As with most cancer therapies in their early years, immunotherapy is celebrated for its many positive outcomes and also evaluated for its side effects, some of them difficult to manage.

As immunotherapy has emerged as the fourth pillar of cancer treatment—alongside surgery, radiation, and chemotherapy—researchers at Yale Cancer Center are scrutinizing its toxicities and investigating ways to minimize risks and amplify benefits.

“Immune checkpoint inhibitors, the most commonly used form of immune therapies, can activate immune cells indiscriminately, including some that cause inflammation in normal organs,” says Harriet Kluger, MD, Harvey and Kate Cushing Professor of Medicine (Oncology) and Dermatology, and director of the Yale SPORE in Skin Cancer.

“The side effects that are most worrisome are the neurologic, cardiac, and pulmonary effects which can be life-altering, if not life-threatening. Diarrhea can also be a life-threatening side effect. Side effects can be very unpredictable and can happen at any time to any organ, which is why it’s so important to develop smarter ways to selectively inhibit the activity of immune cells that are damaging normal organs,” Kluger says.

Kluger and Mario Sznol, MD, professor of medicine (medical oncology and hematology), were among the pioneers in developing immunotherapies for metastatic melanoma, leading to the five-year overall survival rate increasing from 5% to more than 50%.

Now Kluger, Sznol, and others, are focused on the early identification of immune-related adverse events (irAEs), also known as immunotoxicities. The earlier those toxicities can be identified, the more effectively symptoms can be managed so cancer treatments can continue.

The effort reaches across disciplines at Yale Cancer Center and Smilow Cancer Hospital and includes neurologists, cardiologists, pulmonologists, and rheumatologists, to name a few, all working to find solutions for patients.

“We are becoming much more scientific now and it’s opening up a whole other world of research into who develops these toxicities,” Kluger says. “Is it a genetic or tumor-based predisposition? Does it have more to do with the treatment? And how do we mitigate them in patients that are at high-risk for developing toxicities?

“There are several clinical trials open, or poised to open at Yale looking into this, and a number of efforts are ongoing, including developing predictive biomarkers, looking at protein patterns before and on treatment, and studies into the microbiome,” she says. “We are learning a lot about how these agents affect the immune system and what works and what doesn’t.”

How are immunotherapy side effects being studied and addressed?

For example, Sang Taek Kim, MD, PhD, assistant professor of medicine (rheumatology), has an Immunotherapy Adverse Events in Rheumatology Program. Its goal is to manage patients suffering adverse immunotherapy-related events, or who have autoimmune conditions that may cause flare-ups, or a severe onset of symptoms.

“Approximately 20% to 25% of patients with cancer will have rheumatological adverse events after receiving immunotherapy and can include joint or muscle pain, joint swelling, muscle stiffness, vasculitis, dry eyes and mouth, and myositis, which can severely impact quality of life and be organ- or life-threatening,” Kim says. “The goal is to make sure that patients’ treatment regimens aren’t interrupted due to adverse events or autoimmune issues.”

By focusing on understanding the mechanisms, prevention, and management of these toxicities, Yale aims to improve the quality of life for patients being treated with various immunotherapies.

Death from an immunotherapy-associated toxicity is a very rare, but important event, according to a study by Jeffrey Ishizuka, MD, DPhil, assistant professor of medicine (medical oncology and hematology). His study also found that despite the successes of immunotherapy in decreasing melanoma mortality, many patients continue to experience treatment resistance, meaning there is an ongoing need for new therapies.

Thuy Tran, MD, PhD, assistant professor of medicine (medical oncology and hematology), is actively working to develop a drug that could simultaneously activate the immune cells that attack cancer and deactivate the ones contributing to toxicity.

“We have shown that blocking this pathogenic signaling protein reduces and destroys tumors in multiple animal models as well as reduces the severity of inflammation in autoimmune models. We are now evaluating the simultaneous response of treatment against tumors in animals prone to autoimmune toxicities as part of a larger Yale collaboration,” Tran says. “My ultimate goal is to improve immune treatment options and quality of life for patients with metastatic malignancies.”

Such a drug would be welcome news for many oncologists including those treating individuals with lung cancer, a field that has been transformed in recent years by immunotherapy. Challenging questions remain for these thoracic oncologists, on topics ranging from therapy selection, appropriate biomarker-based identification of patients who may derive benefit, the use of immunotherapy in people with autoimmune disorders, and toxicity management.

“The side effects we saw were mainly related to the immune system, which makes sense, because you are activating the immune system to fight the cancer. Varied autoimmune problems occurred including issues with skin, pneumonitis (inflammation of the lung tissue), and colitis (inflammation of the colon),” says Sarah Goldberg, MD, associate professor of medicine (medical oncology and hematology), and co-director of the Center for Thoracic Cancers at Smilow Cancer Hospital. She was among the first to give PD1 inhibitors (a class of immunotherapy drug) to patients with brain metastases from lung cancer and has found that such side effects can be managed with steroids.

Nikhil Joshi, PhD, an associate professor in immunobiology, is developing very sophisticated animal models to study the mechanisms of toxicity, which are poorly understood. Multi-institutional collaborations have also been developed to study subsets of immune cells in the blood prior to treatment, the goal being to determine if there is a way to predict the patients at high risk for severe toxicity, which would greatly impact how these toxicities are managed moving forward.

How do clinicians and patients manage immunotherapy side effects?

Stephen Connor, who was diagnosed with melanoma in 2010 and received the immunotherapy drug pembrolizumab, now known as Keytruda, as part of a clinical trial, knows first-hand just how difficult it can be to manage some of these side effects.

Connor received treatment for two years during which he experienced severe joint inflammation and finally decided to stop treatment when he developed stomach issues. Still, he would not have done anything differently.

“My children were 8 and 10 years old when I was first diagnosed, and now they are in college. Without this clinical trial I would not be here, and not a day goes by that I don’t think about how lucky I am,” Connor says. “I also think about those on the same trial that didn’t make it, or experienced far worse toxicities than me, because it doesn’t work the same way for everyone.”

The bottom line, according to Sznol, is that “although there are currently no clinically feasible tests that will tell you which patients will experience effects and which will not, it’s important to keep in mind that these treatments can be curative, and most side effects are reversible. When faced with a fatal cancer versus reversible, albeit irritating, side effects, most patients choose to continue with treatment when it’s deemed safe.”

Across all researchers and disciplines at Yale Cancer Center and Smilow Cancer Hospital, the end goal is clear: to cure the cancer and return patients to their normal lives with as little residual effects as possible. For patients like Connor, these immunotherapies are lifesaving, and the hope is to find ways to make the treatments more bearable.

“They say not to dwell on the small stuff in life, but I do, because the small things are big things to me now,” says Connor. “There are constantly new treatments and methods being developed; they will figure this out. Some of the smartest people in the world are working on it and they’re right here at Yale.”