Bone Marrow Mesenchymal Stromal Cells to Treat Tissue Damage in Allogeneic Stem Cell Transplant Recipients: Correlation of Biological Markers with Clinical Responses

Abstract

Bone marrow stromal cells (BMSCs) have been used to treat acute graft-versus-host disease (GVHD) and other complications following allogeneic hematopoietic stem cell transplantation (SCT). We conducted a phase I trial using third party, early passage BMSCs for patients with steroid-refractory GVHD, tissue injury or marrow failure following SCT to investigate safety and efficacy. To identify mechanisms of BMSC immunomodulation and tissue repair, patients were serially monitored for plasma GVHD biomarkers, cytokines and lymphocyte phenotype. Ten subjects were infused a fixed dose of 2 × 106 BMSCs/kg intravenously weekly for 3 doses. There was no treatment related toxicity (primary endpoint). Eight subjects were evaluable for response at 4 weeks after the last infusion. Five of the seven patients with steroid-refractory acute GVHD achieved a complete response (CR), two of two patients with tissue injury (pneumomediastinum/pneumothorax) achieved resolution but there was no response in two subjects with delayed marrow failure. Rapid reductions in inflammatory cytokines were observed. Clinical responses correlated with a fall in biomarkers (Reg 3α, CK18, and Elafin) relevant for the site of GVHD or tissue injury. The GVHD complete responders survived significantly longer, had higher baseline absolute lymphocyte and central memory CD4 and CD8 counts. Cytokine changes also segregated with survival. These results confirm that BMSCs are associated with rapid clinical and biomarker responses in GVHD and tissue injury. However BMSCs were ineffective in patients with prolonged GVHD with lower lymphocyte counts, which suggest that effective GVHD control by BMSCs requires a relatively intact immune system.

Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke

“…Stem cell transplantation has proven to be beneficial in injury models such as myocardial infarction and heart failure, with promising work in animal models translating to success in human clinical trials (Lee and Terracciano; Wollert and Drexler; Yin et al , 2014). In this review, we use the words “stem cells transplantation” to refer to all cell transplantation using stem cells and stem cell-derived neural progenitor cells.…”

Recent advances on cellular therapies and immune modulators for graft-versus-host disease

“…A distinct plasma cytokine and GVHD biomarker profile by day 7 after the first administration of MSCs allowed the segregation of responders from nonresponders. GVHD survivors expressed lower levels of acute GVHD biomarkers, such as elafin, IL-2 receptor antagonist, Reg-3a and HGF, with a significantly higher expression of IL-10, IL-12, IL-15 and IFN-g [64]. This study also indicates that responses to MSCs may require a relatively preserved immune system, as MSCs were ineffective in patients with more aggressive GVHD and lower lymphocyte counts.…”

“…In one recent study [64], MSCs were infused at a fixed dose of 2 Â 10 6 /kg in patients with post-transplant complications, including steroid-refractory GVHD. A distinct plasma cytokine and GVHD biomarker profile by day 7 after the first administration of MSCs allowed the segregation of responders from nonresponders.…”

Intravenous mesenchymal stromal cell therapy for inflammatory bowel disease: Lessons from the acute graft versus host disease experience

“…These findings corroborated the studies of Levine et al (2012), describing reg3α as a GI-specific biomarker. CK18 was described as an additional biomarker, with decreasing levels correlating with clinical response [38,101].…”