A new study, published in the Journal of Clinical Investigation, suggests that identifying distinct immune “signatures” in patients may help oncologists predict and prevent adverse events associated with immunotherapy.
This observational study, reportedly the largest of its kind, prospectively enrolled 111 patients with solid tumors receiving immune checkpoint inhibitor (ICI) therapy at Johns Hopkins. Researchers collected blood samples before and during treatment to analyze cytokine profiles and immune cell populations. Patients were then monitored for up to 12 months for the development of immune-related adverse events (irAEs).
Background
Immune checkpoint inhibitors (ICIs) have emerged as a foundational treatment of various solid tumors by bolstering the body’s immune response against cancer cells. Yet immune-related adverse events (irAEs) often accompany their use, often leading to significant morbidity and mortality. Understanding the mechanisms driving irAEs is crucial for identifying patients at risk and developing strategies to mitigate these side effects without compromising the antitumor efficacy of ICIs.
Key findings
- Incidence of irAEs: Approximately 40.5% of patients developed symptomatic irAEs of grade 2 or higher. The most common irAEs included dermatologic issues, hypothyroidism, enterocolitis, and pneumonitis.
- Risk Factors: Combination ICI therapy and a history of autoimmune disorders were significantly associated with an increased risk of developing grade ≥2 irAEs.
- Cytokine Signatures: 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.
- Immune Cell Populations: Expansion of Th17 and Th2 effector memory T cell populations during treatment correlated with the onset of irAEs.
- Prognostic Implications: Elevated levels of IL-6 were not only predictive of irAEs but were also associated with poorer cancer-specific and overall survival outcomes, suggesting that IL-6 may play a dual role in mediating toxicity and impacting treatment efficacy.
The study identified a distinct immune signature linked to severe immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitor (ICI) therapy. This signature pointed to specific cytokine and T helper cell activity, particularly involving the Th17 and Th2 pathways. These findings highlight potential biomarkers for early irAE detection and suggest that targeting these immune pathways could mitigate or prevent these side effects without compromising ICI’s anti-cancer benefits. Notably, the study identified interleukin-6 (IL-6) as a key cytokine associated with both increased irAE risk and poorer survival, making it a promising target for therapeutic intervention.
Implications for future research
The identification of Th17 and Th2 cytokine signatures as predictors of irAEs opens avenues for developing targeted interventions. Further studies are needed to validate these biomarkers in larger, multi-center cohorts and to explore the therapeutic potential of modulating these immune pathways to mitigate irAEs while preserving the efficacy of ICIs
Filed Under: Oncology
