Immunotherapy Treatment Side Effects

If you’ve researched cancer treatment options, you’ve probably heard of immunotherapy, which trains the immune system to attack cancer, rather than attacking the cancer directly. You also might've heard that immunotherapy causes fewer side effects than traditional chemotherapy.

But that’s not always the case.

More than 60% of patients who receive some form of immunotherapy will also develop side effects. Some of those will be severe enough to interrupt or halt their cancer treatments.

Fortunately, doctors continue to learn how to recognize and better manage these side effects, so that more patients can benefit from this highly effective form of therapy. Here’s what patients need to know.

Fatigue, inflammation top common side effects

Examples of immune checkpoint drugs include:

• pembrolizumab (Keytruda)
• nivolumab (Opdivo)
• atezolizumab (Tecentriq)
• ipilimumab (Yervoy)
• avelumab (Bavencio)
• durvalumab (Imfinzi)  

Side effects from these and other immunotherapy drugs often differ from those commonly seen with other types of cancer treatment. 

“As with many cancer therapies, fatigue tends to be one of the most common,” says Van Morris, M.D.

But immunotherapy drugs also can cause inflammation throughout the body. Patients may experience pigment changes, for example, a rash, or even an itchy feeling without a rash. Inflammation of the lungs can cause a cough or chest pains. The colon may also become inflamed (a condition called colitis), causing abdominal pain and diarrhea. 

Other, rarer side effects affect the endocrine system, which is how the body produces and regulates hormones. Some patients may develop diabetes, but a more concerning side effect is hypophysitis – inflammation of the pituitary gland.  

“The biggest challenge is that it manifests in so many ways and can be definitively determined with blood work,” says Sumit Subudhi, M.D., Ph.D. “But the patient may experience fatigue, fever or a headache.”

Some immunotherapy drugs produce fewer or less severe side effects than others  

Immune checkpoint inhibitors, the most common type of immunotherapy drug, work by suppressing the “off switch” that normally prevents T cells from attacking healthy tissues after destroying an invader.  This gives T cells the extra time they need to finish the job with cancer cells, which can take longer to kill than other pathogens.

But data indicates that some immune checkpoint inhibitors are less stressful on the body than others. So, doctors are starting to modify their recommendations to reduce both the number and severity of side effects patients might experience.

“Anti-PD1/L1 therapy is considered more protective than CTLA-4 agents because it is associated with lower recurrence rates of colitis,” notes gastroenterology specialist and researcher Yinghong “Mimi” Wang, M.D., Ph.D. “So, if someone develops colitis after their first round of CTLA-4 or a combination of CTLA-4 and PD-1/L1s, once we get the colitis resolved, we may follow it up with just PD-1/L1.” 

Side effects can show up early in treatment – or, on rare occasions, months or years later

How quickly immunotherapy side effects appear varies, but most patients receiving immunotherapy will see side effects develop during the first few weeks or months of treatment.  

Fortunately, Wang says, “We can usually have patients’ GI symptoms return to baseline and resume cancer therapy again in two to four weeks, especially with our pioneering work in fecal microbiota transplants. That wasn’t even a possibility in the past when our knowledge and experience in this field were still quite limited. Now, resuming immune checkpoint inhibitors after colitis has become the standard of care.” 

Still, since immunotherapy is still relatively new, we don’t have data on if there are delayed side effects from toxicity treatment that may appear years later.

Side effect management depends on the severity

The way that we treat immunotherapy side effects depends on their severity. “Patients receiving immunotherapy have likely already received chemotherapy, so they’re often able to cope better than they expected with mild side effects, like a cough, rash or fatigue,” Morris says.

If a side effect is severe, however, other medications may help.  

“We’ll pause the immunotherapy and prescribe an immunosuppressant, such as an oral steroid, to help cool off the inflammation to a safer level,” Morris says. 

Patients who develop diabetes may require insulin or a period of time off of immunotherapy. 

“The ultimate goal is to cut down on these medications as quickly as possible so the patient can resume immunotherapy,” notes Morris.

Watch for changes in your body

Recognizing side effects early is the key to their effective management. That’s why Wang and the IOTOX team have been developing toxicity algorithms for adverse GI events and 14 other organ systems since 2018 as a part of MD Anderson’s Immuno-Oncology-Toxicity-Initiative (IOTOX). The goal is to give our clinical staff a uniform method of identifying and treating colitis and many other immunotherapy-related side effects.  

MD Anderson’s IOTOX team has released three algorithms to the public so far — GI (2018), kidney (2021) and endocrine (2022). The rest are solely internal guidelines, but they should be approved and released to the public within the next 2-3 years.   

“These algorithms are great for our care teams because they provide a comprehensive evaluation tool and reference for systematic management,” she explains. “If a clinical care provider suspects a patient might have an immunotherapy-related side effect, they can search for a keyword specific to that toxicity, and a toxicity-specific order set will be pulled up, which lays out everything they need to complete the workup.”

Algorithms are also beneficial to our patients. They help ensure side effects will be identified and addressed more quickly when they’re milder and (hopefully) less disruptive.

“We’ve already seen dramatic increases in the number of successful treatments and higher remission rates since the GI algorithm was implemented,” notes Wang. “We’ve also seen decreases in the number of hospitalizations and recurrences of GI toxicities. We’re hoping to see the same improvements in other areas of toxicity management, too.” 

At MD Anderson, all patients receiving immune checkpoint therapy meet with a pharmacist before starting treatment. This helps patients better understand what they’ll be receiving and all possible side effects.

“It really empowers patients to understand what’s happening to their bodies and the treatment better,” Morris says.

Side effects don’t indicate whether immunotherapy is working

The presence — or lack — of a side effect doesn’t always indicate if a drug is working or not. “I want patients to know that it’s OK to feel well on these drugs,” Morris says.  

Still, multiple research studies have noted a connection between patients who develop certain side effects and the chances that they’ll ultimately do well on immunotherapy.

Endocrinologist Priyanka Iyer, M.D., for instance, has observed that thyroid dysfunction is considered a good sign in patients receiving immunotherapy, because “data shows statistically that these patients have a better overall survival and response rate.”

Wang agrees.

“The incidence of immunotherapy-related colitis is associated with better overall survival,” she says. “So, patients shouldn’t necessarily be discouraged if they develop this side effect. It could be a sign that their cancer will be much more responsive to immunotherapy." 

“Our goal is not to stop triggering these side effects by discontinuing the drugs,” she adds. “Instead, we want to treat these toxicities more effectively so that patients can resume immunotherapy for as long as they need to.”

Request an appointment at MD Anderson online or by calling 1-877-632-6789.
 

Immunotherapy has transformed cancer treatment, helping countless patients live longer, healthier lives. But researchers are continuing to work to develop a deeper understanding of this game-changing treatment.

In some cancer patients, immunotherapy can unleash the brakes on a harmful response from the immune system, causing what’s called immune-related adverse events, or irAEs for short. In other words, side effects. With more patients undergoing immunotherapy, there’s a pressing need to better understand and manage these immune-driven side effects.

Kristen Pauken, Ph.D., is an MD Anderson scientist working to better understand the immune system and what causes these side effects. The Immunology assistant professor hopes that by studying autoimmune diseases, she’ll be able to uncover insights that unlock successful treatments for both cancer treatment side effects and autoimmune disease.

For Pauken, the research is personal. She herself struggles with Rheumatoid arthritis, an autoimmune disease in which the body attacks the joints. She first started experiencing symptoms during her postdoctoral training.

“I want to be part of the solution to the autoimmunity problem. I want to bring my unique training history in autoimmunity, chronic infection, and cancer to bring more cures to more patients,” she says. “As an immunologist, I believe that if we knew the right buttons to push and levers to pull, we could restore health and homeostasis, not only in cancer, but in autoimmunity as well.”

A path to the lab

Growing up, Pauken could be found in the backyard, playing in the water and conducting science experiments. “I always knew I wanted to be a biologist,” she says. 

As an undergraduate majoring in microbiology at Colorado State University, Pauken wanted to pursue a career in human health. Here, she was introduced to the immune system; she became completely enthralled by how the immune system deals with chronic disease.

After studying chronic parasitic infection for two years, she transitioned to a Ph.D. in immunology at the University of Minnesota. She wanted to learn more about how T cells were regulated in chronic diseases and ended up joining an autoimmunity lab.

“The immune system has developed dozens of ways to protect self-tissues from accidental damage by the immune system, so when it happens, it looks very different from what anti-pathogen or anti-cancer immune responses look like.”

After completing her Ph.D. in autoimmunity, Pauken diversified her immunology expertise, switching gears to study how checkpoint inhibitors could be used to better leverage the immune system in chronic infection and cancer. She completed postdoctoral training in chronic infection at the University of Pennsylvania and then in cancer at Harvard Medical School. In each position, Pauken focused on how delivering PD-1 checkpoint inhibitors impacted the ensuing immune response and host outcomes, focusing on how different the outcomes could be depending on the underlying immune status in the host.

“It was exciting to feel like I was bringing hope to patients. I was identifying barriers to success and coming up with solutions to solve them,” she says.

An unexpected Rheumatoid arthritis diagnosis

Along the way, she started to experience her own issues with an autoimmune disease, and during her postdoctoral training, she received an unexpected diagnosis.

“One day, I started feeling like I was walking on marbles. Within a few weeks, I couldn’t bend any of my fingers because my joints were so swollen,” she says.

Follow-up analyses confirmed that Pauken had developed Rheumatoid arthritis. Like other autoimmune diseases, this disease requires lifelong symptom management through immunomodulatory drugs.

“Hearing those words – ‘We have found that your immune system is attacking your body, and there are no cures, so we need to discuss your symptom management plan’ – still feels surreal,” she says. “Knowing there is no existing clinical solution to your problem is devastating.”

With this diagnosis, Pauken decided to change her research trajectory.

Unlocking the secrets of the immune system

Upon launching her independent research program, Pauken decided there was no better place for her lab than MD Anderson. 

“The pipeline from my bench to patients felt so much shorter at MD Anderson than anywhere else,” Pauken says.

Now, Pauken’s lab is dedicated to finding ways to help those who suffer from immune-driven pathologies, whether those symptoms are caused by immunotherapy drugs or arise spontaneously for reasons that are not well-understood. An estimated 5% to 8% of people in the United States have an autoimmune disease, and once diagnosed, they will have that disease for the rest of their lives. Physicians can help patients manage their symptoms but cannot cure the underlying disease.

At MD Anderson, Pauken has found a collaborative community dedicated to not only curing cancer but also treating and eliminating the side effects. She became an active part of the Immuno-Oncology Toxicity (IOTOX) Leaders Group, which combines the expertise of MD Anderson’s Internal Medicine and Cancer Medicine teams to support clinical, research and education efforts aimed at solving the problem of irAEs and improving the lives of cancer patients.

“Academia can be competitive, but to really make a difference in a space as complicated as irAEs in cancer, it takes a collaborative environment where people with complementary strengths unite for a common cause,” Pauken says. “This is an area where MD Anderson really excels to improve patient care.”

In 2023, she was awarded an Andrew Sabin Family Fellowship to pursue research in skin irAEs. The Sabin Fellowship is a grant given to early-career faculty that frees them to pursue novel or high-risk, high-reward scientific endeavors early in their careers when federal and private funding opportunities often are limited.

Her lab continues to focus on unlocking secrets and shedding light on the immune system, in hopes of easing the burden for all patients.

Pauken stresses that unleashing the brakes with checkpoint immunotherapy has had such a positive impact on the lives of cancer patients. “To continue maximizing the therapeutic impact of checkpoint inhibitors, we must get better at selectively putting the brakes back on pathogenic immune reactions. This is not exclusively a cancer immunotherapy problem: What we learn here has the potential to transform the way we treat autoimmunity, a class of chronic diseases that, despite decades of research, has no cure,” she says. “I wake up every day to the clinical reality of living with a disease with no cure. Being in the research space for autoimmunity gives me hope. It makes me feel like I am contributing to the solution, even though the problem is hard.”

Learn about research careers at MD Anderson.