The article "Toxicity in the era of immune checkpoint inhibitor therapy" by Keam et al. reviews the current understanding and management of immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs). ICIs, which include CTLA-4 and PD-1/PD-L1 inhibitors, have revolutionized cancer treatment by reinvigorating anti-tumor immune responses. However, these therapies often lead to off-target inflammation and irAEs, which can be severe and require steroid use or cessation of ICI therapy. The review highlights the need for preclinical models to better understand and manage these toxicities. Key points include: 1. **Immune Checkpoints and Their Role**: CTLA-4 and PD-1/PD-L1 play crucial roles in maintaining peripheral tolerance and controlling inflammation. CTLA-4 inhibits T cell activation, while PD-1/PD-L1 axis disruption prolongs T cell activation and effector functions. 2. **ICI-Induced Toxicities**: - **Dermatologic Toxicities**: Common in up to 50% of patients, often mild but can be severe. Mechanisms involve CD8+ T cells and innate immune responses. - **Colitis**: Common irAE, with incidence up to 27%. Involves Th1 and Th17 cell responses and increased CD8+ T cells. - **Neurologic Dysfunction**: Rare but potentially fatal, affecting 1-6% of patients. Can include myasthenia gravis, meningitis, and demyelinating disorders. - **Endocrine Dysfunction**: Common, with thyroid dysfunction being the most frequent. Can lead to hypothyroidism and hyperthyroidism. - **Pneumonitis**: Uncommon but life-threatening, affecting 5-10% of patients. 3. **Management and Mechanisms**: - **Dermatologic Toxicities**: Involves CD8+ T cells and innate immune responses. Treatment options include corticosteroids and biologics. - **Colitis**: Involves Th1 and Th17 cell responses. Treatment includes IL-6 blockade and antibiotics. - **Neurologic Dysfunction**: Involves CD38+ plasma cells, neuromuscular autoantibodies, and microglia. Targeting Syk may be a potential therapeutic strategy. - **Endocrine Dysfunction**: Involves Th17 CD4+ T cells, autoantibodies, and IFN-γ+ CD8+ T cells. Targeting these components may be a new therapeutic approach. - **Pneumonitis**: Involves interstitial lung disease. Treatment includes corticosteroids and bronchodilators. The article emphasizes the need for further research to develop effective and safe management strategies for ICIs-induced toxicities.The article "Toxicity in the era of immune checkpoint inhibitor therapy" by Keam et al. reviews the current understanding and management of immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs). ICIs, which include CTLA-4 and PD-1/PD-L1 inhibitors, have revolutionized cancer treatment by reinvigorating anti-tumor immune responses. However, these therapies often lead to off-target inflammation and irAEs, which can be severe and require steroid use or cessation of ICI therapy. The review highlights the need for preclinical models to better understand and manage these toxicities. Key points include: 1. **Immune Checkpoints and Their Role**: CTLA-4 and PD-1/PD-L1 play crucial roles in maintaining peripheral tolerance and controlling inflammation. CTLA-4 inhibits T cell activation, while PD-1/PD-L1 axis disruption prolongs T cell activation and effector functions. 2. **ICI-Induced Toxicities**: - **Dermatologic Toxicities**: Common in up to 50% of patients, often mild but can be severe. Mechanisms involve CD8+ T cells and innate immune responses. - **Colitis**: Common irAE, with incidence up to 27%. Involves Th1 and Th17 cell responses and increased CD8+ T cells. - **Neurologic Dysfunction**: Rare but potentially fatal, affecting 1-6% of patients. Can include myasthenia gravis, meningitis, and demyelinating disorders. - **Endocrine Dysfunction**: Common, with thyroid dysfunction being the most frequent. Can lead to hypothyroidism and hyperthyroidism. - **Pneumonitis**: Uncommon but life-threatening, affecting 5-10% of patients. 3. **Management and Mechanisms**: - **Dermatologic Toxicities**: Involves CD8+ T cells and innate immune responses. Treatment options include corticosteroids and biologics. - **Colitis**: Involves Th1 and Th17 cell responses. Treatment includes IL-6 blockade and antibiotics. - **Neurologic Dysfunction**: Involves CD38+ plasma cells, neuromuscular autoantibodies, and microglia. Targeting Syk may be a potential therapeutic strategy. - **Endocrine Dysfunction**: Involves Th17 CD4+ T cells, autoantibodies, and IFN-γ+ CD8+ T cells. Targeting these components may be a new therapeutic approach. - **Pneumonitis**: Involves interstitial lung disease. Treatment includes corticosteroids and bronchodilators. The article emphasizes the need for further research to develop effective and safe management strategies for ICIs-induced toxicities.