly a dozen more ICIs approved for various cancers since then. These are home-run, breakthrough therapies, and quite an amazing success story. But by 2016, we started to see an increasing number of patients admitted to our hospital with adverse events after having these novel therapies.
Alexandra-Chloé Villani: The problem is growing as more patients undergo ICI treatment each year, with more than 230,000 patients in the US treated with ICIs in 2020. Of these, most will develop some form of toxicity and, depending on which treatment they received, an estimated ten percent to over fifty percent will develop serious immune-related complications. And with ICIs now approved to treat less advanced cancers and as long-term therapy to prevent cancer’s recurrence, known as adjuvant therapy, the risks of developing chronic complications may outweigh the benefits for some.
Complications from checkpoint inhibitors are unlike effects from chemotherapy, for which you can reverse the hair loss or nausea by stopping treatment. With immunotherapy, it awakens your immune system in a way that’s like a fire in a bush — it doesn’t stop. Patients can even develop life-threatening organ inflammation after a single dose. We don’t have good therapeutic solutions and we often have to stop the antitumor therapy or give large amounts of steroids that will also shut down the very immune response that’s fighting the cancer.
How did you go about launching this effort?
KR: The turning point for me was my patient, David, a 64-year-old man with metastatic melanoma who had two doses of these phenomenal ICIs that eradicated every cell of his melanoma. He had total, complete remission, which is so incredible. But he soon came to the hospital with lung inflammation. At that point in 2016, we knew very little about these conditions. I was at his bedside, where we had him on large amounts of oxygen and administered very, very high doses of steroid therapy. He responded well, yet he returned a month later when his immune system relentlessly attacked his colon and nerves. It was a helpless feeling to have all this modern medicine but not know how to care for him. Before David went to intensive care where he sadly passed away, he said, “Doc, I know this isn’t good, but you have to learn from this.” At that moment, I knew we needed to change our entire structure of caring for patients with these conditions in the Mass General Cancer Center.
We started by bringing in subspecialties to think about best practices for clinical care and to devise research questions to ask. Mass General is an ideal place to do this because we have both a general hospital and a cancer center, so we’ve been able to enlist physicians specializing in every organ system, including ophthalmology, allergy/immunology, gastroenterology, pulmonology, hematology, endocrinology, rheumatology, dermatology, and nephrology. When we launched the SIC service, Chloé had just joined MGH and the ӳý to start her independent research laboratory, and when our department heads heard about our shared interest, they connected us on a “scientific blind date.”
ACV: After my own family member had developed chronic side effects from therapy, I realized there are so many patients who’ll be at risk for deadly inflammation or lifelong conditions like arthritis or diabetes. It’s not sufficient to cure the patient — you also need to ensure that they have a good quality of life. I figured I had some good tools to pursue that goal, with the translational research I’d done, my expertise in immunology and genomics, and the technologies I’d learned during my postdoctoral training at the ӳý.
Kerry and I instantly clicked and together we dreamed up this audacious vision, got clinicians on board, and built it from the ground up. It’s been a labor of love. We’ve secured some funding along the way, but it’s a grassroots initiative at its core. People at every level in the hospital have offered their time to coordinate and collect samples, simply because they want to improve patient care. My lab brings in the big data approach to analyze samples of blood, tumors, and other tissues, and she brings the whole patient experience, which makes it real for my lab members.
Several of my lab members are also physician-scientists who bridge between research in my lab and working in Kerry’s SIC Service to care for these cancer patients who’ve developed treatment toxicities. These physician-scientists, such as Steven Blum and Daniel Zlotoff who co-led our myocarditis effort and Molly Thomas who is a co-senior author, play a critical role in empowering our translational effort and are paving the path for bench-to-bedside translation of findings.
What do you hope to accomplish?
KR: The helpless feeling I had with David still exists today. We know a bit more in terms of treatments to try, but they don’t always work. We’ve got to figure out what is driving this so we can be smart about how we treat it. We can’t just empirically be pulling treatments — they need to be evidence-based from randomized clinical trials. Our research findings are indicating what we should be studying in clinical trials, which is huge progress.
We also need better diagnostics. If we can identify circulating factors for these conditions, we might be able to one day forego costly imaging or more invasive tests like heart biopsy by using a simpler blood test. And I’d like to see us use our findings to better predict who is going to develop an adverse event or have a very severe case, possibly before they even start immunotherapy, so we can monitor them closely or decide whether immunotherapy is the best option.
Our scientific results are the fundamental building blocks towards these longer-term goals. With myocarditis, other studies had concluded that the immune responses in the heart and the tumor were the same, but ours showed that there are instances in which the responses are distinct and that there’s more to the story. That gives us a lot of hope, because we can think about targeting the inflamed organ that is failing without halting the immune response to the tumor. We need more data before we know exactly how to do that in patients, but this shows us that it’s more complicated than people initially thought.
ACV: I knew I wanted my lab to be embedded within the hospital, so that we could work as closely as possible with the clinical researchers and patients. Our effort was among the first of its kind, and one of the only to look across all affected organ systems in parallel. As we build these deep single-cell maps of all the organ systems, we can tell what is alike and what is different. By directly studying patients’ blood and tissue specimens affected by these adverse events, we can generate unique biological insights. Those findings will ultimately help inform the design of more effective diagnostic tools and empower us to nominate new therapeutic targets that would enable mitigating these adverse events while maximizing the anti-tumor efficacy of immune checkpoint inhibitor treatment.
For this translational effort to succeed, it is critical to partner with patients and their families to find solutions for preventing and treating adverse events and improving their quality of life. It is truly humbling to see how generously patients contribute to research. I am deeply grateful for the opportunity to work with this patient population and for their active participation in our efforts.
We are also working to at other clinical and research centers around the country, so that we can collaborate and learn from each other, and so patients everywhere can receive advanced care. In addition, we’re supporting efforts to start a patient advocacy group to bring more awareness to this problem and give families a sense of community.
What would you like patients to know about immunotherapy and these complications?
KR: This work wouldn’t be possible without the generous contributions of our patient participants. When we share our results, in our maps of cells driving these toxicities, I see reflections of each patient and their personal story. They’re such an important part of this journey and we’re incredibly grateful to them.
ACV: Some patients taking checkpoint inhibitors may be hesitant to mention any symptoms they’re having, for fear of being forced to stop their immunotherapy. But the earlier we catch these adverse events, the more easily we can treat them and continue or resume the immune checkpoint inhibitor anti-tumor treatment. The longer patients wait to inform their doctor, the more complex it can become. These adverse events can become irreversible, so I hope patients will not be afraid to speak up; they should always report any side effects to their oncologists and care team and not be afraid of asking questions about treatment and symptoms.
When they work, these drugs can greatly improve a patient’s prognosis, and people should not be afraid of them. We just need to make them work better so that more cancer patients can safely benefit from them.
