Side effects are typically mild, but can be life-threatening

By Jennifer Welsh 

Published on September 13, 2023

 Medically reviewed by Lindsay Cook, PharmD

Immunotherapy is used for a wide variety of cancer types and stages. This type of treatment can be effective but also causes side effects. Most side effects from immunotherapy drugs are mild, but others are severe, life-threatening, and require medical care and even stopping treatment. 

Immunotherapy is a cancer treatment approach that uses your immune system to fight against tumor cells. Treatments boost your immune system's ability to find cancer cells and kill them in various ways.

This article covers everything readers need to know about immunotherapy's side effects, including the most common side effects, the dangers involved with immunotherapy, how sick the treatment may make you, and if it's worse than chemotherapy.

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Why Does Immunotherapy Cause Side Effects?

Immunotherapy works to ramp up the immune system. Some immunotherapy drugs remove blocking effects that typically keep the immune system in check.¹ Immunotherapy side effects stem from an overstimulated or misdirected immune response.²

These changes can lead to side effects of an overactive immune system. Sometimes, these side effects are similar to when you’re sick, causing flu-like symptoms or fatigue. Other times, they’re dangerous overreactions that cause severe allergic or autoimmune reactions. These reactions may attack healthy cells, causing immune-related adverse effects.

These side effects depend on what type of immunotherapy you get, what drug you get, your cancer, your general health, and many other factors. 

How Common Are Immunotherapy Side Effects?

Mild side effects of immunotherapy occur often. These are potent drugs that have a significant impact on your immune system. Most people getting immunotherapy do not have serious adverse events.³

About 20% to 27% of people taking one immunotherapy (immune checkpoint inhibitors) will develop severe adverse effects. If you get two or more types of immunotherapy at once, your risk of severe side effects may be higher—40% to 60%.⁴

Immunotherapy's most dangerous and life-threatening side effects include infusion reactions, allergic reactions, and autoimmune reactions. These can damage organs and organ systems.  

What Are the Most Common Side Effects?  

Commonly, immunotherapy can make you feel a bit sick. The everyday mild side effects widely experienced across the spectrum of immunotherapies for cancer include:²

• Painful swelling of the joints (arthritis)

• Flu-like symptoms, including chills, coughing, fatigue, fever, and muscle aches

• Digestive symptoms, including constipation, decreased appetite, diarrhea, nausea and vomiting

• Headaches

• Pituitary gland issues (hypopituitarism)

• Thyroid issues (hypothyroidism)

• Reactions, including pain, at the site of the infusion

• Skin symptoms including itching and rash at either the infusion site or elsewhere on the body

How Immunotherapy Affects the Body Systems

Immunotherapy reactions and side effects have widespread effects on the body. These drugs can have specific effects on certain body systems. 

Skin

Immunotherapy can cause reactions in the skin. These include itching, a mild rash, and redness. Sometimes called a maculopapular rash, this reaction may be:

• Red with flat and raised areas

• Made up of small bumps that merge

• Covering a large area of skin

More severe but rarer skin side effects include:⁵

• Lichen dermatitis: Inflammation, swelling, and irritation of the skin or inside the mouth

• Psoriasis: An autoimmune skin disease that causes inflammation and patches of dried skin called plaques

• Bullous pemphigoid: A rare skin condition that causes large, fluid-filled blisters

Life-threatening skin-related side effects include the development of erythema multiforme major, also called Stevens-Johnson syndrome, a severe form of red, scaly rash that can be fatal.

Mild rashes typically respond well to corticosteroid-based creams, but some may need more intense treatment.³ They’re more common in people getting immunotherapy for melanoma or non-small cell lung cancer.¹

Liver and Gastrointestinal (GI) System

Digestive symptoms are common with immunotherapies. These treatments may inflame the gut, a condition called colitis. This causes diarrhea, which can be bloody,⁵ and abdominal pain.¹ If diarrhea is severe, it can lead to dehydration.³

Other immunotherapy side effects in the digestive tract include:⁵

• Mouth ulcers

• Anal lesions like fistulas, abscesses, or fissures

• Inflammation of the stomach lining (gastritis)

• Inflammation of the esophagus (esophagitis)

• Swallowing problems¹

A potential side effect of immunotherapy that doesn’t cause symptoms is liver inflammation (hepatitis). In rare cases, severe hepatitis can cause liver damage, resulting in yellowing of the skin.³

Colitis treatment includes drugs to reduce diarrhea and taking in lots of fluids. Severe diarrhea may require hospitalization, infused corticosteroids, and stopping immunotherapy. Rarely, colitis causes a hole in the bowel; it can be life-threatening. It’s treated with surgery and antibiotics.⁵

Lungs and Respiratory System

Immunotherapies can lead to lung swelling (pneumonitis), causing a cough, chest pain, and difficulty breathing. It can be severe if it interferes with breathing.³

Studies have shown that these inflammatory lung reactions may happen in 3% to 20% of people getting immunotherapy. It may be more common in current or former smokers.⁵

Other lung-related side effects that have been noted in immunotherapy trials include:

• Lung scarring 

• Nodules in the lungs (granulomas) 

Lung inflammation, even in mild cases, often requires people to stop immunotherapy and start on corticosteroids to improve their breathing. The inflammation comes back in about one-third of people who start immunotherapy again, so they need to be observed.

Thyroid Gland and Endocrine System

Immunotherapy may cause side effects in the endocrine system and its organs. This system uses hormones to regulate many bodily functions. This system is responsible for keeping your blood pressure, energy levels, and stress responses working right. 

Immunotherapies can inflame many endocrine organs.³ Possible endocrine complications caused by immunotherapies include:⁵¹

• The thyroid becomes either more or less productive (hypo or hyperthyroidism).

• A type of diabetes called checkpoint inhibitor-associated diabetes, or worsening of type 2 diabetes, can cause diabetic ketoacidosis or blood sugar levels that are so high they can be fatal.

• The adrenal gland may stop producing hormones that manage blood sugar and electrolytes.

• An inflamed pituitary gland can cause low levels of essential pituitary hormones.

• Hypoparathyroidism causes low levels of parathyroid hormone.

Hormone replacement therapies can usually counteract these side effects. People with severe complications from immunotherapy should stop their treatment until symptoms resolve.⁵

Brain and Nervous System

Side effects of immunotherapy can impact your brain and nervous system. This can cause changes to your senses, movement issues, and pain and sensation changes called neuropathy. These are rare but possibly severe side effects. 

Complications of immunotherapy on the brain and nervous system include:¹

• Chronic muscle inflammation, weakness, and sometimes pain (inflammatory myopathies)

• Myasthenia gravis a chronic autoimmune disease of the nerves and muscles that causes weakness

• Sensory disturbances that start in the feet and progress upwards, a symptom of small fiber sensory type neuropathy

• A nerve disorder caused by a dysregulated immune system (immune-mediated neuropathy) 

• Inflammation or damage to a nerve in the head and face (cranial mononeuropathies)

• Inflammation of the brain’s protective covering (the meninges)

• Immune system attacks on the brain, causing swelling

• Worsening or new onset multiple sclerosis

Immunotherapies should be stopped or paused immediately and treated if symptoms are severe. If the respiratory muscles are impacted, you may need to be admitted to the intensive care unit (ICU) for close observation and ventilation.⁵

Heart and Cardiovascular System

Side effects of immunotherapy in the heart and blood vessels are rare but can be severe and life-threatening, as follows:¹

• Inflammation of the blood vessels (vasculitis), which can cause fever, fatigue, weight loss, and muscle and joint pain

• Inflammation of the lining around the heart (pericarditis) 

• Fluid in the sac around the heart (pericardial effusion), which can interfere with the heart’s functioning (cardiac tamponade)

• Stress-induced cardiac dysfunction

• Inflammation of the heart muscle (myocarditis) leading to tissue death

• Failure of the heart’s left ventricle

• Sick sinus syndrome, causing a slow heart rate

• Irregular heart rhythm, including atrial fibrillation and other arrhythmias

• Slow or stopped electrical signals in the heart, called heart blocks

People with these types of complications from immunotherapy need treatment. People with immunotherapy-related arrhythmias can take drugs and may require a pacemaker. Immunotherapy may be stopped if symptoms stick around longer than three months, are life-threatening, or you’ll need to stay on immunosuppressive therapies.⁵

Joints

Immunotherapy can impact your joints, muscles, and bones. These changes can cause arthritis-type pain, joint swelling, and muscle cramping.³

What About Different Types of Immunotherapy?

All types of immunotherapy work differently, so they tend to have unique side effects and complications. 

Immune Checkpoint Inhibitors (ICI)

Immune checkpoint inhibitors remove blocks in the immune system that typically keep your body from attacking healthy cells but are often used by cancer cells to hide from the immune system. Checkpoint inhibitors remove these blocks to enable the immune system to attack cancer.⁶

Some of the more common side effects of checkpoint inhibitors include: 

• Digestive issues like diarrhea, nausea, loss of appetite, and constipation

• Flu-like symptoms like fatigue, cough, and muscle and joint pain

• Skin rash

Checkpoint inhibitors can also cause severe rare side effects that can be life-threatening:

• Infusion reactions may happen while you’re getting the immunotherapy at the clinic. The symptoms of this reaction can include fever, chills, flushing of the face, rash, itchy skin, dizziness, wheezing, and trouble breathing.

• Autoimmune reactions are when the immune system attacks other parts of the body. These can cause damage to the lungs, intestines, liver, endocrine glands, or kidneys.

Adoptive Cell Therapy (T-Cell Transfer Therapy)

Cell therapies like T-cell transfer therapy and adoptive cell therapy remove immune cells from the body. These cells are manipulated so they can better find and fight cancer cells when they are returned to the body. Common side effects of adoptive cell therapies include:⁷

• Kidney damage

• Bleeding 

• Irregular heartbeat and high heart rate

• Flu-like symptoms, including chills, cough, fatigue, and fever

• Digestive symptoms, including constipation, decreased appetite, diarrhea, nausea, and vomiting

• Brain symptoms include delirium, dizziness, headache, and tremors

• Swelling

• Low blood pressure

• Low oxygen levels

Because cell therapies are complex procedures, they also have complex complications. Cytokine release syndrome is when high levels of cytokines (signaling proteins of the inflammatory process) enter the blood and send the immune system into overdrive. Severe cases can cause problems with many organs in the body.

Cytokine release syndrome can cause:⁸

• High fever (with chills) 

• Fast heartbeat

• Rash

• Shortness of breath

• Low blood pressure

Immune effector cell-associated neurotoxicity syndrome, which affects a person's nervous system, can occur with adoptive cell therapies.⁹ Unique symptoms include:

• Confusion

• Behavioral changes

• Inability to speak or understand speech (aphasia)

• Attention, thinking, and memory problems

• Muscle jerks and twitching

• Seizures

Cell therapies may decrease bone marrow function. Your bone marrow makes blood cells, leading to low levels of red blood cells, platelets, and white blood cells. These changes can weaken the immune system, raising the risk of infections. They can also cause bleeding issues.⁸

Other complications include:

• Allergic reactions during the infusion

• Abnormal levels of minerals in the blood, such as low potassium, sodium, or phosphorous levels

• Hemophagocytic lymphohistiocytosis: A buildup of white blood cells in the skin, spleen, and liver

• A loss of healthy B-cells (called aplasia) due to attacks by the modified immune cells

• Disseminated intravascular coagulation: A bleeding and clotting disorder that is potentially life-threatening

• Capillary leak syndrome: Fluid and proteins leak from small blood vessels into surrounding tissues, causing low blood pressure, multiple organ failure, and shock

Monoclonal Antibodies

Monoclonal antibodies are human-made versions of complex proteins made by the immune system. Antibodies recognize and tag specific proteins in the body, typically marking them as foreign and for destruction.¹⁰

Side effects of monoclonal antibodies include:

• Skin reactions at the needle site 

• Flu-like symptoms

• Digestive symptoms

• Mouth and skin sores that can lead to severe infections

• High blood pressure

• Congestive heart failure

• Heart attacks

• Inflammatory lung disease

• Anemia, bleeding, and infections from low blood cell counts¹¹

• Pain in the abdomen, back, and musculoskeletal system

• Nerve damage causes weakness, numbness, and pain, usually in the hands and feet

More complex and severe reactions can occur with antibody treatments. These include:

• Allergic reactions that may be severe and life-threatening

• Capillary leak syndrome

• Cytokine release syndrome

Other reactions are specific to the target of the antibodies. These include:¹²

• Antibodies that target the vascular endothelial growth factor (VEGF) protein can cause high blood pressure, bleeding, poor wound healing, blood clots, and kidney damage.

• Antibodies that target the epidermal growth factor receptor (EGFR) protein can cause severe rashes.

Treatment Vaccines

Typically, vaccines are used to prevent or weaken infections and the illnesses they cause. But cancer treatment vaccines spur the immune system to fight back against cancer. They can cause side effects, including flu-like symptoms.¹³

Other common side effects of cancer vaccines may include:¹⁴

• Loss of appetite

• Back pain

• Headache 

• Nausea

• Sharp nerve pains

These are also possible:¹³

• Severe allergic reaction

• Stroke

• Tumor lysis syndrome, in which large numbers of cancer cells break apart and die, can cause damage to organs like the kidneys, heart, and liver.

Some cancer vaccines can cause herpesvirus infection. Symptoms include:

• Pain, burning, or tingling in a blister around the mouth, genitals, fingers, or ears

• Eye pain, sensitivity, discharge from the eyes, and blurry vision

• Weakness in the arms and legs

• Extreme fatigue and drowsiness

• Confusion

Immune System Modulators (Immunomodulators)

Immune system modulators are drugs that turn the immune system up. This can have many side effects, including flu-like symptoms. Cytokines are a type of immunomodulator drug naturally found in the body. Cytokine drugs can have serious side effects, including:¹⁵

• Breathing issues

• Low or high blood pressure

• Severe allergic reactions

• Reduced blood cell counts, which can raise the risk of infections and cause bleeding and clotting problems 

• Mood, behavior, thinking, and memory changes

• Skin problems, such as rash, burning at the injection site, and ulcers

• Organ damage 

• High levels of bilirubin in the blood causing jaundice¹⁶

Other immunomodulators, such as Thalomid (thalidomide), Revlimid (lenalidomide), and Pomalyst (pomalidomide), can cause side effects that include:¹⁵

• Nerve pain, numbness, tingling, swelling, or muscle weakness

• Congenital disabilities

• Severe blood clots that start in the leg and can travel to the lungs)¹⁷

How Long Immunotherapy Side Effects Last

Most immunotherapy side effects may start with the first treatment, but some—especially more complex complications—may come later. Most will clear up when you stop immunotherapy. Chronic side effects persist for more than three months after treatment has stopped.¹⁸

Regarding checkpoint inhibitors, 43% of people in one study had lingering, chronic side effects; 96% of these long-term side effects were mild. They included rashes, thyroid issues, and joint pain.

But there are some instances in which side effects or complications from treatment will crop up months or years after you've finished. These are called late or long-term side effects.¹

Often, people want to compare the side effects of different cancer treatments. This isn't easy to do since many are very personal. Some people have very mild side effects of immunotherapy, while others have life-threatening reactions and must stop treatment. Chemotherapy is less likely to cause life-threatening side effects. 

Compared to chemotherapy, immunotherapy is generally well tolerated. But often, someone on immunotherapy may stay on it for a long time, while chemotherapy is given in cycles for a set amount of time. Then, the side effects you get on chemotherapy and immunotherapy are different: 

• Immunotherapy typically causes flu-like symptoms

• Chemotherapy causes digestive issues, hair loss, and sores in the mouth, among other side effects

 Chemotherapy vs. Immunotherapy: Uses, Benefits, Side Effects, and More

How to Manage Immunotherapy Side Effects

If you have side effects of immunotherapy treatments, mention them to your care team. They may have ways of treating these side effects or want to monitor these side effects for changes or if they become more problematic. Report any changes in your health to your care team, even if you don't think they're related to your treatment.¹

If your side effects are moderate to severe, your cancer treatment may need to stop while you are treated for the side effects. Sometimes, you can restart treatment. If the side effect returns, you may need to stop altogether. 

You can take some steps to lessen mild side effects at home. While getting cancer treatment, try your best to eat a healthy diet and stay hydrated. Focus on fruits and veggies, low-fat foods, and protein-rich snacks.¹⁹

If you're tired, get some light exercise, which can help with your symptoms of fatigue and nausea. Start slowly with gentle activity such as walking, just for short periods. Take this opportunity to get active by doing things you enjoy—exercise shouldn't be a chore.

If you're having digestive distress while on checkpoint inhibitors, try these tips:

• Avoid high-fat animal products and salty foods.

• Avoid caffeine and alcohol.

• Avoid hot, spicy foods.

• Stay away from overly sweet or greasy foods.

• Drink lots of water and other clear liquids.

• Eat small, frequent meals—try splitting your food intake into 6 to 8 smaller meals.

• Eat dry foods such as crackers or dry cereal.

Listen to your body and get rest when you need it. Ask your friends and family to pitch in so you can take it easy. If you're emotionally challenged with your cancer, cancer treatment, or side effects, talk to your care team about additional mental health support for your anxiety and stress.¹

Do Side Effects Mean Immunotherapy Is Working?

Side effects could indicate that the treatment is effective for at least some specific checkpoint inhibitors. Because these side effects are related to the immune system’s increased activity, they may also mean the immune system is attacking the cancer.²⁰

But this isn’t the case in people who are getting other immunotherapies or those who are also getting other cancer treatments (combination therapies). This is not necessarily true for other cancer treatments. For example, no proof exists that having more or fewer side effects from chemotherapy means it is working. 

However, that also doesn’t mean a lack of side effects indicates the treatment won’t work.

Summary

Immunotherapy is a treatment that boosts your immune system to fight cancer. It can be effective but may have side effects. Immunotherapy side effects range from mild to severe. Common side effects include joint pain, flu-like symptoms, digestive issues, headaches, and skin problems.

Immunotherapy can affect different body systems. These include the skin, liver, lungs, thyroid, and nervous system, causing various symptoms. Severe side effects include infusion reactions, autoimmune reactions, and organ damage. These are less common.

Side effects and complications depend on the type of immunotherapy. Checkpoint inhibitors can cause digestive issues and skin problems. Adoptive cell therapy may lead to kidney damage and neurological symptoms.

Immunotherapy side effects may appear with the first treatment. Many will go away when you stop treatment. Chronic side effects last longer than three months. In some cases, immunotherapy side effects could indicate the treatment is working.

Manage side effects alongside your healthcare team. Keep a healthy diet, stay hydrated, and get light exercise.