APPROXIMATELY 40% of people with cancer who receive immune checkpoint inhibitors will experience immune-related adverse events (irAEs), ranging from mild symptoms of fatigue and rash to life-threatening conditions that can lead to hospitalizations and even death.

To help understand and prevent the unintended consequences of immune checkpoint inhibitors, researchers presented data at an educational session April 26 at the American Association for Cancer Research (AACR) Annual Meeting 2025 in Chicago focusing on some of the more common irAEs, including pneumonitis, which is inflammation of the lungs, and colitis, which is inflammation in the colon lining. (The AACR publishes Cancer Today.)

Perturbing the Immune System

The immune system offers an orchestrated defense of our bodies, ready to thwart harmful invaders like viruses and bacteria. But to avoid damaging healthy cells, it also has built-in “off switches” that tell it when to slow down or stop the attack. Two of these off switches are proteins called PD-1 and CTLA-4 found on immune cells known as T cells. These proteins help prevent the immune system from attacking healthy cells.

“This is the eloquent design of the immune system that allows for it to be shut off in the right conditions,” said Elad Sharon, a medical oncologist at Dana-Farber Cancer Institute in Boston, referring to the way the immune system modulates its response.

Immune checkpoint inhibitors are drugs that block PD-1 (or its complement PD-L1) or CTLA-4. By doing so, they release the brakes on the immune system so it can fight cancer.

“We’re perturbing this situation through the use of antibodies—either inhibitory antibodies to CTLA-4 or to PD-1. What we’re essentially doing is we’re inducing an immune regulatory deficiency to patients,” Sharon said.

Growing Applications

Immune checkpoint inhibitors have been approved to treat a range of cancers—including melanoma and liver, bladder, and non-small lung cancer. The first Food and Drug Administration approval of an immune checkpoint inhibitor came in 2011 with the CTLA-4 inhibitor Yervoy (ipilimumab) for metastatic melanoma. In 2013, PD-1 inhibitor approvals followed, with Opdivo (nivolumab) and Keytruda (pembrolizumab) for melanoma. These approvals and the number of immune checkpoint inhibitors have expanded since then.

“The reason we care so deeply about all of these adverse events is really the breadth of efficacy that we have seen with immune checkpoint inhibitors over the years,” said Sharon. “We have had 91 different approvals of PD-1 inhibitors or PD-L1 inhibitors in different settings, and sometimes in the same setting with the different agents, but it’s really dramatic. And that’s why this is such a critical question.”

In many cases, people who receive immune checkpoint inhibitors experience mild symptoms, such as fatigue, rash and itching. However, between 10% and 15% of people with lung cancer who use immune checkpoint inhibitors will experience pneumonitis, which can lead to hospitalization if not treated early.

Researchers know that “there are some predictable patterns” depending on the type of immune checkpoint inhibitor used, said Sharon, which helps in identifying issues. Pneumonitis, for example, is more common with PD-1 inhibitors compared with CTLA-4 inhibitors while colitis occurs with both CTLA-4 inhibitors and PD-1/PD-L1 inhibitors, he noted. Adverse events in general are more common when two categories of immune checkpoint inhibitors, such as CTLA-4 and PD-1 inhibitors, are used together. He also pointed out that Type 1 diabetes, while not common, can also occur with PD-1 inhibitors.

Adverse Events and Outcomes

When immune checkpoint inhibitors were first used in clinical practice, researchers observed that many patients who experienced irAEs also seemed to have greater tumor response.

“Around the time that we were doing this, there was kind of a popular theory that irAEs in general may provide positive survival impact, that it is sort of a marker that you are getting a great tumor response,” said Karthik Suresh, a pulmonary and critical care physician-scientist who assesses patients with irAEs at Johns Hopkins Medicine in Baltimore.

But serious irAEs—those categorized as grade 3 or 4—can lead to discontinuation of therapy and hospitalization. In addition, patients are often administered corticosteroids to tamp down the immune response, but the steroids can also reduce the effectiveness of the immune checkpoint inhibitors.

To monitor for pneumonitis, the patient’s care team will take note of signs of hypoxia—low blood oxygen that is often characterized by shortness of breath—fatigue and coughing. If patients develop pneumonitis, they typically receive corticosteroids to control the condition. In addition, physicians may reduce the dose of the immune checkpoint inhibitor, pause treatment or stop it completely, depending on the severity of the adverse event.

Diagnosing pneumonitis is not always straightforward, the experts noted. For example, breathing difficulties can also be caused by lung infection. In addition, patients with breathing difficulties may not be well enough to receive a bronchoscopy, which allows physicians to take a fluid sample, called a bronchoalveolar lavage fluid, from the lungs to check for signs of viral or bacterial infection. It’s important to properly diagnose the condition since an infection would require antibiotics and taking steroids would interfere with the ability of the immune system to clear the infection.

Because of the challenge of assessing these breathing difficulties, Johns Hopkins brings together pulmonologists, oncologists and radiologists to determine the diagnosis and plan for treatment. Research from the Johns Hopkins team has shown that pneumonitis is associated with reduced survival compared with those treated with immunotherapy who do not develop this condition.

Sharon and colleagues published an analysis of previous research looking at patients with a range of rare cancers who had adverse events in the first cycle of immunotherapy. Patients were treated with Yervoy and Opdivo combined—a combination that is known to have a high rate of irAEs. His team found those who had grade 1 or grade 2 adverse events typically had better overall survival compared to those who had no adverse reactions and those who had more severe grade 3 or 4 reactions. “Those patients who have grade 1 and grade 2 adverse events, they can typically continue on therapy,” Sharon said.

“I think what we are seeing with these lower-grade adverse events are immune systems that can be perturbed to the benefit of the patient,” Sharon said. “Those who get grade 3 and 4 adverse events are individuals who have significant likely hospitalization and potentially-life threatening toxicities, and those patients typically stop therapy with their immune checkpoint inhibitors. They also are much more likely to get steroids or other immunosuppressants, which probably have some degree of effect on toxicity or ultimate effect on overall survival.”

Robert Zeiser, a physician-scientist at the University of Freiburg Medical Center in Freiburg, Germany, shared pathology slides that showed how second-line immunosuppressants for immune-related colitis can decrease tumor-fighting immune cells in tumor tissue. He also shared data from his research in mice exposed to corticosteroids and PD-L1 inhibitors have fewer T cells and lymphocytes in the spleen, an organ that activates these immune cells. This suggests that treatments that control irAEs can also curb the power of immune checkpoint inhibitors. “We should think about how much corticosteroids we give to our patients,” said Zeiser.

Zeiser went on to present data from a treatment called extracorporeal photopheresis (ECP) that has been used to manage other immune-related conditions. ECP involves taking a person’s white blood cells and exposing them to a light-sensitizing drug and UVA light. These cells are then returned to the body, where they help to regulate the immune system. Data from his lab showed patients with severe irAEs who were not responsive to other types of immune-suppressive treatments had complete resolution of their colitis with ECP, as well as resolution of liver issues and skin rash. The approach, he said, did not decrease immune cells—and in some cases patients were able to resume immune checkpoint inhibitors.

The goal for research in this area is to better understand the biology of irAEs, to develop better ways to intervene when these events occur, and to determine those most at risk for developing them, Sharon noted.

The management and diagnosis of irAEs remains a challenge since lifting the brakes on the immune system to fight cancer can also cause an immune attack on any organ in the body. This is why multidisciplinary review, including pathology, oncology and radiology, as well as gastroenterology, dermatology and cardiology, depending on the organ affected, is important. “The differential diagnosis of an irAE is not a trivial task, and involvement of subspecialty services can be essential,” Sharon said.

Marci A. Landsmann is the managing editor of Cancer Today.