A MULTINATIONAL randomised clinical trial reports that precision immunotherapy tailored to patients’ underlying immune dysregulation significantly improved organ dysfunction in sepsis, although it did not reduce short-term mortality.
Sepsis is increasingly recognised as a heterogeneous syndrome, with patients exhibiting divergent immune responses ranging from hyperinflammation to immune suppression. This variability has contributed to repeated failures of “one-size-fits-all” immunotherapies. The ImmunoSep trial was designed to test whether matching immunotherapy to specific immune phenotypes could improve outcomes.
Tailoring Treatment to Immune Profiles in Sepsis Patients
The double-blind, placebo-controlled study enrolled 276 patients with sepsis across six countries between 2021 and 2024. Eligible patients met Sepsis-3 criteria and had pneumonia or bacteraemia as the source of infection. Participants were stratified based on immune status into two groups: those with macrophage activation–like syndrome, defined by markedly elevated ferritin levels, and those with sepsis-induced immunoparalysis, characterised by low ferritin and reduced HLA-DR expression on monocytes.
Patients were randomly assigned to receive standard care plus precision immunotherapy or standard care plus placebo for up to 15 days. Those with macrophage activation-like syndrome received intravenous anakinra, an interleukin-1 receptor antagonist, while patients with sepsis-induced immunoparalysis were treated with subcutaneous recombinant human interferon gamma. Placebo recipients received matching intravenous and subcutaneous placebo treatments.
The primary endpoint was improvement in organ dysfunction, defined as a decrease of at least 1.4 points in the Sequential Organ Failure Assessment (SOFA) score by day 9. This endpoint was achieved in 35.1% of patients in the precision immunotherapy group, compared with 17.9% in the placebo group, representing a statistically significant absolute difference of 17.2%. These findings indicate a clinically meaningful improvement in multiorgan dysfunction among patients receiving tailored immunotherapy.
However, 28-day mortality did not differ significantly between the two groups, suggesting that improved early organ function may not immediately translate into a survival benefit. Safety analyses showed a high overall rate of serious treatment-emergent adverse events, reflecting the severity of illness in the study population. Anemia occurred more frequently in patients receiving anakinra, while haemorrhagic events were more common in those treated with interferon gamma.
Next Steps for Personalised Immunotherapy in Sepsis
The investigators conclude that precision immunotherapy guided by immune profiling can improve organ dysfunction in sepsis. They suggest that immune-based stratification may represent a critical step toward more effective, personalised treatments, while emphasising the need for further studies to assess long-term outcomes and survival benefits.
Reference
Giamarellos-Bourboulis EJ et al. Precision Immunotherapy to Improve Sepsis Outcomes: The ImmunoSep Randomized Clinical Trial. JAMA.2025;doi: 10.1001/jama.2025.24175
