A recent study from Johns Hopkins Kimmel Cancer Center, published in the Journal of Clinical Investigation, has identified immune signatures that can predict which cancer patients are likely to develop severe side effects from immunotherapy. The findings suggest potential strategies for preventing these adverse events, which can range from mild to life-threatening.
Predicting irAEs with Immune Signatures
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by boosting the body’s natural defenses against cancer cells. However, a significant proportion of patients experience immune-related adverse events (irAEs) as a result of this heightened immune response. The study prospectively enrolled 111 patients with solid tumors receiving ICI therapy and monitored them for up to 12 months. Approximately 40.5% of these patients developed symptomatic irAEs of grade 2 or higher, with common manifestations including dermatologic issues, hypothyroidism, enterocolitis, and pneumonitis.
Key Predictive Factors
The research team, led by Mark Yarchoan, MD, and Won Jin Ho, MD, collected blood samples before and during treatment to analyze cytokine profiles and immune cell populations. They found that early treatment-related increases in Th17-related cytokines (IL-6, IL-17f), Th2-related cytokines (IL-5, IL-13, IL-25), and Th1-related cytokine (TNF-α) were predictive of subsequent development of severe irAEs. Expansion of Th17 and Th2 effector memory T cell populations during treatment also correlated with the onset of irAEs.
Notably, elevated levels of interleukin-6 (IL-6) were not only predictive of irAEs but were also associated with poorer cancer-specific and overall survival outcomes. According to Ho, IL-6 appears to have a dual role in cancer progression and promoting immune adverse events, making it a promising target for therapeutic intervention.
Clinical Trial to Prevent irAEs
In response to these findings, Aliyah Pabani, MD, co-director of the Immune-Related Toxicity Team at Johns Hopkins, has initiated a clinical trial to determine if IL-6 inhibitors can prevent adverse effects in patients who have previously experienced irAEs and need to restart immunotherapy. This trial exemplifies the bench-to-bedside approach, translating research discoveries into improved therapies for patients.
Implications for Personalized Treatment
The study also highlighted that combination ICI therapy and a history of autoimmune disorders were significantly associated with an increased risk of developing grade ≥2 irAEs. The researchers plan to recruit an additional 500 patients to validate their findings and investigate specific cytokine profiles linked to different irAEs. By understanding which immune signatures are associated with various adverse effects, oncologists could develop more personalized treatment plans, potentially mitigating irAEs while preserving the efficacy of ICIs.
