Sepsis is a life-threatening condition caused by a dysregulated immune response to infection. Many immunotherapy trials have failed because sepsis presents with highly variable immune states, ranging from excessive inflammation to profound immunosuppression. A precision-medicine approach, guided by rapid biomarker-based immune profiling, may therefore be needed.
Recent evidence shows that patients with septic shock can be grouped into three immune phenotypes using blood ferritin levels and monocyte HLA-DR expression:
- Macrophage activation–like syndrome (MALS): a hyperinflammatory state driven by excessive IL-1 production.
- Sepsis-induced immunoparalysis (SIP): a hypoinflammatory state marked by lymphocyte and myeloid cell exhaustion or apoptosis.
- Unclassified: patients who fit neither pattern.
A new phase 2b trial tested whether tailoring immunotherapy, using anakinra for MALS or interferon-γ for SIP, could improve organ dysfunction in septic patients compared with placebo. The trial was conducted across six countries. It enrolled patients meeting Sepsis-3 criteria who had pneumonia (community-acquired, hospital-acquired, or ventilator-associated) or bacteremia, and who demonstrated either macrophage activation–like syndrome (ferritin >4420 ng/mL) or sepsis-induced immunoparalysis (ferritin ≤4420 ng/mL plus low monocyte HLA-DR expression).
Eligible patients were randomised to either standard care plus precision immunotherapy or standard care plus placebo. In the precision-immunotherapy arm, patients with macrophage activation–like syndrome received IV anakinra, while those with sepsis-induced immunoparalysis received subcutaneous interferon-γ; each also received a matching placebo to maintain blinding. The placebo group received both IV and subcutaneous placebos. All treatments were given for up to 15 days. The primary endpoint was achieving at least a 1.4-point reduction in the mean SOFA score from baseline by day 9.
Of 672 screened patients, 281 were randomised, and 276 were included in the primary analysis (mean age 70 years; 34% female; median baseline SOFA score 9). The primary endpoint was achieved in 35.1% of the precision-immunotherapy group vs 17.9% of the placebo group, a significant difference of 17.2%. However, 28-day mortality did not differ significantly between groups. Serious treatment-emergent adverse events occurred in 88.8% of participants; anaemia was more common with anakinra, and haemorrhage was increased with interferon-γ.
The study showed that a precision immunotherapy approach, targeting macrophage activation–like syndrome and sepsis-induced immunoparalysis, improved organ dysfunction by day 9 compared with placebo. Although mortality did not differ significantly, several secondary outcomes favoured precision therapy, including organ function by day 15, reversal of immune dysfunction, and infection resolution. No major safety concerns were identified.
The results align with prior research suggesting the benefits of tailoring immunotherapy to immune phenotypes in severe infection. Precision-guided anakinra has already been authorised for COVID-19–related hyperinflammation. Earlier sepsis trials of anakinra did not show survival benefit overall, but post hoc analyses indicated improved outcomes in patients with macrophage activation–like features. Interferon-γ has also long been considered for sepsis because it can restore monocyte HLA-DR expression and enhance immune responsiveness, with supportive findings from small clinical studies.
The study reinforces the use of SOFA score improvement as a useful surrogate endpoint, consistent with other emerging therapies such as nangibotide and adrecizumab. A key challenge highlighted is that most screened patients could not be classified using ferritin and HLA-DR alone, suggesting that more comprehensive biomarkers or machine-learning–based immunotypes may be needed. Further work comparing different immunophenotyping strategies for enriching future immunotherapy trials remains a priority.
Source: JAMA
Image Credit: iStock
