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- Presentation
PD-1 Immune Checkpoint Agonists as a Potential Therapy for Autoimmunity
Description
The speaker explains that immune responses normally include an active resolution phase in which inhibitory mechanisms, or immune checkpoints, help shut down inflammation and prevent autoimmunity. While checkpoint blockade is widely used in cancer therapy, it can trigger autoimmune side effects, which motivates the opposite strategy in autoimmunity: agonizing inhibitory receptors to restore immune balance. The talk focuses on PD-1 because it is the most advanced checkpoint agonist in development, especially for rheumatoid arthritis. PD-1 is expressed on pathogenic T-cell subsets, including effector and follicular helper cells, and the PD-1 agonist rosnilimab can both suppress PD-1–intermediate cells and deplete PD-1–high cells. In a translational study, treatment reduced pathogenic synovial T cells and inflammatory T- and B-cell signaling, with efficacy comparable to existing RA therapies such as JAK1, TNF, and IL-6 blockade. Safety data through 38 weeks has been reassuring, and some responders maintained benefit three months after stopping treatment, suggesting possible durable remission. The speaker concludes that PD-1 agonism looks promising for rheumatoid arthritis and may eventually help some skin diseases, but key questions remain about which checkpoint is best for which disease, long-term remission, and long-term safety.
View moreConclusions
- Immune checkpoint agonism, especially PD-1 activation, is proposed as a way to restore active immune resolution and treat autoimmunity by applying the immune system’s natural brakes.
- PD-1 is a particularly promising target because it is expressed on pathogenic T-cell subsets involved in autoimmune inflammation, including effector, follicular helper, and peripheral helper T cells.
- Rosnilimab, a PD-1 agonist, appears to reduce pathogenic immune activity in rheumatoid arthritis by lowering inflammatory T-cell and B-cell signals in inflamed tissue.
- Early clinical data suggest rosnilimab has efficacy that is at least comparable to established RA therapies such as JAK1, TNF, and IL-6 pathway inhibitors.
- The safety profile reported so far for rosnilimab looks favorable, with no major safety signal and no clear increase in malignancy or other serious adverse outcomes.
- Some patients maintained low disease activity after stopping rosnilimab, suggesting PD-1 agonism may support durable remission rather than only transient suppression.
- Although the results in rheumatoid arthritis are encouraging, it remains unclear which autoimmune or dermatologic diseases will benefit most from PD-1 agonism.
- Other immune checkpoints besides PD-1, such as CD200R and LAG-3, may also be viable therapeutic targets, but their comparative usefulness is still unknown.
- Key unanswered questions include long-term safety, durability of remission, and how to match specific immune checkpoint agonists to specific skin diseases.
- Vesely MD et al. J Invest Dermatology. 2025.