PD-1 Immune Checkpoint Inhibitors and Immune-Related Adverse Events: Understanding the Upside of the Downside of Checkpoint Blockade

Cancer cells produce tumor antigens (TAs) that can be recognized by the immune system and induce tumor rejection.¹ Unfortunately, neither spontaneous nor vaccine-induced TA-specific T cells have yet produced substantial numbers of anticancer responses in patients with advanced cancer.² Research has clarified that tumor-associated T cells were terminally exhausted secondary to chronic antigen exposure, similar to what was initially observed in mice chronically infected with lymphocytic choriomeningitis virus, a state manifested by upregulation of multiple immune inhibitory receptors, including PD-1 (programmed cell death 1), T-cell Ig and mucin domain-containing protein 3 (TIM-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and lymphocyte-activation gene 3 (LAG3).³ The PD-1 blockade restores T-cell numbers and function, and therapeutic targeting of this axis has shown impressive activity in multiple cancers, including cutaneous squamous cell carcinoma, head and neck squamous cell carcinoma, Hodgkin lymphoma, Merkel cell carcinoma, microsatellite unstable or mismatch repair–deficient tumors, non–small cell lung cancer (NSCLC), melanoma, renal cell carcinoma, small cell lung cancer, and urothelial carcinoma.⁴