Early Apoptotic Cells (ApoCell) As Prophylaxis of Graft-Versus-Host Disease Is Safe and Effective: 1 Year Follow-up and Mechanism of Action

Apoptotic cells infusion (ApoCell, by Enlivex Ltd) is a novel cellular therapy that was found to be effective in a variety of mouse models of autoimmune diseases. ApoCell was tested in humans in addition to cyclosporine and methotrexate, as prophylaxis of graft-versus-host disease (GVHD) in HLA-matched myeloablative allogeneic bone marrow transplantation (alloBMT) from a related donor. We conducted a phase I//IIa clinical trial where 13 patients (median age, 37 years; range, 20-59 years) with advanced hematologic malignancies that received conventional myeloablation were treated with 35, or 70, or 140, or 210x10⁶ cell/kg of donor ApoCell, on day -1 of transplantation (Mevorach et al. BBMT 2014).

We now report the summary of biomarkers measurement (ELISA) as a correlation to the clinical grading. These include serum levels of Il-1b, IL-2RA, IL-6, IL-7 IL-8, IL-15, TNF-R1, and HGF (hepatic growth factor). We further report the ApoCell clearance following the infusion, using short tandem repeats (str) and the tolerogenic effect of ApoCell on immature dendritic cells (iDC) exposed to maturation stimuli. In addition, a 1 year follow-up, and a clinical comparison to matched historical controls was evaluated.

The results show an excellent correlation between biomarkers to clinical grading with a distinctive pattern between high-grade (III-IV) to low grade GvHD. A rapid clearance of the infused ApoCell that disappear from circulation within few hours and ApoCell dose-dependent tolerogenic effect on iDC (p<0.001), was observed. The 1 year overall survival rate was 62% with a non-relapse survival rate of 89% (100% for the two higher cohorts), and a significant (p<0.05) lower occurrence (23% in total and 0% in the two higher dosages) of high-grade GvHD (II-IV) in comparison to historical controls.

These results suggest that single-infusion high-dose donor early apoptotic cells in HLA-matched myeloablative alloBMT may be a safe and effective prophylaxis for acute GVHD (clinicaltrials.gov no. NCT00524784).