Pembrolizumab and nivolumab are anti-PD-1 monoclonal antibodies used in cancer immunotherapy. Immune-related adverse events (irAEs) in these drugs are caused by which mechanism?

• A Loss of peripheral T-cell tolerance checkpoints, allowing autoreactive T cells to attack normal tissues ✓
• B Direct cytotoxicity of the antibody to normal tissues expressing PD-L1
• C Complement activation by the Fc region of the antibody causing tissue inflammation
• D Antibody-dependent cellular cytotoxicity (ADCC) against normal cells expressing PD-1

Explanation

PD-1 (programmed death-1) is an immune checkpoint receptor on activated T cells; its ligands PD-L1/PD-L2 on tumor cells or normal tissues suppress T-cell activity, maintaining peripheral tolerance. By blocking PD-1, pembrolizumab/nivolumab disinhibits T-cell activity, restoring anti-tumor immunity. However, the same disinhibition also removes peripheral tolerance to self-antigens, allowing pre-existing autoreactive T cells to attack normal tissues — producing immune-related adverse events (irAEs) such as immune-mediated colitis, pneumonitis, hepatitis, thyroiditis, and hypophysitis. irAEs are managed with corticosteroids.

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

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Written and medically reviewed by the StethoPrep medical team.