Who Is Most at Risk for Checkpoint Inhibitor Side Effects?

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Who Is Most at Risk for Checkpoint Inhibitor Side Effects?

By Peter Teoh, Science Writer

Several clinical and patient-related features are linked to a higher risk of immune-related side effects from checkpoint inhibitors, but none are perfectly predictive. pmc.ncbi.nlm.nih

Treatment-related risk factors

• Drug class and combination
  • CTLA-4 inhibitors (e.g., ipilimumab) generally cause more and more severe immune-related adverse events (irAEs) than PD-1/PD-L1 inhibitors. pmc.ncbi.nlm.nih
  • Combination therapy (e.g., ipilimumab + nivolumab) has the highest rates of grade 3-4 irAEs, much higher than single-agent PD-1/PD-L1. jitc.bmj
• Dose and schedule
  • Higher doses of CTLA-4 inhibitors are associated with more frequent and severe toxicities. pmc.ncbi.nlm.nih
  • Prolonged exposure (many cycles) increases the opportunity for late-onset and chronic irAEs to emerge. cancer

Patient-related risk factors

• Pre-existing autoimmune disease
  • Patients with conditions like rheumatoid arthritis, psoriasis, inflammatory bowel disease, or lupus have higher rates of autoimmune flares and new irAEs, though many can still be treated carefully. pmc.ncbi.nlm.nih
• Prior or current immunosuppression
  • Baseline steroids or other immunosuppressants may both mask and complicate emerging irAEs; some data suggest altered patterns of toxicity and infection risk. pmc.ncbi.nlm.nih
• Older age and comorbidities
  • Older patients and those with significant heart, lung, liver, or kidney disease are more vulnerable if an irAE affects that same organ (e.g., pneumonitis in someone with severe COPD). pmc.ncbi.nlm.nih
• Cancer type and burden
  • Certain cancers (e.g., melanoma and lung cancer) show higher overall rates of irAEs, partly because they often receive combination or prolonged ICI therapy. pmc.ncbi.nlm.nih
  • Higher tumor burden and strong early immune activation may correlate with both better responses and more toxicity in some studies. pmc.ncbi.nlm.nih

Biomarkers and lab features (emerging, not routine)

• Baseline inflammation markers
  • Elevated CRP, high neutrophil-to-lymphocyte ratio, or other systemic inflammation markers have been linked in some analyses to higher irAE risk, but this is not yet used routinely. pmc.ncbi.nlm.nih
• Autoantibodies and HLA types
  • Pre-existing organ-specific autoantibodies and certain HLA genotypes have been associated with specific irAEs in small studies, suggesting an underlying autoimmune tendency. pmc.ncbi.nlm.nih
• Late-onset risk factors
  • Longer survival and longer follow-up increase the chance of “late” irAEs (after 6-12 months or even post-treatment), and chronic endocrine or rheumatologic irAEs are more likely in patients who have already had an acute event. jamanetwork

Practical implications

• The strongest, consistent risk factors in practice are: use of combination ICI, CTLA-4-containing regimens, pre-existing autoimmune disease, and significant comorbid organ dysfunction. pmc.ncbi.nlm.nih
• Because prediction is imperfect, guidelines emphasize baseline assessment, patient education on early symptoms, and low threshold for workup and steroids when irAEs are suspected. cancerresearchuk