Nonmyeloablative Allografts in DLA-haploidentical Dogs: Engraftment and GVHD

Fred Hutchinson Cancer Research Center, Seattle WA

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Abstract

The long-term objective of this project is to develop a safe and reliable nonmyeloablative approach at[unreadable] hematopoietic cell transplantation (HCT) from dog leukocyte antigen (DLA)-haploidentical donors, which can[unreadable] be translated into clinical trials. The studies will focus on the bi-directional immunologic barriers, host-versus-graft[unreadable] (HVG) and graft-versus-host (GVH) reactions, which must be overcome in order to achieve both[unreadable] uniform and sustained hematopoietic engraftment and graft-host tolerance. Two goals were pursued during[unreadable] the current grant period. One included extension of work in DLA-identical littermates in which we[unreadable] successfully substituted monoclonal antibodies (MAbs) directed at either TCRalpha-beta or the ubiquitous[unreadable] hematopoietic antigen, CD45, which were labeled with an alpha-emitting radionuclide Bismuth-213 (213Bi), for[unreadable] 2 Gy TBI. We also established successful DLA-haploidentical grafts when recipients were treated first with[unreadable] an anti-CD44 antibody combined with 4.5 Gy TBI and then given mycophenolate mofetil (MMF) and[unreadable] cyclosporine (CSP) after HCT for control of residual HVG reactions and for GVHD prevention. However,[unreadable] when the TBI dose was decreased to the sublethal range of 2 Gy, the engraftment rate declined to 50%,[unreadable] while the remainder of the dogs eventually rejected their grafts and survived with autologous marrow[unreadable] recovery. Also, GVHD control, which is largely T-cell mediated, has not been uniform.[unreadable] The current proposal seeks to continue the studies on DLA-haploidentical grafts since development of[unreadable] safe approaches will expand the choice of potential donors. Two principal experimental approaches will be[unreadable] taken. One involves combining low-dose TBI with relatively non-toxic biological and pharmacological[unreadable] immunosuppressive agents, including 213Bi-labeled antibodies to natural killer (NK) cells, all aimed at[unreadable] reducing both host NK and T cell responses and T cell responsiveness of the graft. The other is to administer[unreadable] chemotherapy early after transplant to not only control GVHD but also facilitate engraftment. After we have[unreadable] determined the optimal tinning and dosing of posttransplantation chemotherapy, we will evaluate the use of[unreadable] donor cells transduced with drug resistance genes which will allow using higher doses of posttransplantation[unreadable] chemotherapy for both induction of donor chimerism and control of GVHD. GVHD prevention will also[unreadable] include control of donor lymphocyte replication with certain immunosuppressive agents, e.g., MMF and[unreadable] sirolimus, combined with blockers of T-cell costimulation.[unreadable] Our ultimate aim is to develop allogeneic HCT strategies for patients with alternative donors with the[unreadable] least short- and long-term toxicities, which can be successfully applied to human patients.