Allogenic Bone Marrow Mesenchymal Stem Cells Infusion in Patients With Steroid-refractory GVHD
Condition: Graft Versus Host Disease
MeSH terms: Graft vs Host Disease
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Graft versus host disease is a serious and often life-threatening complication in allogeneic
      haematopoietic stem cell transplantation. Although corticosteroids are the first-choice of
      treatment in these patients, but about 30-50% patients do not respond to it and develop
      steroid-refractory GVHD. Mesenchymal stem cells (MSC) have emerged as a promising treatment
      option in these patients. This phase-I/II clinical trial aims at establishing the safety and
      clinical efficacy of allogenic ex-vivo cultured MSCs to treat steroid-refractory GVHD in a
      Pakistani HSCT cohort.
    

Detailed description: 
      Allogeneic haematopoietic stem cell transplant has become first choice of treatment for many
      malignant and non malignant haematological disorders. Although great progress has been made
      to prevent and minimize transplant-associated complications, yet graft versus host disease
      (GVHD) remains a significant complication affecting these the outcome in these patients. It
      is a severe inflammatory condition that arises when recipient tissues are attacked by immune
      mediated donor T cells during transplantation. Acute GVHD predominately affects the skin,
      upper and lower GI tract, liver and occasionally the eye and oral mucosa, whereas chronic
      GVHD resembles more with autoimmune disorders in its clinical symptoms. These symptoms can be
      organ-specific or generalized throughout body.

      The pathophysiology of GVHD shows that it has different phases. In first phase i.e., afferent
      phase, damage to host tissue occurs. In second phase i.e., Induction and expansion phase,
      donor T cells are triggered and activated by recipient and donor APC as well as the
      inflammatory cytokines. Activated T cells produce IL-2 and IFN-γ (or Th1 response).
      Allogeneic immune response is amplified by IL-2, which activates more T cells and natural
      killer cell responses, triggering macrophages to release TNF-α and further inflammation
      damages skin and gut. The third phase i.e., effector phase, is characterized by cytotoxic
      damage against host cells by activated donor T-cell-mediated through Fas-Fas ligand
      interaction, perforin-granzyme and TNF-α. The latter has a central role in the
      pathophysiology, stimulating cytokine production (IL-1, IL-6, IL-10, IL-12 and TNF-α). This
      dysregulation leads to the clinical manifestations of acute GVHD.

      The cells involved in GVHD pathophysiology include CD4+ T cells; for maintaining the
      expansion of CD8+ T cells that mediate GVHD, APCs; these have role in the initiation phase of
      acute GVHD as described in murine models and Natural killer (NK) cells; contribute to tissue
      damage in the effector phase by releasing inflammatory cytokines and nitric oxide. However,
      natural killer cells mediate cell death by two important pathways: Fas-Fas-ligand-mediated
      apoptosis and perforin-granzyme-B-mediated cytolysis.

      HLA differences between donor and recipient are the major predictor of GVHD. Other affecting
      factors include age, gender mismatch between donor and recipient, minor histocomapatability
      antigen expression difference(mHA) in otherwise identical HSCT, donor age, source and dose of
      stem cells (PBSCT greater risk than BM), intensity of conditioning and GVHD prophylaxis.

      Steroids are the first line therapy for acute GVHD patients and are standard treatment for
      grade II-IV acute GVHD. Adverse effects of glucocorticoids include hypertension hyperglycemia
      and psychosis, immunosuppression, infections, myopathy, osteoporosis and avascular necrosis
      of bone, cataracts and fat re-distribution etc. If acute GVHD is not improved after 5-7 days
      treatment with steroids then it is considered as steroid-refractory. Various agents that are
      being investigated from last two decades as second line therapy include low-dose MTX, MMF,
      extracorporeal photopheresis, IL-2R targeting, antibody therapy against CD3, CD7, CD25, CD52,
      CD147, IL-2R, IL-1, and TNF-α (i.e., basiliximab, daclizumab, denileukin, diftitox and
      alemtuzumab), horse ATG, etanercept, infliximab, and sirolimus and recently infusions of
      mesenchymal stem cells.

      Mesenchymal stem cells (MSCs) are defined as self-renewing, multipotent progenitor cells with
      potential to differentiate into other cell types of mesodermal origin, such as adipocytes,
      osteocytes, and chondrocytes. Mesenchymal and Tissue Stem Cell Committee of the International
      Society for Cellular Therapy developed the minimal criteria for definition of MSCs which is
      as follows: first, adherence to plastic; Second, positivity for the cell-surface molecules
      CD105, CD73, and CD90 and negativity for CD45, CD34, CD14 or CD11b, CD79a or CD19, and human
      leukocyte antigen (HLA)-DR; and third, the ability to differentiate into osteoblasts,
      adipocytes, and chondroblasts under standard in vitro differentiation conditions. Since Le
      Blanc and colleagues first reported successful treatment of a patient with severe acute GVHD
      using third-party haploidentical MSCs in 2004, many clinical trials worldwide have described
      the benefits of MSC therapy in GVHD.

      The proposed project is a phase I/II clinical trial of single group, open label,
      interventional study design. The objective is to observe the safety and efficacy of
      intravenous injection of ex-vivo expanded bone marrow mesenchymal cells from a third party
      donor for treating refractory GVHD. The study will also document the type and frequency of
      any adverse event or side effects, if discovered.
    

Intervention name(s): Mesenchymal Stem Cells
Intervention type(s): Biological
Intervention description(s): Allogenic Human Bone Marrow Mesenchymal Stem Cells (ex-vivo expanded in pooled human platelet lysate)
Other intervention name(s): Allogenic Bone Marrow MSCs
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: acute GVHD; chronic GVHD; steroid-refractory; Mesenchymal Stem Cells