Cord blood transplantation (CBT) has clear advantages over transplantation with bone marrow or peripheral blood stem cells, but its wider use has been limited by the low dose of stem and progenitor cells in CB units, leading to delays in engraftment and a substantial rate of engraftment failure. During the past PO1 funding period, we developed a marrow-derived mesenchymal stromal cell (MSC)-CB coculture system that allowed us to significantly accelerate the time to neutrophil and platelet engraftment. This advance was paralleled by results showing that ex vivo cell-surface fucosylation of CB, using the fucosyltransferase (FT)-6 enzyme with GDP-fucose can boost engraftment by promoting CB homing to marrow. Thus, in Project 1, we now propose a revised series of studies directed to our long-term goal: bringing the results of CBT in line with outcomes being reported for G-CSF-mobilized peripheral blood progenitor cells (Aims 1 and 2). This effort will test CBT based on the combination of MSC-expansion of CB cells followed by exofucosylation with FT-7 a second fucosyltransferase that is more physiologic than FT-6 and could be even more effective at enhancing engraftment in the marrow. Additionally, graft-versus-host disease (GVHD) continues to restrict the utility of CBT, an issue we did not address specifically during the past PO1 award. Rates of grade III-IV GVHD after CBT range from 5% to 30%. In our patients, those with acute liver and gastrointestinal (GI) GVHD have significantly benefited from MSC treatment. In a xenogenic GVHD model, we have observed that fucosylated MSCs can enhance homing to sites of inflammation, resulting in a striking survival benefit compared with the outcome of unmanipulated MSC treatment. We have also recently observed that CB tissue-derived MSCs are logistically easier to obtain and expand much more rapidly than marrow-derived MSCs. Thus we now propose to test whether CB tissue-derived, fucosylated MSCs can be used to abrogate acute, steroid-refractory liver and/or GI GVHD (Aim 3). The interactive potential of this project is considerable, for example, the clinical trial in Aim 1 will likely stimulate collaborations with Project 2 (reconstitution of virus-specific CTLs), Project 3 (NK cell recovery) and Project 4 (recovery of tumor-specific immunity). Finally, we would stress that many of the findings from Project 1 will not be restricted to CBT, but could extend well beyond times to engraftment to settings as diverse as GVHD and regenerative medicine.
Project 1 seeks to overcome barriers to cord blood (CB) transplantation by improving the expansion of CB cells, and directing their migration to the marrow, after they are transplanted into patients. We will also generate CB tissue-derived mesenchymal stromal cells, to eliminate GVHD.
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