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Immune regulation with PLX
HAIFA, Israel—Pluristem Therapeutics Inc. recently published results from a mechanism-of-action study featuring its PLacental eXpanded (PLX) cells in the journal Stem Cells. The study was conducted by independent scientists at the Berlin-Brandenburg Center for Regenerative Therapy at Charité - University Medicine Berlin, who also co-authored the paper along with Pluristem scientists. The results appeared in a paper titled “Mesenchymal stromal cells prevent allostimulation in vivo and control checkpoints of Th1 priming: migration of human DC to lymph nodes and NK cell activation.”
“Our findings in this study provide novel evidence for the regulation of several checkpoints of T cell priming by PLX cells and other MSC, via modulation of the crosstalk between myeloid dendritic cells and natural killer cells. While the complete mechanism of immunomodulation by PLX cells requires further investigation, this study demonstrates how PLX cells might inhibit the immune responses of Type 1 T helper cells,” said Dr. Hans-Dieter Volk, director of the Berlin-Brandenburg Center for Regenerative Therapy, head of the Institute of Medical Immunology at the Charité and principal investigator for the study.
As noted on the Pluristem website, the company’s PLX cells are “off-the-shelf placenta-derived mesenchymal-like adherent stromal cells that are suitable for allogeneic administration without HLA-matching due to their low immunogenicity and immune-modulatory properties.” In the study, it was seen that in vitro, PLX cells and other mesenchymal stromal cells (MSC) control the induction of an immune system response at several points, with their main target being dendritic cells, the primary inducer of a T cell immune response. In addition, in-vivo data from a Phase 1/2 study of patients with critical limb ischemia who received PLX cells demonstrated that HLA-unmatched PLX cells did not trigger an immune response in immunocompetent patients.
The study found that PLX cells act upon complex pathways to prevent the priming of Type 1 T helper cell (Th1) responses in the face of major histocompatibility complex (MHC) mismatches. Peripheral blood mononuclear cells (PBMC) were collected during a study of PLX cells in patients with critical limb ischemia and re-stimulated with corresponding PLX-PAD cells or unrelated third-party donor PBMC. The in-vivo induced memory Th1 response was measured with the IFN-g Elispot test, which found only marginal or no Th1priming specific for the MHC-mismatch. The PLX cells were found to inhibit an immune response by modulating the myeloid dendritic cell.
“The investigation of the interaction between unmatched PLX cells and patient immune systems is central to Pluristem’s clinical research. This research may lead to a new understanding of how PLX cells influence, and potentially heal, the immune system, thereby possibly expanding the use of PLX cells for new indications,” Zami Aberman, CEO of Pluristem, said in a press release. “By modulating a patient’s immune response, PLX cells could potentially help treat severe diseases of the immune system such as aplastic anemia, which has been designated as an orphan indication, autoimmune diseases such as multiple sclerosis and lupus, as well as graft-versus-host disease.”
Aberman says that when he joined the company 10 years ago, Pluristem’s focus was on bone marrow and umbilical cord blood cells. Since then, the company has moved solely to placenta-derived cells for their numerous advantages. Placental cells are rich and diverse, and highly potent, being both pro-angiogenic and immunoregulatory. The cells are easy to collect and virtually unlimited, with a Pluristem presentation noting that more than 20,000 doses of 300 million cells can be harvested per placenta. In addition, this source doesn’t have any of the ethical concerns associated with other stem cell options.
“The placenta is the only place in nature where you have two systems—a mother and a baby—growing together, interacting together, without immunological response one against the other, so it’s a very unique environment,” Aberman explains. “And thinking about an off-the-shelf product, that’s exactly what is needed: a system that doesn’t induce the patient immune system to react against the cells.”
Pluristem is developing its PLX cells in several different directions. PLX-PAD produces a variety of growth factors and cytokines, including HGF, IDO, IL-28, IL-22 and IL-10RA, all of which, Aberman says, are immune-modulation cytokines “responsible for the shift of the immune system of the patient.” PLX-PAD is advancing in the clinic in a number of indications, including critical limb ischemia (Phase 1), intermittent claudication (Phase 2), muscle injury (Phase 2), pulmonary arterial hypertension (Phase 1) and preeclampsia (preclinical). PLX-R18 is being advanced in hematological indications, including bone marrow transplant failure (Phase 1), acute radiation syndrome (preclinical) and as support for hematopoietic cell transplantation (preclinical).
Aberman tells DDNews that Pluristem has filed an Investigational New Drug application and had a meeting with the U.S. Food and Drug Administration regarding PLX-R18, “and now we are waiting for the results of this meeting, which will hopefully clear our pathway to move into those indications in U.S.”