Immune Checkpoint Inhibitors and Associated Immune-Related Adverse Events

How to Cite This Chapter: Chan SWS, Goffin JR. Immune Checkpoint Inhibitors and Associated Immune-Related Adverse Events. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. Accessed May 22, 2024.
Last Updated: January 19, 2024
Last Reviewed: January 19, 2024
Chapter Information

Physiology and Mechanism of ActionTop

One of the underpinnings of the immune system is the ability to differentiate self from nonself, thus distinguishing aberrant cells from normal cells. Malignant cells develop the ability to evade the adaptive immune system through several immunosuppressive mechanisms. On naive T cells, typically within the lymph nodes and under normal circumstances, the cytotoxic T-lymphocyte antigen-4 (CTLA-4) receptor serves as an important negative-feedback loop in T-cell activation in response to antigen presentation. Similarly, the interaction between the programmed death receptor 1 (PD-1) on the T-cell surface and its corresponding ligand, programmed death ligand 1 (PD-L1), on the cancer cell leads to immune cell exhaustion, inhibition of apoptotic mechanisms, and reduction in the immune system effector response to the tumor.

Immune checkpoint inhibitors (ICIs) block these “brakes” on the immune system, disrupting the CTLA-4 and PD-1/PD-L1 pathways to improve the adaptive immune response to malignancies. These medications include PD-1/PD-L1 inhibitors such as pembrolizumab, nivolumab, and atezolizumab and a CTLA-4 inhibitor, ipilimumab.

Differences Between Immune Checkpoint Inhibitors and Conventional Cytotoxic Therapies

There is an increasing number of indications for ICI therapy, including lymphoproliferative disorders, lung cancer, melanoma, renal cell carcinoma, and hepatocellular carcinoma. It is an attractive first-line therapy for patients, as it has demonstrated improved survival and substantially higher response rates when compared with chemotherapy, with better quality of life. A subset of patients (~15%) develops a durable clinical response, which prolongs their survival for years. While the adverse effects of ICI therapy are common, they are generally less severe and quality of life is better preserved than with other treatments. For example, when used alone, ICIs typically induce less fatigue, nausea and vomiting, and myelosuppression when compared with chemotherapy.

Immunotherapy also has downsides compared with other systemic therapies. Activation of the immune system can lead to the development of unintended inflammatory states in any organ system, termed immune-related adverse events (irAEs). Therefore, prior to initiating immunotherapy, patients are assessed for preexisting autoimmune conditions that may preclude its use, such as a history of colitis or inflammatory conditions affecting the joints, skin, brain, or other sites. Evidence to date also suggests that, as with chemotherapy, patients require an Eastern Cooperative Oncology Group (ECOG) ( performance status (a measure of the patient's functional ability) of 0 to 2 (out of 5) to derive benefit. ICIs are exceptionally expensive. Their cost exceeds 100,000 United States dollars per year of treatment, placing the drugs out of reach in some jurisdictions.

Immune-Related Adverse EventsTop

Etiology and Pathogenesis

The increasing use of ICIs has changed the landscape of medical oncology. While being generally more tolerable than chemotherapy, ICI treatment causes unique adverse events requiring timely diagnosis and management. It is therefore pertinent that health-care workers outside of the patient’s oncology team consider immune toxicity when such patients present with symptoms.

The toxicity of immune checkpoint inhibition represents the failure of T cells to recognize normal cells as “self.” The clinical features of irAEs are diverse and vary according to the organ affected. As recommended by the Cancer Evaluation Program (CTEP) (, the irAE severity is graded from 1 to 5 (starting from mild [grade 1] through moderate [grade 2], severe [grade 3], and life-threatening [grade 4], and ending up with causing death [grade 5]), which helps guide management. IrAEs can involve almost any organ system; however, the most affected sites are the skin, endocrine glands, colon, and liver. Although rare, cardiovascular and neurologic events can be life-threatening. On the other hand, dermatologic complications and fatigue are among the most common adverse events, but they are more often lower grade.

Clinical Presentation

The timeline and likelihood of the occurrence of irAEs vary depending on organ system involvement, regimen (dual therapy vs monotherapy vs combination with chemotherapy), duration of exposure, and time since the last dose. IrAEs can occur within days of ICI administration or during several months (rarely years) after therapy completion. Clinical manifestations range from asymptomatic findings on laboratory investigations (eg, low-grade transaminitis or nephrotoxicity) to fulminant organ failure requiring critical care (Table 1).

History-taking in patients with suspected irAEs should include any preexisting autoimmune conditions, as they may be exacerbated by ICIs. Detailed history-taking should be performed and physical examination should be conducted to grade the toxicity. The diagnosis may be complicated by concomitant administration of other anticancer drugs, and the differential diagnosis should include all the usual culprits, such as disease progression and infections. IrAEs may be subtle and require a certain index of suspicion. Laboratory testing and imaging are specific to organ involvement. Tissue biopsy and specialist consultations may be required when the diagnosis is unclear or the grade indicates severe disease. Involvement of an oncology specialist is recommended in most instances.


Management of irAEs and the need for hospitalization are guided by the severity (ie, grade) of symptoms and speed of their progression. Detailed management: Table 1.

General principles and considerations:

1) All toxicity presentations are nonspecific and require a high index of suspicion. Non–drug-related causes should be excluded.

2) Except for cardiac irAEs, which are considered dangerous in all cases (grade 4), patients need to be stratified based on the severity grade to determine further treatment.

3) For most grade 1 irAEs, there is no urgent need for immunosuppression, but symptomatic treatment and further monitoring are important. Treatment interruption should generally be considered if the irAE severity grade is >1.

4) Systemic glucocorticoid use is usually required for grade 2 irAEs.

5) The initial treatment is typically prednisone at a dose of 0.5 to 1 mg/kg/d. More severe cases require methylprednisolone at a higher dose of 1 to 2 mg/kg/d.

6) Glucocorticoid treatment should be tapered according to symptom response, but it is to be continued for ≥4 weeks to avoid rebound toxicity. When longer treatment is required, consider proton pump inhibitors, Pneumocystis jiroveci prophylaxis, and osteoporosis prevention strategies.

7) IrAEs refractory to glucocorticoids require specialist guidance. Treatment may include additional immunosuppressive agents such as infliximab and mycophenolate mofetil (MMF), but it depends on the organ system involved and local institutional practices.

8) In most cases the occurrence of grade 3 and grade 4 toxicity leads to permanent discontinuation of immune therapy.

9) It is recommended that an oncology specialist be consulted in most cases.

10) Ocular toxicities are exceedingly rare and usually manifest with an inflammatory eye disease that requires formal ophthalmologic input, which exceeds the scope of this chapter.


Table 13.2-1. Presentation, investigation, and treatment of immune-related adverse events


Common clinical manifestations

Initial investigations

General approach to treatment

Skin lesions

– The most common irAE (20%-40% of patients)

– Typically rash (grade 1)

– Other various presentations including bullous pemphigoid, psoriatic lesions, SJS/TEN

– Desquamation is considered grade 4 irAE

– Physical examination

– Consider skin biopsy if the diagnosis is unclear or indicates a severe disease

– Mild (grade 1) skin lesions can be treated with 1% hydrocortisone or 0.1% betamethasone cream for symptomatic pruritic rashes. Symptomatic treatment includes cold compresses and systemic antihistamines

– Systemic glucocorticoids can be considered for grade ≥2 symptoms, and high-dose therapy for symptoms of grade ≥3 with a dermatology consultation

– Consider tocilizumab or infliximab in glucocorticoid-refractory cases

Gastrointestinal abnormalities

– Diarrhea can be the sole symptom

– Diarrhea with abdominal discomfort or bloody stool is more suggestive of immune therapy-induced colitis

Abdominal CT to assess bowel thickening, areas affected, and complications

– Mild (grade 1) diarrhea can be treated with antidiarrheal agents (eg, loperamide) and should be closely monitored. Start glucocorticoids in grade 1 diarrhea if it is refractory to loperamide or in grade 2 unless transient

– For symptoms of grade ≥3, consider hospital admission for resuscitation and high-dose glucocorticoids, with gastroenterology/general surgery consultation

– Consider infliximab or vedolizumab in glucocorticoid-refractory cases

Liver abnormalities

– Elevated levels of transaminases, GGT, and rarely bilirubin, without symptoms

– Possible fatigue, abdominal pain, and nausea

– AST, ALT, ALP, GGT, bilirubin, and albumin levels; INR

– Abdominal ultrasonography or CT

– Exclude other causes (eg, viral hepatitis)

– Systemic glucocorticoids for sustained symptoms of grade ≥2 and high-dose treatment for grade ≥3

– Consult a gastroenterology/hepatology specialist regarding symptoms of grade ≥2. Consider liver biopsy to exclude alternative etiologies when considering nonglucocorticoid immunosuppressants

– Consider MMF, tacrolimus, azathioprine, and cyclosporine in glucocorticoid-refractory cases

Pulmonary abnormalities

– Shortness of breath—new or worsening from baseline

– Cough, chest pain, hypoxia

– Chest CT (ground-glass opacities, consolidation, reticular infiltrates, pneumonitis, granulomas, or organizing pneumonia)

– Oxygen saturation

– Exclude other causes (infections, venous thromboembolism)

– High-dose glucocorticoids for symptoms of grade ≥2. Consider empiric antibiotics

– Consider hospital admission for symptoms of any grade ≥3 or of grade 2 if not improved within 48 h

– Consult respirology and infectious disease specialists and perform bronchoscopy as needed

– Consider tocilizumab, infliximab, MMF, or cyclosporine if refractory to glucocorticoids

Thyroid abnormalities

– Hyperthyroidism or hypothyroidism

– Autoimmune thyroiditis can lead to hypothyroidism

TSH, FT4, and FT3 levels

– For symptomatic hyperthyroidism initiate a beta-blocker (eg, PO propranolol 10-40 mg qid). To provide urgent relief of symptoms of a higher grade, consider using methimazole (20-30 mg/d) with endocrinology guidance

– Consider high-dose glucocorticoid treatment and hospital admission for symptoms of grade ≥3

– In hypothyroidism, replace thyroid hormones for irAEs of grade ≥2 (symptomatic). In case of severe symptoms (grade ≥3), admit the patient to hospital and administer high doses of glucocorticoids until hypoadrenalism is excluded

Hypophysitis (pituitary gland inflammation)

Headache, visual impairment, labile moods, weakness, fatigue, confusion

– TSH, FT3, FT4, morning cortisol, ACTH, LH, FSH, GH, prolactin, and, if the patient is symptomatic, testosterone or estrogen

– MRI of the pituitary gland

– High-dose glucocorticoids for symptoms of grade ≥2, with slow tapering

– Hospitalization for severe symptoms (grade ≥3)

– Hormone replacement depending on endocrinology studies (eg, replace thyroid hormones and cortisol as indicated)

– Involve an endocrinologist early

Adrenal insufficiency

Abdominal pain, fatigue, refractory hypotension, hyponatremia, hyperkalemia

Morning cortisol, ACTH, aldosterone, renin

– A clinically unwell patient (shock) should be admitted to hospital to exclude other causes

– Asymptomatic grade 1 irAE may not require glucocorticoid treatment. For grade ≥2, consider high-dose glucocorticoids, while for grade ≥3, consider a stress dose

– For grade ≥3, consider mineralocorticoid replacement (eg, fludrocortisone)

– Consult an endocrinologist


Polyuria, polydipsia, weight loss, fatigue

– Antibodies to GAD-65 or islet cells

– C-peptide, HbA1c, fasting glucose levels

– Similar as in type 1 diabetes; insulin replacement therapy is recommended

– Refer the patient to an endocrinologist

Rheumatologic disease

– Rheumatoid arthritis, reactive arthritis, seronegative spondyloarthritis

– Inflammatory joint pain (joint ache, morning stiffness, improvement with exercise, erythema, swelling)

– Radiography and other imaging modalities, if appropriate, to exclude bone metastases

– Consider testing for antinuclear antibodies, rheumatoid factor, anti–citrullinated protein antibody

– NSAIDs for relief of mild (grade 1) symptoms

– For moderate symptoms (grade 2), use low-dose glucocorticoids (prednisone 10-20 mg/d). Use high doses for more severe symptoms

– Refer patient with symptoms of grade ≥2 to a rheumatologist, as workup depends on the presenting disease

– Tailored treatment for specific syndromes (eg, DMARDs)

– If biologics are considered, IL-6 receptor inhibitors are preferred over TNF-alpha inhibitors

Cardiac abnormalities

Myocarditis, pericarditis, cardiomyopathy, left ventricular dysfunction

– Troponin levels

– Electrocardiography, echocardiography

– For symptoms of all grades, admit the patient to hospital with urgent referral to a cardiologist

– High-dose glucocorticoids (1-2 mg/kg/d)

– Consider adjunct immunosuppression including tocilizumab, MMF, alemtuzumab, or abatacept

Renal abnormalities

– Increased serum creatinine

– If severe, failure can result in anuria, volume overload, acid-base disturbances, and electrolyte disorders

– Electrolyte, serum creatinine, urine protein levels

– Urine microscopy

– Renal ultrasonography

– Minimize nephrotoxic drug use

– Systemic glucocorticoids for symptoms of grade ≥2 and high doses for grade ≥3

– Consider MMF, infliximab, or azathioprine if symptoms are refractory to glucocorticoids

– Correct electrolyte imbalances and perform dialysis as guided by the specialist

– Consult a nephrologist

– Consider renal biopsy if the etiology is unclear

Neurologic abnormalities

– Peripheral nervous system: Sensory or motor neuropathy, myasthenia gravis, Guillain-Barré syndrome

– Central nervous system: Meningitis, autoimmune encephalitis, cerebral vasculitis, transverse myelitis, optic neuritis

– Head MRI

– Consider lumbar puncture, nerve conduction studies, electromyography

– Consult a neurologist

– Systemic glucocorticoids for symptoms of grade ≥2, high doses for grade ≥3, and glucocorticoids for all cases of Guillain-Barré syndrome, myasthenia gravis, encephalitis, and transverse myelitis

– If symptoms are refractory, consider additional immunosuppressive agents, such as infliximab, MMF, and IVIG, and plasmapheresis depending on the presenting illness

Hematologic toxicities

 – Anemia (aplastic or hemolytic)- Leukopenia including neutropenia or lymphopenia

–Thrombocytopenia (immune mediated)

– Pancytopenia (rarely consumptive thrombotic disorders or hemophagocytic lymphohistiocytosis)

– Acquired clotting disorders

 – Complete blood count with blood film, fractionated bilirubin, LDH, haptoglobin, reticulocytes, direct antiglobulin test (or the Coombs test)

– Consider syndrome-directed investigations including bone marrow examination, flow cytometry, and specific thrombotic or hemophilia workup

– Treatment depends on grade and specific syndrome

– Early consultation with a hematologist is recommended

– Supportive management including blood products and growth factor support may be necessary

– Most patients respond to glucocorticoid treatment, but refractory cases should be tailored to the clinical syndrome including IVIG, rituximab, plasmapheresis, MMF, or cyclosporine (INN cyclosporin)

ACTH, adrenocorticotropic hormone; ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; CT, computed tomography; DMARD, disease-modifying antirheumatic drug; FSH, follicle-stimulating hormone; FT3, free triiodothyronine; FT4, free thyroxine; GAD-65, glutamic acid decarboxylase 65; GGT, gamma-glutamyl transferase; GH, growth hormone; HbA1c, glycated hemoglobin; IL, interleukin; INR, international normalized ratio; irAE, immune-related adverse event; IV, intravenous; IVIG, intravenous immunoglobulin; LDH, lactic dehydrogenase; LH, luteinizing hormone; MMF, mycophenolate mofetil; MRI, magnetic resonance imaging; NSAID, nonsteroidal anti-inflammatory drug; PO, oral; qid, 4 times a day; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; TSH, thyroid-stimulating hormone.

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