Pembrolizumab is an anti-PD-1 checkpoint inhibitor used for various cancers. Its immune-related adverse events (irAEs) are predominantly mediated by:

• A Pembrolizumab directly activating cytotoxic CD8 T cells against self-antigens
• B Pembrolizumab acting as a cytokine (IL-6 analogue), triggering systemic inflammatory response
• C Cross-reactivity of pembrolizumab Fc region with complement, triggering complement-mediated organ damage
• D Removal of PD-1-mediated inhibitory brake on T cells, causing unbridled T-cell activation against both tumour and normal tissues ✓

Explanation

PD-1 on activated T cells binds PD-L1/PD-L2 on tumour cells or APCs, transmitting inhibitory signals that prevent T-cell over-activation and maintain self-tolerance. Pembrolizumab blocks PD-1, removing this checkpoint and enabling sustained T-cell activation — directed against tumour antigens but also normal tissues. This accounts for irAEs including immune colitis, pneumonitis, hepatitis, hypophysitis, thyroiditis, and adrenalitis, which are typically managed with corticosteroids or immunosuppressants.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.