Application of MultiStem® Allogeneic Cells for Immunomodulatory Therapy: Clinical Progress and Pre-Clinical Challenges in Prophylaxis for Graft Versus Host Disease

Abstract

The last decade has seen much progress in adjunctive cell therapy for immune disorders. Both corporate and institutional Phase III studies have been run using mesenchymal stromal cells (MSC) for treatment of Graft versus Host Disease (GvHD), and product approval has been achieved for treatment of pediatric GvHD in Canada and New Zealand (Prochymal®; Osiris Therapeutics). This effectiveness has prompted the prophylactic use of adherent stem cells at the time of allogeneic hematopoietic stem cell transplantation (HSCT) to prevent occurrence of GvHD and possibly provide stromal support for hematopoietic recovery. The MultiStem® product is an adult adherent stem cell product derived from bone marrow which has significant clinical exposure. MultiStem cells are currently in phase II clinical studies for treatment of ischemic stroke and ulcerative colitis, with Phase I studies completed in acute myocardial infarction and for GvHD prophylaxis in allogeneic HSCT, demonstrating that MultiStem administration was well tolerated while the incidence and severity of GvHD was reduced. In advancing this clinical approach, it is important to recognize that alternate models exist based on clinical manufacturing strategies. Corporate sponsors exploit the universal donor properties of adherent stem cells and manufacture at large scale, with many products obtained from one or limited donors and used across many patients. In Europe, institutional sponsors often produce allogeneic product in a patient designated context. For this approach, disposable bioreactors producing <10 products/donor in a closed system manner are very well suited. In this review, the use of adherent stem cells for GvHD prophylaxis is summarized and the suitability of disposable bioreactors for MultiStem production is presented, with an emphasis on quality control parameters, which are critical with a multiple donor approach for manufacturing.

Different Culture Conditions Modulate the Immunological Properties of Adipose Stem Cells

“…Several recognized clinical studies have thus been performed to investigate the potential of BMSCs for the treatment of GVHD [15,[70][71][72][73]. In addition, both preclinical and clinical studies have been performed to evaluate the use of ASCs to prevent acute GVHD, as reviewed by Leto Barone et al [74].…”

Painting factor H onto mesenchymal stem cells protects the cells from complement- and neutrophil-mediated damage

“…Despite all the efforts over the years and more than 400 registered MSC-based clinical trials (www.clinicaltrials.gov), there has been no approved MSC product in the US for treating inflammatory diseases. However, even though the results from a recently completed Phase III clinical trial using MSCs to treat GVHD failed to meet the primary endpoints when all patients were considered [9], subsequent analyses demonstrated treatment efficacy in the pediatric subgroup [10]. Although the results of these clinical studies and promising results from previous in vitro studies and in vivo studies in animals strongly argue that MSCs have potential for development as a new therapy for inflammatory diseases, current MSC-based therapies need to be improved in order to be successful.…”

Clinical-Grade Multipotent Adult Progenitor Cells Durably Control Pathogenic T Cell Responses in Human Models of Transplantation and Autoimmunity

“…This may be advantageous in a translational context, because it enables clinical manufacturing through the creation of a master cell bank and production of uniform clinical doses without the use of multiple donors. Clinical-grade MAPCs have been isolated using these conditions and are currently active in phase II clinical development as an "off-the-shelf" infused cell product for ulcerative colitis and ischemic stroke (10). A single master cell bank has been sufficient to support these and previous phase I studies in acute myocardial infarction and allogeneic bone marrow transplant in which all doses were safe and well tolerated (10,11).…”

“…Clinical-grade MAPCs have been isolated using these conditions and are currently active in phase II clinical development as an "off-the-shelf" infused cell product for ulcerative colitis and ischemic stroke (10). A single master cell bank has been sufficient to support these and previous phase I studies in acute myocardial infarction and allogeneic bone marrow transplant in which all doses were safe and well tolerated (10,11). However, despite their ongoing evaluation in autoimmune and allogeneic solid organtransplantation settings, data supporting the immune regulatory potential of clinical-grade MAPCs are limited.…”