Independent Scholar
See Also: Eyes: Development and Regeneration Potential; Eyes: Existing or Potential Regenerative Medicine Strategies; Eyes: Major Pathologies; Eyes; Stem and Progenitor Cells in Adults; Retinal Stem Cells.
Further Readings
Blenkinsop, T.A., B. Corneo, S. Temple, et al. “Ophthalmologic Stem Cell Transplantation Therapies.” Regenerative Medicine, v.7 (2012).
John, S., S. Natarajan, P. Parikumar, et al. “Choice of Cell Source in Cell-Based Therapies for Retinal Damage Due to Age-Related Macular Degeneration: A Review.” Journal of Ophthalmology, v.2013 (2013).
Wright, L. S., M. J. Phillips, I. Pinilla, et al. “Induced Pluripotent Stem Cells as Custom Therapeutics for Retinal Repair: Progress and Rationale.” Experimental Eye Research, v.123 (June 2014).
Clinical Trials, U.S.: Graft Failure, Graft-Versus-Host Disease
Clinical Trials, U.S.: Graft Failure, Graft-Versus-Host Disease
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Clinical Trials, U.S.: Graft Failure, Graft-Versus-Host Disease
Graft-versus-host disease (GVHD) is an immune-mediated syndrome that often occurs after hematopoietic cell transplantation (HCT), and is associated with a higher rate of morbidity, mortality, protracted immune suppression, impaired functionality, and poor quality of life. Though poorly understood, the pathophysiology of GVHD is believed to be due to the interaction of tissue damage and proinflammatory cytokines, donor T cell activation by antigen-presenting cells, and tissue injury by effector T lymphocytes. GVHD occurs in both acute and chronic forms and remains one of the major barriers to improving long-term outcomes in allogeneic stem cell transplant recipients. According to the Glucksberg criteria, which describes severity of GVHD between I and IV (IV being the most severe), acute GVHD (aGVHD) is observed within the first 100 days post transplantation, whereas chronic GVHD (cGVHD) is observed after 100 days post transplantation.
Multivariate analysis has determined that patients who have received mismatched sex or HLA-A, -B, -C, or –DRBI, peripheral blood stem cells, CD3+ replete T cells, who are older, and who have advanced disease are risk factors for the development of GVHD. GVHD is less likely to develop or will be mitigated by ensuring a close donor match. First-line treatment of both acute and chronic GVHD includes the use of corticosteroids (e.g., prednisone) and a variety of immunosuppressive agents; however, this therapy often fails (50 percent), especially when a mismatched donor was used. If the patient fails to respond to steroidal therapy, mortality can be as high as 85 percent. This rate of mortality can be abated by tapering the steroid therapy, particularly in mismatched patients, because it is associated with a desired effect (graft versus tumor).
Glucocorticoid therapy is intended to suppress the T cell–mediated immune attack on host tissues, but in high doses, immune suppression can increase the risk of infection and even cancer relapse, as well as encourage chronic steroid use. Second-line therapies are extensive, have low efficacy, and outcome success is mixed. Therefore, it is important to find alternative targeted therapies, including pharmacologic, biological, or cellular agents that can selectively target immunological pathways and optimize their activity. Stem cell therapy, mesenchymal stem cells (MSCs) in particular, has emerged as a promising alternative since pioneering studies by the Karolinska Institute in treating steroid-resistant aGVHD.
Stem cells are undifferentiated cells that can be divided into two major types: embryonic and adult. Embryonic stem cells are termed pluripotent due to their ability to become any cell type with the appropriate cell signal. Adult cells, which are found in umbilical cord blood, peripheral blood, bone marrow, and organ tissues, are more limited in the types of cells they can become. There are ethical concerns in the experimental use of embryonic stem cells because they are obtained from a developing human, whereas adult stem cell experimentation does not have these concerns. Mesenchymal stem cells, which are obtained in bone marrow, peripheral blood, and umbilical cord blood, appear to have great potential for GVHD and autoimmune disorders due to their immunomodulatory properties. These properties are not well understood, but their ability to secrete soluble factors for cell protection, to home in on damaged areas, and to modulate immune responses are largely believed to be key factors.
Clinical Trials: MSCs to Treat GVHD
Currently, there are a large number of clinical trials evaluating the use of stem cells in the prevention or treatment of GVHD, based on preliminary pilot study results. In a multicenter Phase II trial, 55 patients with severe, steroid-resistant aGVHD were treated with MSCs (median dose 1.4 x 106 cells/kg), expanded in vitro, and in varying doses of cells obtained from HLA-identical sibling donors, haploidentical donors, and third-party donors. These subjects were followed for 60 days. Thirty patients experienced a complete response and nine demonstrated improvement; response was not HLA-match-dependent. Administration of MSCs was deemed safe and the overall two-year survival rate was higher in the patients who were complete responders than those who were partial responders.
Chronic GVHD resembles autoimmune disease in some aspects, and the efficacy of 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