Immune checkpoint inhibitors: mechanism and irAE management

PD-1, PD-L1 and CTLA-4 blockade, how immune-related adverse events are graded, and how to hold, treat and refer

For clinicians and students · Special tutorial · Across cancers · 11 min read · last reviewed September 30, 2026

Indications and scope

Immune checkpoint inhibitors (ICIs) are standard therapy across many tumours, in the metastatic, adjuvant and neoadjuvant settings, alone or in combination. This primer covers how they work, how immune-related adverse events (irAEs) are graded and managed, and when to hold, rechallenge, discontinue or refer. Regimen dosing is in the individual tutorials and your institutional protocols.

Mechanism

• CTLA-4 (cytotoxic T-lymphocyte antigen 4):
• An inhibitory receptor that acts mainly during T-cell priming in lymph nodes. It outcompetes CD28 for the B7 ligands (CD80/CD86) on antigen-presenting cells.
• Blocking CTLA-4 widens T-cell activation and reduces regulatory T-cell suppression.
• Effects are broad, so irAEs are more frequent, earlier and more severe, especially colitis and hypophysitis.
• PD-1 / PD-L1:
• PD-1 on activated T cells binds PD-L1 (on tumour and immune cells) and PD-L2, which dampens effector T cells in peripheral tissues and the tumour.
• Blocking PD-1 or PD-L1 restores antitumour T-cell activity.
• irAEs are less frequent than with CTLA-4 blockade. They are dominated by thyroiditis, skin, pneumonitis, hepatitis and colitis.
• LAG-3: relatlimab (combined with nivolumab) blocks another inhibitory receptor, with a PD-1-like toxicity profile.
• Combinations: anti-CTLA-4 plus anti-PD-1 (for example ipilimumab + nivolumab) has the highest irAE rates. Grade 3–4 events occur in more than half of melanoma patients on the traditional ipilimumab 3 mg/kg schedule.

Common agents

BC Cancer SCIMMUNE notes that the extended-interval PD-1/PD-L1 schedules (for example pembrolizumab 400 mg every 6 weeks, nivolumab every 4 weeks) have pharmacokinetics, efficacy and safety similar to standard schedules. irAE incidence does not increase with the larger individual doses.

Timing of irAEs

• Most irAEs appear in the first 3–6 months:
• skin first (weeks),
• then colitis and hepatitis (about 6–12 weeks),
• then endocrinopathies (about 2–6 months), with hypophysitis classically around 2–3 months into ipilimumab.
• Neurological irAEs typically occur within the first 3 months (SITC).
• Myocarditis is usually early, often within the first 1–2 doses, particularly with combination ICIs.
• Late and delayed irAEs can occur months to years later, including after treatment has stopped (BC Cancer, eviQ). Take a medication history covering past immunotherapy in every patient who presents acutely unwell.

Baseline work-up (before the first dose)

The SITC baseline is:

• CBC and differential, a comprehensive metabolic panel (electrolytes, creatinine, liver tests, glucose), TSH and free T4,
• urinalysis to consider.

Protocols such as BC Cancer's add:

• morning cortisol, LDH, lipase if indicated, and chest imaging,
• HBV/HCV (and HIV where indicated),
• a pregnancy test,
• baseline ECG ± troponin, which many centres do, although eviQ notes limited evidence.

Also document:

• baseline bowel habit, skin, oxygen saturation and pre-existing autoimmune disease,
• symptoms of a pre-existing neuromuscular disorder.

Before each dose: CBC, creatinine, liver panel, electrolytes, glucose and TSH. Check cortisol and other hormones when clinically indicated.

General grading and management principles

irAEs are graded with CTCAE v5.0. ASCO, ESMO, SITC, NCCN and BC Cancer SCIMMUNE share the same framework:

Taper: taper steroids over at least 4 weeks, or 4–6 weeks after grade 3 or higher and for pneumonitis and hepatitis (SCIMMUNE, SITC). Tapering too fast causes flares.

While on prolonged steroids:

• Give PJP prophylaxis when prednisone is 20 mg/day or more for 1 month or longer (SITC).
• Consider a PPI, glucose monitoring, bone protection, and antifungal prophylaxis in selected patients.

Rechallenge:

• Often feasible after grade 2 events, and after selected grade 3 events once they have resolved to grade 1 or less.
• Avoid rechallenge after grade 4 events, and after myocarditis, severe neurological events or SJS/TEN.
• Recurrence of the same or a different irAE is common. Decide jointly with the specialist and the patient.

Organ-specific management

Summarized from BC Cancer SCIMMUNE and the ASCO, ESMO and SITC guidelines.

Skin (the most common irAE)

• Presentations: maculopapular rash, pruritus, lichenoid or psoriasiform eruptions, vitiligo (melanoma).
• Grade 1–2 (30% of body surface area or less): continue the ICI. Give topical corticosteroids, emollients and oral antihistamines. If the rash persists beyond 1–2 weeks, hold and start prednisone 0.5–1 mg/kg.
• Grade 3 (more than 30% BSA or limiting self-care): hold, give prednisone 0.5–1 mg/kg, and refer to dermatology. Consider biopsy.
• Blistering, mucosal involvement or skin pain suggest SJS/TEN or DRESS. Stop the ICI permanently, admit, and involve dermatology and burn-unit care.

Gastrointestinal: diarrhoea and colitis

• Grade 1 (fewer than 4 stools per day over baseline): continue, with antidiarrhoeals and fluids.
• Grade 2 (4–6 stools per day over baseline, pain, or blood or mucus):
• Hold the ICI and send stool cultures and C. difficile testing.
• Start prednisone 1 mg/kg/day immediately if there are colitis symptoms. If the only symptom is diarrhoea, start it when diarrhoea persists beyond 2–3 days (1–2 days on combination ICIs).
• Refer to gastroenterology.
• Grade 3–4 (7 or more stools, incontinence, fever, peritonism):
• Admit. Rule out perforation before giving steroids.
• Give methylprednisolone 1–2 mg/kg/day IV. Consider endoscopy.
• If there is no response in about 72 hours (SCIMMUNE: 1–5 days), add infliximab. SITC gives infliximab 5 mg/kg at weeks 0, 2 and 6, or vedolizumab 300 mg at weeks 0, 2 and 6 (vedolizumab is gut-selective and preferred by some after infliximab failure).
• Early biologics in patients with high-risk endoscopic features shorten steroid exposure.
• Discontinue the ICI after grade 4 or persistent grade 3. Anti-CTLA-4 is usually stopped permanently after grade 3 colitis.

Hepatitis

• Grade 2 (ALT or AST 3–5 × ULN, or bilirubin 1.5–3 × ULN):
• Hold the ICI and exclude viral, drug, alcohol, obstructive and metastatic causes. Check LFTs every 3 days.
• If the elevation persists beyond 3–5 days, give prednisone 0.5–1 mg/kg.
• Grade 3–4 (ALT above 5 × ULN or bilirubin above 3 × ULN):
• Permanently discontinue (BC Cancer). Give prednisone or methylprednisolone 1–2 mg/kg and involve hepatology.
• If refractory: mycophenolate mofetil 1–2 g/day in divided doses (SITC). Avoid infliximab because of its own hepatotoxicity.

Pneumonitis

• Presentations: cough, dyspnoea, hypoxia, new ground-glass or organising-pneumonia patterns. Always consider infection and progression as alternatives.
• Grade 1 (radiographic only): consider holding and reassess every 2–3 days.
• Grade 2: hold the ICI. Consider high-resolution CT, bronchoscopy and empiric antibiotics. SCIMMUNE uses prednisone 1–2 mg/kg (SITC: 0.5–1 mg/kg). Involve respiratory medicine. Taper over at least 4–6 weeks.
• Grade 3–4: admit and permanently discontinue. Give methylprednisolone 1–2 mg/kg IV. If there is no improvement in 48 hours, add infliximab, mycophenolate, IVIG or cyclophosphamide per specialist advice.

Endocrinopathies (often permanent; ICI can usually continue)

• Thyroid: the most common endocrine irAE.
• It is typically painless thyroiditis, with transient hyperthyroidism (managed with a beta-blocker; steroids rarely needed) followed by hypothyroidism.
• Replace levothyroxine per SCIMMUNE: 1–1.8 mcg/kg/day, or 12.5–25 mcg/day with slow titration in older or cardiac patients.
• Continue the ICI in most cases. Graves-type disease (TRAb-positive) is rarer and is treated with methimazole.
• Hypophysitis: most common with anti-CTLA-4.
• Presents with headache, fatigue, visual symptoms and hyponatraemia.
• Check ACTH, cortisol (before steroids if feasible), TSH/FT4, LH/FSH, testosterone or oestradiol, prolactin and electrolytes, and arrange a pituitary MRI.
• Physiological hydrocortisone replacement is lifelong in most patients, because the ACTH deficiency rarely recovers.
• High-dose steroids are reserved for mass effect such as severe headache or visual compromise.
• Start glucocorticoid before thyroxine when both axes are deficient, to avoid precipitating adrenal crisis.
• Primary adrenal insufficiency: rare. Needs lifelong hydrocortisone and fludrocortisone.
• Suspected adrenal crisis (hypotension, shock, severe dehydration) is an emergency. SCIMMUNE: stress-dose hydrocortisone 50–100 mg IV and IV fluids, and rule out sepsis.
• ICI-induced type 1 diabetes: often presents abruptly in DKA with low C-peptide.
• Hold the ICI until DKA resolves, then give lifelong insulin.
• Steroids do not help and are not recommended.
• Patient teaching: everyone on glucocorticoid replacement needs sick-day rules, a steroid emergency card, and an injectable hydrocortisone plan.

Renal (nephritis)

• Grade 2 (creatinine 1.5–3 × ULN): hold the ICI, exclude other causes (NSAIDs, PPIs, contrast, obstruction), refer to nephrology, and give prednisone 1 mg/kg.
• Grade 3–4: permanently discontinue and give 1–2 mg/kg. Consider biopsy. Mycophenolate is an option if refractory.

Neurological

• Syndromes: peripheral neuropathy, Guillain-Barré syndrome, myasthenia gravis, aseptic meningitis, encephalitis, transverse myelitis.
• Grade 2: hold and consider prednisone 0.5–1 mg/kg, with a neurology consult.
• Grade 3–4: discontinue. Give methylprednisolone 1–2 mg/kg and consider IVIG or plasmapheresis (particularly for Guillain-Barré and myasthenia).
• Myasthenia: often overlaps with myositis and myocarditis (the "triple M" syndrome). Check CK, troponin and respiratory function (vital capacity or negative inspiratory force).

Cardiac (myocarditis)

• Presentations: rare (under 1–2%) but mortality is high. May present with fatigue, dyspnoea, chest pain, arrhythmia or heart block, or only as a rising troponin, often with raised CK (concurrent myositis).
• Work-up: ECG, troponin, BNP, echo and cardiac MRI. Admit with telemetry and involve cardiology urgently.
• Treatment: permanently discontinue the ICI. Start high-dose corticosteroids immediately. Guidelines describe pulse IV methylprednisolone (commonly 1 g daily for 3–5 days) for severe or unstable cases.
• Refractory cases: mycophenolate, abatacept, ATG or other agents per cardio-oncology guidance.

Other irAEs

• Rheumatological: inflammatory arthritis and polymyalgia-like syndromes. Treat with NSAIDs or low-dose prednisone. Rheumatology can use DMARDs, often allowing the ICI to continue.
• Ocular: uveitis and episcleritis need topical corticosteroids and urgent ophthalmology review.
• Haematological: autoimmune haemolytic anaemia, ITP, and haemophagocytic lymphohistiocytosis (HLH).
• Pancreatic: pancreatitis. An isolated lipase rise without symptoms usually does not need treatment.
• Severity principle: any severe or clinically significant irAE means discontinuing the ICI, giving prednisone or methylprednisolone 1–2 mg/kg/day, and referring (SCIMMUNE).

When to refer or admit

• Admit:
• any grade 3–4 irAE,
• suspected myocarditis, myositis or myasthenia, encephalitis, Guillain-Barré, SJS/TEN, adrenal crisis or DKA,
• colitis with signs of peritonism,
• pneumonitis with hypoxia.
• Early specialist referral (gastroenterology, hepatology, respiratory, endocrinology, nephrology, neurology, cardiology, dermatology, rheumatology, ophthalmology) at grade 2 or higher, or when the diagnosis is uncertain.
• Always inform the treating oncology team. Irreversible harm comes more often from delayed recognition than from the treatment itself.

Patient education: symptoms to report

Tell patients to call the cancer centre's 24-hour line the same day for:

• new or worsening cough or shortness of breath,
• diarrhoea (4 or more extra stools per day), blood or mucus in stool, or abdominal pain,
• yellow skin or eyes, dark urine or easy bruising,
• a new rash, blisters, mouth sores or peeling skin,
• severe fatigue, headache, dizziness or fainting, or vision changes,
• excessive thirst or urination, or confusion (hyperglycaemia or DKA),
• muscle weakness or aching, drooping eyelids, double vision, or difficulty swallowing or breathing,
• chest pain or palpitations,
• reduced urine output or swelling,
• joint pain or swelling.

Also teach patients to:

• carry an immunotherapy alert card and show it to any emergency or non-oncology clinician, because irAEs can appear months after the last dose,
• never stop replacement hormones (hydrocortisone, levothyroxine, insulin) abruptly,
• follow steroid sick-day rules.

Clinical pearls

• "Think irAE" for any new symptom in a patient on, or previously on, an ICI. Rule out infection and progression, but don't delay steroids in severe presentations while waiting for results.
• A painless rising TSH usually needs levothyroxine only. It does not need prednisone or ICI discontinuation.
• When cortisol is low, think pituitary before thyroid. Replace hydrocortisone first.
• Troponin plus CK plus ptosis is a medical emergency (myocarditis-myositis-myasthenia overlap).
• Use mycophenolate, not infliximab, for hepatitis.
• Steroid-refractory colitis at 72 hours needs a biologic. Escalating steroids further does not help.
• Steroids for irAEs do not appear to reduce ICI efficacy in most analyses. Prompt treatment is the priority, but avoid unnecessary prolonged high doses.
• Pre-existing autoimmune disease is not an absolute contraindication. Expect flares, co-manage with the relevant specialist, and decide case by case.

Educational material for health professionals and students. Not a prescribing order; it does not replace your institution's approved protocol, pharmacy verification or clinical judgement.

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