Key Facts

Immunotherapy has transformed cancer treatment by harnessing the patient's own immune system. Immune checkpoint inhibitors are now standard of care for many tumour types. Understanding mechanisms, indications, and management of immune-related adverse events is essential.

Epidemiology

• Immunotherapy is now used in >50 cancer types
• Approvals expanding rapidly; ICIs are standard of care in melanoma, NSCLC, renal cell, urothelial, head and neck, Hodgkin lymphoma, and many others
• Response rates vary: 15-60% depending on tumour type and biomarker status

Aetiology

• Not applicable (treatment modality)

Pathophysiology

• Tumours evade immune destruction by upregulating inhibitory checkpoints (PD-L1, CTLA-4)
• PD-1/PD-L1 pathway: PD-L1 on tumour cells binds PD-1 on T-cells, causing T-cell exhaustion
• CTLA-4 pathway: CTLA-4 competes with CD28 for B7 binding on APCs, reducing T-cell activation
• ICIs release the 'brakes' on the immune system, allowing T-cells to attack tumour cells
• CAR-T cells: T-cells genetically modified to express chimeric antigen receptor targeting specific tumour antigen (e.g. CD19); infused back into the patient
• Cytokine release syndrome (CRS): major toxicity of CAR-T therapy; managed with tocilizumab (anti-IL-6)

Indications

• Melanoma: pembrolizumab/nivolumab ± ipilimumab (adjuvant and metastatic)
• NSCLC: pembrolizumab (first-line if PD-L1 ≥50%); combinations with chemotherapy
• Renal cell carcinoma: nivolumab + ipilimumab (first-line intermediate/poor risk)
• Urothelial cancer: atezolizumab, pembrolizumab
• Hodgkin lymphoma: nivolumab, pembrolizumab (relapsed/refractory)
• MSI-H/dMMR tumours: pembrolizumab (tumour-agnostic indication)

Immune-Related Adverse Events (irAEs)

• Dermatitis (most common; 30-40%): rash, pruritus, vitiligo
• Colitis (15-20%): diarrhoea, abdominal pain, bloody stool
• Hepatitis (5-10%): elevated transaminases
• Pneumonitis (3-5%): cough, dyspnoea; potentially fatal
• Endocrinopathies (10-20%): thyroiditis (hypo/hyperthyroid), hypophysitis, adrenal insufficiency, type 1 diabetes
• Neurological (rare): myasthenia gravis, Guillain-Barré, encephalitis

Red Flags

• New-onset diarrhoea (>4 stools/day over baseline): colitis
• Dyspnoea with new infiltrates on CXR: pneumonitis
• Severe fatigue, hypotension, hyponatraemia: adrenal crisis
• Visual disturbance, headache: hypophysitis
• Rapid deterioration with muscle weakness: myasthenia/myositis

Bedside

• Observations (temperature, HR, BP, SpO2)
• Stool chart if diarrhoea
• Glucose monitoring if new diabetes suspected

Bloods

• Baseline and pre-cycle: FBC, U&Es, LFTs, TFTs, glucose, cortisol
• If irAE suspected: LFTs (hepatitis), TFTs (thyroiditis), cortisol and ACTH (adrenal/hypophysitis), lipase (pancreatitis), troponin and CK (myocarditis/myositis)
• Anti-nuclear antibodies if autoimmune cause suspected

Imaging

• CT chest: pneumonitis assessment
• MRI brain (pituitary protocol): if hypophysitis suspected
• CT abdomen: colitis assessment (wall thickening)

Special Tests

• PD-L1 immunohistochemistry: predictive biomarker (tumour proportion score, TPS)
• MSI/MMR testing: dMMR/MSI-H predicts response to pembrolizumab
• Tumour mutational burden (TMB): emerging biomarker
• Colonoscopy: for severe colitis (biopsy for histological confirmation)
• Bronchoscopy + BAL: for pneumonitis

Non-pharmacological

• Patient education about irAEs: provide alert card
• Regular monitoring with blood tests before each cycle
• Low threshold for investigation of new symptoms
• Specialist oncology review for any Grade ≥2 irAE

Pharmacological

• Grade 1 irAE: continue ICI, symptomatic treatment, close monitoring
• Grade 2 irAE: hold ICI; prednisolone 0.5-1mg/kg/day; taper over 4-6 weeks
• Grade 3 irAE: hold ICI; prednisolone 1-2mg/kg/day (or IV methylprednisolone 1-2mg/kg); specialist input
• Grade 4 irAE: permanently discontinue ICI; IV methylprednisolone 1-2mg/kg; consider infliximab 5mg/kg (colitis) or mycophenolate 1g BD (hepatitis)
• Endocrinopathies: often require permanent hormone replacement (levothyroxine, hydrocortisone) rather than immunosuppression
• CRS (CAR-T): tocilizumab 8mg/kg IV; dexamethasone if refractory

Surgical/Interventional

• Rarely required; colectomy for refractory colitis with perforation

Referral Criteria

• Any suspected irAE: discuss with oncology team
• Grade ≥3 irAE: inpatient management under oncology
• Endocrine irAEs: endocrinology input
• Pneumonitis: respiratory input
• Neurological irAEs: urgent neurology review

• ICIs have transformed outcomes in several cancers:
  • Metastatic melanoma: 5-year survival improved from 5% to 40-50% with ICIs
  • Advanced NSCLC (PD-L1 ≥50%): 5-year survival 25-30% with pembrolizumab
• Durable responses: some patients maintain response for years after stopping treatment
• irAEs: most are manageable with steroids; rare fatalities (0.3-1.3%), most commonly myocarditis and pneumonitis
• CAR-T for DLBCL: complete response rate 40-60%; long-term remission in 30-40%

irAE Grading and Management

Key Checkpoint Inhibitors (UK Approved)