Human Placenta-Derived Adherent Cells Delivered Intralesionally Inhibit Myeloma Bone Disease and Tumor Growth, While Intravenously Are Capable of Trafficking to Myelomatous Bone.
Authors: Li Xin , Ling Wen , Pennisi Angela , Wang Yuping , Khan Sharmin , Heidaran Mohammad , Pal Ajai , Zhang Xiaokui , He Shuyang , Zeitlin Andy , Abbot Stewart , Faleck Herbert , Hariri Robert , Shaughnessy John , Rhee Frits van , Nair Bijay , Barlogie Bart , Epstein Joshua , Yaccoby Shmuel 
Published: October 2019

Abstract
Abstract 3717
Human placenta has emerged as a valuable, uncontroversial source of transplantable cells for many cytotherapeutic purposes, including modulation of inflammation, bone repair, and cancer. Placenta-derived adherent cells (PDAC) are mesenchymal like adherent cells isolated from postpartum human placenta and capable of supporting bone formation in vivo. Multiple myeloma (MM) is closely associated with induction of bone disease and large lytic lesions, which are often not repaired and are usually the sites of relapses. The aim of the study was to evaluate the antimyeloma therapeutic potential, in vivo survival, and trafficking of PDAC in the SCID-rab model of MM-associated bone disease. SCID-rab system constructed by implanting a 4-weeks old rabbit bone into which primary human myeloma cells were directly injected (Yatta et al., Leukemia 2004; Yaccoby et al., Blood 2007). Bone disease was evaluated by measurements of bone mineral density (BMD) and X-rays. MM growth was determined by human immunoglobulin (hIg) ELISA and histologically. For in vivo tracking PDAC were transduced with a luciferase/GFP reporter in a lentiviral vector. SCID-rab mice engrafted with primary myeloma cells from 2 patients. Upon establishment of MM growth, PDAC (1×106 cells/bone) or vehicle were injected into the implanted myelomatous bone (Patient's 1, 5 mice/group; Patient's 2, 7 mice/group). While BMD of the implanted bones was significantly reduced in control hosts, intralesional PDAC cytotherapy significantly increased BMD of the implanted bones from pretreatment levels by >37% (p<0.01 versus control) and inhibited MM growth in the 2 sets of experiments (p<0.04). The bone anabolic effect of PDAC was associated with increased number of osteoblasts (p<0.003) and reduced number of osteoclasts (p<0.004). Intralesional PDAC cytotherapy also promoted bone formation in nonmyelomatous SCID-rab mice. Intralesional but not subcutaneous engraftment of PDAC inhibited bone disease and tumor growth in SCID-rab mice. In contrast to intra-bone injection in SCID-rab mice, intra-tumor injection of PDAC had no effect on subcutaneous growth of the H929 myeloma cell line in SCID mice (8 mice/group). Live-animal imaging revealed that the majority of PDAC disappeared from the injected bones within 4 weeks. To test their systemic behavior, PDAC were intravenously injected into 18 SCID-rab mice engrafted with H929 myeloma cells. The presences of PDAC in various organs were evaluated 1, 2 and 7 days after injection. Ex vivo bioluminescence analysis of the implanted myelomatous bones detected PDAC in two of five bones on day 1, in four of four bones on day 2, and in four of nine bones on day 7. Intravenously injected PDAC were also detected in lungs not in any other murine tissues. Immunohistochemical staining for GFP in myelomatous bone sections detected GFP-expressing PDAC in rabbit marrow areas infiltrated with myeloma cells, supporting bioluminescence analysis. Our study suggest that PDAC stimulate bone formation by acting as bystander cells that increase endogenous osteoblastogenesis and inhibit osteoclastogenesis, and that alteration of the bone marrow microenvironment by PDAC attenuates growth of MM. PDAC cytotherapy is a promising therapeutic approach for myeloma bone disease.

Disclosures:
Khan: Celgene Cellular Therapeutics: Research Funding. Heidaran:Celgene Cellular Therapeutics: Employment. Pal:Celgene Cellular Therapeutics: Employment. Zhang:Celgene Cellular Therapeutics: Employment. He:Celgene Cellular Therapeutics: Employment. Zeitlin:Celgene Cellular Therapeutics: Employment. Abbot:Celgene Cellular Therapeutics: Employment. Faleck:Celgene Cellular Therapeutics: Employment. Hariri:Celgene Cellular Therapeutics: Employment.