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Remestemcel-L is a third-party, off-the-shelf suspension of ex-vivo cultured adult human mesenchymal stem cells intended for intravenous infusion. The mesenchymal stem cells are derived from the bone marrow of unrelated and human leukocyte antigen (HLA)–unmatched healthy adult donors and have the ability to differentiate into different tissue cells. It was approved for use in Canada in May 2012 as Prochymal for the management of refractory acute Graft versus Host Disease (aGvHD) in children who are unresponsive to systemic steroid therapies, with the approval conditional upon further trials being conducted. aGvHD is a T-cell mediated disease that occurs after allogeneic hematopoietic stem cell transplant and is a reaction of donor immune cells against host tissues developed by 30-80% of the recipients . aGvHD is often characterized by the presence of inflammatory cascades through signalling of activated T cells. While systemic corticosteroids and other immunosuppressive agents are commonly used as first-line treatments to manage aGvHD, about 30-50% of patients with aGvHD experience inadequately control of disease with first-line therapies, putting them in a risk for poor outcomes and creating a significant clinical challenge . It is estimated that the patients with the most severe forms of refractory aGvHD that do not respond to steroid therapy have expected one-year survival rates of only 5% to 30% . Human mesenchymal stem cells (hMSCs) serve to down-regulate inflammatory responses and produce anti-inflammatory cytokines and growth factors to promote tissue repair . In clinical studies, patients treated with remestemcel-L demonstrated an improvement in their aGvHD and improved survival rates at subsequent days following intravenous infusion . Based on its tolerability and safety profile, remestemcel-L is a promising alternative to second-line immunosuppressive agents .
Remestemcel-L is a third-party, off-the-shelf suspension of ex-vivo cultured adult human mesenchymal stem cells intended for intravenous infusion. The mesenchymal stem cells are derived from the bone marrow of unrelated and human leukocyte antigen (HLA)–unmatched healthy adult donors and have the ability to differentiate into different tissue cells. It was approved for use in Canada in May 2012 as Prochymal for the management of refractory acute Graft versus Host Disease (aGvHD) in children who are unresponsive to systemic steroid therapies, with the approval conditional upon further trials being conducted. aGvHD is a T-cell mediated disease that occurs after allogeneic hematopoietic stem cell transplant and is a reaction of donor immune cells against host tissues developed by 30-80% of the recipients . aGvHD is often characterized by the presence of inflammatory cascades through signalling of activated T cells. While systemic corticosteroids and other immunosuppressive agents are commonly used as first-line treatments to manage aGvHD, about 30-50% of patients with aGvHD experience inadequately control of disease with first-line therapies, putting them in a risk for poor outcomes and creating a significant clinical challenge . It is estimated that the patients with the most severe forms of refractory aGvHD that do not respond to steroid therapy have expected one-year survival rates of only 5% to 30% . Human mesenchymal stem cells (hMSCs) serve to down-regulate inflammatory responses and produce anti-inflammatory cytokines and growth factors to promote tissue repair . In clinical studies, patients treated with remestemcel-L demonstrated an improvement in their aGvHD and improved survival rates at subsequent days following intravenous infusion . Based on its tolerability and safety profile, remestemcel-L is a promising alternative to second-line immunosuppressive agents .
Pathogenesis of acute graft versus host disease: Acute graft versus host disease (aHvGD) occurs in recipients of allogenic stem cell transplantation and is characterized by differentiation and activation of alloreactive T lymphocytes. aGvHD is associated with tissue injury in various organs such as the liver, skin and intestinal mucosa . Acute GvHD can be summarized in a three-step process: conditioning phase, donor T-Cell activation, and cellular and inflammatory effector phase . The first phase involves the tissue damage induced by conditioning regimen (irradiation and chemotherapy) and production of inflammatory factors such as cytokines and adhesion molecules . The expression of MHC antigens and adhesion molecules is recognized by donor T cells. These donor T cells are activated in phase 2, resulting in subsequent proliferation, differentiation and secretion of cytokines including IL-2 and IFN-γ . These cytokines enhance T-cell expansion, induce cytotoxic T cells (CTL) and natural killer (NK) cell responses and facilitate the production of TNF-α and IL-1 by monocular phagocytes . Inflammatory cytokines promotes the production of inflammatory chemokines, thus recruits effector cells into target organs and initiates phase 3 of the disease . Phase 3 involves cascades of cell-mediated cytotoxicity and signalling of multiple inflammatory effectors , leading to amplification of local tissue injury and further promotion of an inflammatory response . Mechanism of action of remestemcel-L: Human mesenchymal stem cells (hMSCs), or remestemcel-L, are derived from the bone marrow are capable of differentiation into cells derived from the mesoderm germ layer, such as osteocyte, adipocyte and chondrogenic cells . Once administered, they migrate to the site of inflammation to reduce the production of pro-inflammatory cytokines. It has been demonstrated that hMSCs secrete a wide range of bioactive molecules, such as growth factors, cytokines, and chemokines, that mediate regenerative and anti-apoptotic actions . Some molecules released by hMSCs include PGE2 and IL-10 for anti-inflammatory effects, or TGFβ1 and HLA-G5 for suppression of T cell proliferation . There is evidence that hMSCs interact with natural killers cells, monocytes, macrophages, effector T cells and regulatory T cells to shift their pro-inflammatory Th1 cytokine secretion profile to an anti-inflammatory Th2 cytokine profile . hMSCs also suppress NK cell proliferation and disrupts the migration, maturation, and antigen presentation of dendritic cells that differentiated from monocytes . In a mouse model of ischemia, remestemcel-L have been shown to stimulate the growth of new blood vessels, which is a process crucial to tissue repair, through secretion of factors such as VEGF. Overall, hMSCs exert immunomodulatory actions to inhibit inflammatory responses in aGvHD.
Indicated for in the management of acute Graft versus Host Disease (aGvHD) in pediatric patients. Acute GvHD should be refractory to treatment with systemic corticosteroid therapy and/or other immunosuppressive agents. Remestemcel-L may be used for Grades C and D of the disease in any organ. Remestemcel-L may also be used in the management of Grade B aGvHD involving any visceral organ, including the GI tract and the liver, but excluding skin.
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