What are immunotherapy drug side effects, and how are they treated?

Cancer immunotherapy boomed with development of immune checkpoint inhibitors. These drugs remove T cells’ blindness to cancer, activating immunity against it.

Well-known drugs have been developed against immune checkpoints and received FDA approval . Two classes of immune checkpoints have been identified: first discovered was the CTLA-4 system, followed by the PD-1 - PD-L1 system.

The CTLA-4 immune checkpoint system

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The PD-1 and PD-L1 immune checkpoint system

Although cancer treatment uses 8 different immunotherapy types , today the first thought on hearing immunotherapy is immune checkpoint inhibitors (ICIs) .

Immune checkpoint inhibitors have so far received approval for;

• Aggressive malignant melanoma skin cancer,
• Non-small cell lung cancer,
• Hodgkin lymphoma,
• Kidney cancer,
• Bladder and urinary tract cancer, 
• Head and neck cancers,
• Merkel cell carcinoma, 
• Large bowel (colon and rectal) cancer, 
• Stomach cancer, 
• Liver cancer, 
• Small cell lung cancer, 
• Squamous cell skin cancer, 
• Tumor biomarker-based treatment regardless of organ, and 
• Breast cancer (triple-negative) FDA approval.

Below, the most common immunotherapy side effects by organ are illustrated:

- Related topic: Immunotherapy and Cancer Vaccines 

Immunotherapy side effects - general characteristics 

• It is untrue that immunotherapies have no side effects. Compared with chemotherapy, they cause fewer side effects, but overactivation of immunity can cause serious effects, although most are mild. 
• These effects occur when immunity activated against cancer also harms normal body parts. 
• Generally, anti-CTLA-4 monoclonal antibody immunotherapies (such as ipilimumab-containing Yervoy) have more frequent and severe side effects than anti-PD-1 or anti-PD-L1 therapies (such as Opdivo, Keytruda, Imfinzi, Tecentriq and Bavencio). 
• Reported frequency varies across trials. Some report any-grade effects up to % 90, while anti-PD-1/PD-L1 agents in a phase-3 trial produced rates below %30. 
• Combination immunotherapies cause more frequent and severe effects than single-agent (monotherapy) treatments. 
• Almost every organ system can be affected: most commonly skin, bowel, endocrine system and lungs; less often cardiovascular system, marrow, kidneys, nervous system and eyes.
• Effects are generally mild (grade 1 and 2), but unlike chemotherapy effects, can sometimes last years. 
• The most common are mouth sores (mucositis), diarrhea, skin allergies and flu-like complaints (fatigue, fever, chills, weakness, nausea, vomiting and rash). 
• Patients should avoid the sun, use sunscreen and protect directly exposed areas with hats and clothing as much as possible. 
• In 2016, a study involving 471 patients, a clinical trial, found 5 patients (%1.1) died from ipilimumab-associated effects: 3 from colitis (2 with bowel perforation), 1 from myocarditis (heart damage), and 1 from Guillain–Barre syndrome-associated multiorgan failure. Other studies also found cardiac and pulmonary effects can be fatal. During treatment, serious symptoms such as chest pain, respiratory distress, lung or leg edema and irregular heartbeat should therefore be recognized as potentially immunotherapy-related, even though very rare. 
• Managing this variety of effects exceeds one physician’s knowledge and skills. As in many oncology areas, multidisciplinary teamwork is needed, including rheumatology, endocrinology, cardiology and dermatology.

The graph below shows a PD-1 inhibitor, nivolumab (brand name Opdivo), and onset and resolution times of its most common side effects:

The graph below, for PD-1 and anti-PD-L1 inhibitors, shows rates of the most common effects :

Looking at effects individually;

Rash / Skin allergies

The most common immunotherapy effect is rash and/or itching. With the CTLA-4 inhibitor ipilimumab (Yervoy), approximately %50 of patients experience it. Rash is also among the most common anti PD-1 (nivolumab-Opdivo and pembrolizumab-Keytruda) effects, though fortunately severe rash rates with these agents are low. Cortisone creams may be used with oral antihistamines for itching. Severe rash should be treated with oral cortisone tablets.

Diarrhea / Colitis (inflammatory abdominal pain)

Diarrhea is common with immunotherapies, but severe (grade 3 – 4) diarrhea occurs in only %1-2. Diarrhea and colitis share symptoms but differ. Colitis is associated with abdominal pain, and bowel inflammation can be shown through radiological or endoscopic imaging. Diarrhea simply means increased stool frequency. The first management step must always identify other causes, such as bacterial or viral infections. After excluding them, antidiarrheals such as loperamide may be used in mild cases. If symptoms persist or worsen, oral or intravenous cortisone should be used. Unfortunately, no treatment has been shown to prevent immunotherapy-related diarrhea.

Liver damage

Immunotherapy-related hepatitis is associated with elevated AST and ALT, indicators of liver damage, and sometimes bilirubin, an indicator of jaundice. Many patients have no symptoms. Liver function should be checked before each administration; if elevated, viral and other drug-related hepatitis causes should be excluded. As with other immune-related effects, prompt corticosteroid (cortisone) treatment is recommended if no other underlying cause is found. Rarely, AST and ALT elevations resist cortisone; every 12 hours, 500 mg mycophenolate mofetil may be effective.

Endocrinopathy / Thyroid dysfunction / Hormonal disorders

Although the above effects are usually directly visible, diagnosing checkpoint blockade-related endocrinopathy and thyroid dysfunction may be harder. Nonspecific complaints such as fatigue, nausea and headache require caution from treatment providers. Hypophysitis (pituitary inflammation) and hypothyroidism (low thyroid hormones) are most common, generally occurring with CTLA-4 blockade in up to %10 of patients. Endocrinopathy is less frequent with PD-1 or PDL-1 agents, but monitoring must not be neglected.

Although high-dose corticosteroids are thought to reverse inflammatory endocrinopathy, many patients need long-term levothyroxine thyroid hormone replacement and/or cortisone.

Pneumonitis / Lung inflammation

Pneumonitis with CTLA-4 and PD-1 blockers is rare (under %10) but potentially life-threatening. Any patient with pulmonary complaints such as upper respiratory infection, new cough or breathlessness should undergo imaging to identify the cause. In moderate to severe cases, bronchoscopy (examining airways with a camera-equipped instrument) should exclude bacterial infection before immunosuppression. Severe cases require high-dose corticosteroids; additional immunosuppressants such as infliximab may be appropriate. Immunotherapy should not be considered after pneumonitis.

Conclusion

As immunotherapy develops into a revolutionary model for advanced cancers, better recognition of side effects is needed. Early diagnosis and aggressive treatment of mild (grade 1 and 2) immune-related effects are recommended to prevent patient harm without compromising checkpoint inhibitor efficacy. Future studies gathering information about steroid and nonsteroid drugs have become essential to using immunotherapies most effectively.