Precision Immunotherapy Improves Organ Function in Sepsis: ImmunoSep Trial
Greece: The phase IIb ImmunoSep trial has found that adding precision immunotherapy—targeting macrophage activation-like syndrome and sepsis-induced immunoparalysis—to standard care improved organ dysfunction by day 9 in sepsis patients compared with standard care plus placebo. However, 28-day mortality did not differ significantly between the groups.
Published in JAMA, the multicountry randomized clinical trial was led by Evangelos J. Giamarellos-Bourboulis and colleagues from the National and Kapodistrian University of Athens. Sepsis is known to be a highly heterogeneous condition, and clinicians have long struggled with how best to tailor immunomodulatory treatments to its diverse biological subtypes.
The ImmunoSep trial set out to test whether an individualized approach—based on identifying either macrophage activation–like syndrome (MALS) or sepsis-induced immunoparalysis (SIP)—could translate into improved organ function during the early phase of illness.
The trial enrolled adult patients diagnosed with sepsis according to Sepsis-3 criteria across centers in six countries. Eligible participants had pneumonia (community-acquired, hospital-acquired, or ventilator-associated) or bacteremia and showed laboratory evidence consistent with either MALS or SIP. Classification was based on a ferritin threshold of more than 4420 ng/mL for MALS, or ferritin at or below that level, along with fewer than 5000 HLA-DR receptors on CD45/CD14 monocytes for SIP.
Participants were randomized to receive standard care with targeted immunotherapy or standard care with a matching placebo. Patients categorized with MALS received intravenous anakinra, while those identified with SIP were treated with subcutaneous recombinant human interferon gamma. The placebo group received both intravenous and subcutaneous placebo injections. Treatment was administered for up to 15 days.
Of the 672 patients screened, 281 were randomized, and 276 were included in the primary analysis. The average age was 70 years, and the median baseline SOFA score was 9, reflecting substantial organ dysfunction.
Key Findings:
- By day 9, 35.1% of patients receiving precision immunotherapy showed an improvement of at least 1.4 points in SOFA score, compared with 17.9% in the placebo group.
- The absolute difference between the groups was 17.2%, indicating a statistically significant benefit in organ function with precision immunotherapy.
- Despite these improvements, 28-day mortality did not differ meaningfully between the treatment and placebo groups.
- Serious treatment-emergent adverse events were common across all patients, as expected in severe sepsis.
- Anemia occurred more often among patients treated with anakinra.
- Bleeding events were more frequently reported in those who received interferon gamma.
Researchers highlighted key limitations: the primary outcome was a surrogate marker rather than a direct patient-centered measure like mortality; ferritin and HLA-DR testing may be difficult to implement widely due to limited availability and longer assay times; immune subtypes may shift over time; and the results apply only to sepsis linked to pneumonia or bacteremia.
"Despite these challenges, the trial provides evidence that an individualized immunotherapy strategy can meaningfully improve early organ dysfunction in sepsis. Further large-scale studies will be essential to determine whether this precision approach can ultimately improve survival and broader clinical outcomes," the authors concluded.
Reference:
Giamarellos-Bourboulis EJ, Kotsaki A, Kotsamidi I, et al. Precision Immunotherapy to Improve Sepsis Outcomes: The ImmunoSep Randomized Clinical Trial. JAMA. Published online December 08, 2025. doi:10.1001/jama.2025.24175
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