Immune checkpoint inhibitors (ICIs) are an advancement in cancer treatment, offering a distinct approach compared to traditional therapies like chemotherapy. These medications fall under immunotherapy, harnessing the body’s own immune system to fight cancer. Unlike treatments that directly target cancer cells, ICIs modify the immune system’s natural regulatory mechanisms. They aim to unleash a more robust immune response against cancerous growths.
How Immune Checkpoint Inhibitors Cause Side Effects
Immune checkpoint inhibitors function by “releasing the brakes” on the immune system, allowing immune cells, particularly T cells, to recognize and attack cancer cells. Normally, immune checkpoints act as safeguards, preventing the immune system from becoming overactive and harming healthy tissues. By blocking these inhibitory pathways, ICIs enhance the immune system’s ability to identify and eliminate malignant cells.
This heightened immune activity, while beneficial for fighting cancer, can lead to the immune system mistakenly targeting healthy cells and tissues throughout the body. This unintended immune response results in “immune-related adverse events” (irAEs). The mechanisms leading to irAEs are believed to be similar to those that promote anti-tumor responses, involving the expansion of various immune cell populations. irAEs are a consequence of ICI therapy, reflecting the broad activation of the immune system.
Common Side Effects
Patients receiving immune checkpoint inhibitor therapy often experience a range of common side effects, which are generally less severe than organ-specific reactions. Fatigue is a frequently reported symptom, described as persistent tiredness that does not improve with rest. This fatigue results from widespread inflammation caused by the activated immune system.
Skin reactions are prevalent, manifesting as rashes, redness, and itching. These dermatological issues may appear within days to weeks of starting treatment. Diarrhea is another common gastrointestinal side effect, sometimes accompanied by abdominal pain or cramping. Nausea and muscle or joint pain are also observed, stemming from the immune system’s generalized inflammatory response.
Flu-like symptoms, such as fever, chills, and body aches, can occur, especially shortly after an infusion. These side effects can appear within days of the first dose or several weeks to months into treatment. While most people experience mild side effects, severity can increase with higher doses or combination ICI therapies.
Organ-Specific Side Effects
Beyond common symptoms, immune checkpoint inhibitors can lead to more serious, organ-specific immune-related adverse events. These reactions occur when the overactive immune system targets healthy organs. Reporting any new or worsening symptoms to the healthcare team is important for timely intervention.
Gastrointestinal
Gastrointestinal complications include colitis (inflammation of the colon) and hepatitis (inflammation of the liver). Colitis can cause abdominal pain and diarrhea, sometimes with blood or mucus. Hepatitis may present with fever, abdominal pain, nausea, vomiting, or jaundice, and can be detected by elevated liver enzymes.
Endocrine System
Endocrine system involvement can lead to thyroid dysfunction (hyperthyroidism or hypothyroidism), adrenal insufficiency, where the adrenal glands produce insufficient hormones, and hypophysitis (inflammation of the pituitary gland). These conditions often require long-term hormone replacement therapy.
Pulmonary, Renal, and Cardiovascular
Pulmonary side effects include pneumonitis (inflammation of the lungs), causing cough or shortness of breath. Renal complications can manifest as nephritis (inflammation of the kidneys), identified by changes in kidney function tests. Cardiovascular issues can include myocarditis (inflammation of the heart muscle), potentially causing chest pain or shortness of breath.
Neurological
Neurological adverse events can encompass peripheral neuropathy, affecting nerve function, or encephalitis (inflammation of the brain). These can lead to symptoms from numbness and tingling to more severe cognitive changes.
Musculoskeletal
Musculoskeletal reactions include arthritis (joint inflammation and pain) and myositis (inflammation of the muscles), leading to weakness and discomfort.
Managing Side Effects
Managing side effects from immune checkpoint inhibitors involves early detection and appropriate intervention. Healthcare providers closely monitor patients for any signs or symptoms of immune-related adverse events throughout treatment and even after it concludes, as some side effects can appear months later. Side effects are graded from mild (Grade 1) to severe (Grade 3 or 4), which guides the treatment strategy.
For mild side effects, ICI therapy may continue with close observation. Moderate side effects often necessitate temporarily interrupting the treatment. Severe reactions require immediate discontinuation of the ICI and prompt medical intervention.
Corticosteroids, such as prednisone, are the primary treatment for most moderate to severe immune-related adverse events. These medications suppress the immune system to reduce inflammation. Dosage and duration depend on the specific side effect and its severity, with gradual tapering over several weeks once symptoms improve. If corticosteroids are not effective, other immunosuppressive medications may be considered.
Symptomatic management also plays a role, with medications like anti-diarrhea agents or pain relievers used to alleviate discomfort. A multidisciplinary care team, including oncologists, nurses, and specialists such as gastroenterologists, endocrinologists, or pulmonologists, is often involved in managing complex irAEs. This collaborative approach ensures management is tailored to the specific side effect and its impact on the patient’s well-being.