Allocetra-Ots: Early Apoptotic Cells for Immune Homeostasis in Human Stem Cell Transplantation (HSCT) and for the Prevention of Graft Versus Host Disease (GvHD)

Abstract

Allocetra-OTS was developed as a cell-based therapeutic composed of unmatched donor mononuclear cells induced to an early apoptotic state, indicated for the prevention of graft vs. host disease (GvHD) in patients receiving human stem cell transplantation (HSCT). Allocetra-OTS harnesses the naturally occurring activity of early apoptotic cells to induce an immuno-modulated state. Allocetra-OTS, as do naturally occurring apoptotic cells within the body, signals to the macrophages and dendritic cells to react less aggressively to immunogenic agents, thereby resetting the system towards immuno-homeostasis. Three types of experiments showed safety and clinical efficacy in murine models. Administration of a single dose of Allocetra-OTS in a murine model of GvHD had a beneficial effect on GvHD prevention. Allocetra-OTS was also evaluated as an ancillary treatment to the current standard of care for the prevention of GvHD, i.e. GvHD prophylaxis standard-of-care (SOC) regimen using cyclosporin A (CSA) and methotrexate (MTX) in mice. The study showed that combined treatment of immunosuppressors with Allocetra-OTS was safe and effective. Finally, in a mice model with co-existing leukemia, Allocetra-OTS was effective against GvHD without interfering with the graft-versus-leukemia (GvL) effect of the BM transplanted cells. Taken together, in mice models, Allocetra-OTS is safe and significantly improves GvHD both by itself or in addition to SOC, without reducing GvL effect. The clinical development program of Allocetra-OTS for GvHD consists of 2 clinical studies, a completed Phase 1/2a study (TLX-APO-101IL) for related donors (Allocetra), and a planned Phase 2/3 study (ENX-CL-01-002) for unrelated donors. In addition, Allocetra-OTS is being evaluated for sepsis in an ongoing Phase 1b open-label study (ENX-CL-02-001) and is included in the overall safety database. Overall, 21 subjects were exposed to at least 1 dose of Allocetra or Allocetra-OTS and no safety concerns were detected. The first GvHD study included dose-escalation of four sequential cohorts (35, 70, 140 and 210 × 106 cells/kg) and was conducted at 3 sites in Israel. Thirteen eligible subjects with hematologic malignancies, who received conventional myeloablative conditioning were enrolled. The results of this study suggested that a single infusion of donor early apoptotic cells (Allocetra) as prophylaxis for GvHD in myeloablative HSCT is safe and potentially effective and led to 0% (0/6) of acute high grade II-IV GvHD in the two higher dosages compared to 52% in matched historical control. The planned Phase 2/3 multi-center, open-label, 2-arm study (ENX-CL-01-002), in Israel and Germany, will evaluate the efficacy and safety of Allocetra-OTS (140 × 106 cells/kg) with or without anti-thymocyte globulin (ATG) for the prevention of GvHD in subjects undergoing HLA-matched HSCT from an unrelated donor.