Precision Immunotherapy in Sepsis

Abstract Precision immunotherapy is usually used as an adjunctive treatment in patients with sepsis and/or septic shock. Previously reported clinical trials have failed to prove efficacy due to great heterogeneity among sepsis patients. This has led to the need for a different strategic approach. At the first stage, patient stratification has been performed based on transcriptional endotypes, clinical-based phenotypes, or biomarker-enriched endotypes, the latest being the most convenient and commonly used. Biomarker endotypes can be broadly categorized into hyperinflammation, immunoparalysis and endothelial dysfunction endotypes, each with different subclasses. The biomarker used for the diagnosis reflects a specific dysregulated immune pathway that is being targeted for treatment. The SAVE-MORE and the ImmunoSep clinical trials are examples of a biomarker-enriched classification system that guided precision immunotherapy. In the SAVE-MORE randomized controlled clinical trial, patients with COVID-19 pneumonia who were at risk for developing severe respiratory failure and who were defined by soluble urokinase plasminogen activator receptor levels ≥ 6 ng/mL were treated with either anakinra or placebo. The study met the primary endpoint and a lower 28-day mortality in favor of anakinra was also found. Based on these findings, anakinra received approval by the European Medicines Agency for this indication. In the ImmunoSep clinical trial, patients with macrophage activation-like syndrome, defined as those with ferritin levels > 4,420 ng/mL, were treated with anakinra or placebo, and patients with immunoparalysis, defined as those with the combination of ferritin ≤ 4,420 ng/mL and < 5,000 HLA-DR receptors on CD45 +/CD14 + monocytes, were treated with rhIFNγ or placebo. The study met its primary endpoint. Several clinical trials of precision immunotherapy are actively recruiting patients using biomarker classification systems. There are still unanswered questions regarding the stability of endotypes over the course of illness and whether time can affect the efficacy of precision immunotherapy.