MSCs has been observed in treating autoimmune diseases in murine models. Hence, several studies have focused on the use of MSCs in the treatment of cGVHD. One study by Weng et al. observed that 14 of 19 patients who were treated with a median dose of 0.6 × 106 cells/kg of MSCs showed partial or complete response (comparable to aGVHD). Interestingly, significant changes were observed in the proportion of T cells and B cells in responders compared to non-responders. In the responsive group, CD8+ CD28+ T cells decreased when cGVHD improved and CD5+ CD25+ CD19+ cells increased. It is the increase in CD25+ cells that are suspected to be responsible for immunomodulation by MSCs. Though this and other similar results in clinical studies warrant larger clinical trials, a caveat of decreasing GVHD is that it also reduces the graft-versus-leukemia effect, or can even cause a leukemic relapse. To reduce this effect, genetic modification of MSCs has been suggested that will introduce a cell fate control gene that will elicit apoptosis of cells after pro-drug administration.
In May 2012, Osiris Therapeutics conducted a Phase II trial using their new stem cell drug, Prochymal (hMSCs), for the treatment of grade B-D steroid-refractory aGVHD in pediatric patients. Seventy-five patients received eight biweekly infusions of 2 x 106 hMSCs/kg for four weeks. An additional four weekly infusions were administered in patients who had either partial or mixed responses. Since GVHD affects many organ systems, effect was measured in improvement of symptoms in gastrointestinal (GI), liver, or skin disease. At day 28, 61.3 percent of patients experienced improvement of symptoms (58.5 percent GI, 75.6 percent skin, and 44.4 percent liver). Survival rate at day 100 post infusion was significantly improved (78.1 percent versus 31 percent). The Prochymal dose regimen was deemed safe and effective.
Before MSCs can be applied as an alternative therapy to steroid-resistant GVHD, several issues need to be addressed, including determination of safety, availability of sources, and ease of obtaining MSCs, quality control of in vitro–cultured MSCs, and optimizing the dosing regimen. These questions can be answered by conducting multicenter randomized clinical trials that are adequately powered.
Mandy McBroom
University of Texas Southwestern Medical Center
See Also: Bone Marrow Transplants; Clinical Trials, U.S.: Hematological Cancers; Hematopoietic Transplantation: Cancer.
Further Readings
Kawase, T., Y. Morishima, K. Matsuo, et al. “High-Risk HLA Allele Mismatch Combinations Responsible for Severe Acute Graft-Versus-Host Disease and Implication for Its Molecular Mechanism.” Blood, v.110/7 (2007).
Rocha, V., M. Labopin, G. Sanz, et al. “Transplants of Umbilical-Cord Blood or Bone Marrow From Unrelated Donors in Adults With Acute Leukemia.” New England Journal of Medicine, v.351/22 (2007).
Socie, G., P. Loiseau, R. Tamouza, et al. “Both Genetic and Clinical Factors Predict the Development of Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation.” Transplantation, v. 72/4 (2001).
Clinical Trials, U.S.: Heart Disease
Clinical Trials, U.S.: Heart Disease
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Clinical Trials, U.S.: Heart Disease
Heart disease is consistently the leading cause of mortality in the United States. A range of pathologies can lead to heart disease, including chronic ischemia, hypertension, acute myocardial infarction (AMI), endocarditis, and congenital malformations; however, few standard treatments aside from cardiac transplantation address the fundamental loss of functional cardiomyocytes that occurs in many cases of heart disease.
Over the past 20 years, stem cell (SC) studies have gained significant attention due to their potential to generate functional cardiomyocytes. Although SC treatments for heart disease in the United States are currently only approved within clinical trials, Phase I/II results suggest that some SC treatments can help prevent, and even reverse, disease progression for clinically significant outcomes. In this review, clinical trials are organized by stem cell type; and within each type, current clinical indications, limitations, and treatment methods necessary to treat heart disease are discussed.
Clinical Trials of Skeletal Myoblast–SC Treatments for Heart Disease
Adult skeletal myoblasts (SMs) were the first type of SC therapy used to treat heart disease. These cells harbor precursor cells, called satellite cells, which have regenerative potential due in part to their characteristic expression of PAX3 and PAX7, without expression of CSPG4. In normal skeletal muscle, these cells quiescently exist, but with injury, signals cause them to proliferate, forming multinucleated myotubes. Studies suggest that this process also occurs when SMs are introduced to injured cardiac muscle. Clinical trials of SMs have extensively explored their use to treat congestive heart failure (CHF). SM treatments are commonly autologous, and harvested SMs are abundantly available, easy to proliferate in culture, and relatively more resistant to ischemic conditions than cardiac cells. Despite this potential, clinical trials have not resulted in clinically significant improvements for heart disease. The MARVEL trial at Duke University demonstrated that in patients with severe CHF and ejection fraction (EF) < 35 percent, no significant improvement resulted in functional capacity analyzed by the walk test and the Minnesota Living With Heart Failure Score after intramyocardial-SM injections. In the U.S.-collaborated SEISMIC trial, no significant difference in global left ventricular (LV)-EF resulted between patients with low, high, or placebo-dose SM treatments after 6 months, as verified by multigated acquisition scans. Importantly, several studies demonstrate that SMs do not form electromechanical connections with surrounding cardiomyocytes due to their inability to express connexin 43. Consequently, several clinical trials have demonstrated adverse events such as ventricular tachyarrhythmia.
Bone Marrow–SC Treatments for Heart Failure
Adult bone marrow (BM) includes several cell types, including hematopoietic and non-hematopoietic SCs. Hematopoietic stem cells can generate red blood cells, lymphocytes, neutrophils, monocytes, and other mononuclear SCs. Together, hematopoietic SCs are called BM-mononuclear cells (BM-MNCs). A majority of BM-MNCs clinical trials use autologous transplantation; however, the FOCUS-CCTRN trial at the Texas Heart Institute demonstrated limitations of autologous treatments in patients with chronic diseases and elderly age.
To improve these limitations, other trials demonstrated that extracorporeal shock wave increases chemokines and other factors that improve BM-MNC retention among cardiomyocytes. Some studies suggest that when administered to patients, BM-MNCs fuse with recipient cardiomyocytes, or release biologically active factors that stimulate recipient cardiac SCs to proliferate. In contrast to other types of SCs, the 2004 C. E. Murry et al. clinical trial published in Nature demonstrated that BM-MNCs themselves do not transdifferentiate into functional cardiomyocytes.
Some BM-MNC trials indicate improvement in ischemic heart disease (IHD). The TIME and LateTIME trials at the Minneapolis Heart Institute found no significant improvement in global or regional LV function, or in wall motion changes of the post-AMI zone, at six months after autologous intracoronary BM-MNC treatment administered three to seven days post-AMI. However, other studies suggest that long-term follow-up and designation of new endpoints may reveal previously hidden benefits of BN-MNC treatment. The U.S.-collaborated REPAIR-AMI trial showed a sustained average improvement in LVEF of 8 percent at 5 years and a reduction of post-AMI size by 5.5 percent at four months, and retrospective analysis demonstrated that the
