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Mechanism of Action of PLX-R18, a Placental-Derived Cellular Therapy for the Treatment of Radiation-Induced Bone Marrow Failure

Racheli Ofir, Lena Pinzur, Akyüz Levent, Zami Aberman, Raphael Gorodetsky and Hans Dieter Volk

Abstract

Bone marrow (BM) failure occurs in individuals who fail to produce sufficient red blood cells, white blood cells, or platelets. This may be a result of damage to hematopoietic stem cells by a congenital defect or by exposure to a noxious substance or factor.

PLX-R18 are 3D-expanded placenta-derived cells, with biological properties including a profound capacity to protect and regenerate bone marrow. The cells secrete a broad array of cytokines including G-CSF, IL-6, MCP-1, MCP-3 and GRO that contribute to the reconstitution of the hematopoietic and immune systems.

To assess their therapeutic potential, PLX-RAD cells were administered to C3H/HeN male mice intramuscularly, one and five days following 7.7 Gy total body irradiation. Body weight and animal survival were monitored for 3 weeks, then the animals were euthanized for BM and blood analysis. In the PLX-R18-treated group, 10 out of 11 (91%) animals survived, compared to only 4 out of 9 in the vehicle treated group (44%), (P < 0.05). Weight reduction after irradiation was also improved in the PLX-RAD treated mice where the average weight loss was less than 10% compared to almost 20% for vehicle-treated controls. Consistent with the improved survival, cell counts of all the three hematopoietic lineages were significantly increased in the BM and blood of PLX-R18 treated mice as compared to the control animals, and attained close to normal levels. Analysis of plasma in the irradiated treated animals detected the presence of critical, PLX-R18-derived (human) cytokines as well as alterations in the equivalent murine cytokines, suggesting a direct role of PLX-R18 secreted cytokines in animal survival. Interestingly, human cytokines were detected only after irradiation and were not present in the plasma of sham non-irradiated animals treated with PLX-R18. This may imply that the active in vivo cytokine secretion by PLX-R18 is a response to signals from the environment in the irradiated animals. Already by day 4-6 after irradiation, the number of colony forming progenitors in the BM of PLX-R18 treated animals was significantly higher than in control animals suggesting that earlier regeneration of BM induced by PLX-R18 secreted cytokines results in improved blood counts and increased survival. Studies in vitro demonstrated that PLX-R18-derived conditioned medium induced the formation of all colony types in a methyl cellulose colony formation assay as well as a 3.1 fold-increase in the number of migrating cells in a BM migration assay compared to the SDF-1-supplemented positive control. These results, in vivo and in vitro, reveal key clues to the resolution of the underlying mechanism of action.

Administration of the novel cell product PLX-R18 markedly improved survival and recovery of the three hematopoietic blood lineages after radiation induced BM failure indicating potential as a highly effective therapy for general radiation-induced BM damage, or in a nuclear disaster scenario. Further clinical studies are planned.

Disclosures Ofir: Pluristem ltd: Employment. Pinzur: Pluristem ltd: Employment. Aberman: Pluristem ltd: Employment. Gorodetsky: Pluristem ltd: Consultancy. Volk: Pluristem ltd: Consultancy.

  • * Asterisk with author names denotes non-ASH members.