Apoptotic Cells for Therapeutic Use in Cytokine Storm Associated With Sepsis- A Phase Ib Clinical Trial.

Background: Sepsis has no proven specific pharmacologic treatment and reported mortality ranges from 30%-45%. The primary aim of this phase IB study was to determine the safety profile of Allocetra™-OTS (early apoptotic cell) infusion in subjects presenting to the emergency room with sepsis. The secondary aims were to measure organ dysfunction, intensive care unit (ICU) and hospital stays, and mortality. Exploratory endpoints included measuring immune modulator agents to elucidate the mechanism of action. Methods: Ten patients presenting to the emergency room at the Hadassah Medical Center with sepsis were enrolled in this phase Ib clinical study. Enrolled patients were males and females aged 51-83 years, who had a Sequential Organ Failure Assessment (SOFA) score ≥2 above baseline and were septic due to presumed infection. Allocetra™-OTS was administered as a single dose (day +1) or in two doses of 140×106 cells/kg on (day +1 and +3), following initiation of standard-of-care (SOC) treatment for septic patients. Safety was evaluated by serious adverse events (SAEs) and adverse events (AEs). Organ dysfunction, ICU and hospital stays, and mortality, were compared to historical controls. Immune modulator agents were measured using Luminex® multiplex analysis. Results: All 10 patients had mild-to-moderate sepsis with SOFA scores ranging from 2-6 upon entering the study. No SAEs and no related AEs were reported. All 10 study subjects survived, while matched historical controls had a mortality rate of 27%. The study subjects exhibited rapid resolution of organ dysfunction and had significantly shorter ICU stays compared to matched historical controls (p<0.0001). All patients had both elevated pro- and anti-inflammatory cytokines, chemokines, and additional immune modulators that gradually decreased following treatment. Conclusion: Administration of apoptotic cells to patients with mild-to-moderate sepsis was safe and had a significant immuno-modulating effect, leading to early resolution of the cytokine storm. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT03925857. (https://clinicaltrials.gov/ct2/show/study/NCT03925857).

Apoptotic cell therapy for cytokine storm associated with acute severe sepsis.

Sepsis has no proven pharmacologic treatment other than appropriate antibiotic agents, fluids, vasopressors as needed, and possibly corticosteroids. It is generally initiated mainly by the simultaneous recognition by various components of the innate immune system of either pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). In the current study, we employed the murine cecal ligation and puncture (CLP) model for sepsis to evaluate the effect of post-CLP infusion of apoptotic cells (Allocetra-OTS) on a CLP severe sepsis model. Cardiovascular evaluation, acute kidney injury (AKI), acute liver injury (ALI), and hematological and metabolic function were evaluated. Cytokine and chemokine profiles were measured by Multiplex ELISA and mitochondrial function, and glycolysis by Seahorse. The Murine Sepsis Score (MSS) was used for disease severity definition. CLP mice had low blood pressure, poor cardiac output, and lung dysfunction, as well as AKI, ALI, and thrombocytopenia, which correlated with the MSS and corresponded to a cytokine/chemokine storm. Apoptotic cell administration markedly improved the cytokine and chemokine storm and restored the impaired mitochondrial and glycolytic function in white blood cells leading to increased survival, from 6 to 60% (P < 0.0001), together with a significant improvement in organ dysfunction. We conclude that the deleterious immune response in CLP-induced sepsis can be successfully modified by apoptotic cell infusion.