Bone marrow transplantation (BMT) is an important therapeutic approach for the treatment of malignancies and provides curative therapy for most leukemias. However, the lack of HLA-matched donors limits its utility. There is considerable interest in using matched unrelated donors as an alternative source of compatible stem cells. Use of mismatched family members extends this modality to those minorities which are currently under-represented in the national registries. While the major complication of this approach [graft-vs-host-disease (GVHD)] has been reduced using several T cell depletion methods, it is difficult to show a survival benefit because of increased morbidity related to graft failure and increased immunosuppression. This proposal outlines a consecutive series of phase I protocols which are expected to improve survival in unrelated and mismatched BMT recipients. This will be accomplished by expanding upon the successful allogeneic graft engineering strategy involving elutriation and CD34+ selection. Specifically, the first set of protocols will determine whether durable engraftment Can be achieved by increasing stem cell dose using purified CD34+ cells obtained from a) elutriation of donor bone marrow (BM), b) additional isolation from donor peripheral blood stem cell(PBSC) harvests and c) ex-vivo expansion of purified CD34+ donor stem cells. The objectives of the 2nd group of protocols is to determine whether augmenting grafts with purified lymphoid [CD4,CD8,NK(LAK)] subpopulations or using pharmacologic agents such as cytokines (IL-2, GM-CSF) in vivo and/or ex vivo (during the expansion of purified ancillary graft cells) will enhance anti-tumor activity as measured by T cell cytolytic and NK activity and the kinetics of peripheral blood lymphoid subset (CD4,CD8,NK) reconstitution. This systematic approach to graft engineering should result in decreased transplant related morbidity in recipients of alternative donor grafts without sacrificing the beneficial anti-tumor properties of allogeneic BMT.
| Noga, S J (1999) Engineering hematopoietic grafts using elutriation and positive cell selection to reduce GVHD. Cancer Treat Res 101:311-30 |
| Noga, S J; Seber, A; Davis, J M et al. (1998) CD34 augmentation improves allogeneic T cell-depleted bone marrow engraftment. J Hematother 7:151-7 |
| O'Donnell, P V; Jones, R J; Vogelsang, G B et al. (1998) CD34+ stem cell augmentation of elutriated allogeneic bone marrow grafts: results of a phase II clinical trial of engraftment and graft-versus-host disease prophylaxis in high-risk hematologic malignancies. Bone Marrow Transplant 22:947-55 |
| Noga, S J; Vogelsang, G B; Seber, A et al. (1997) CD34+ stem cell augmentation of allogeneic, elutriated marrow grafts improves engraftment but cyclosporine A is still required to reduce GVHD and morbidity. Transplant Proc 29:728-32 |
