Each year more than 15,000 patients receive allogeneic hematopoietic progenitor cell transplants (HPCT). The major causes of morbidity and mortality following allogeneic HPCT include graft versus host disease (GvHD), relapse and opportunistic infections. Multiple strategies of graft engineering involving depletion of T-cells from the graft have reduced the incidence of GvHD but have not resulted in significant improvements in survival outcomes due to higher rates of infection and relapse. Poor cellular immune reconstitution contributes to death from opportunistic infection in up to 40% of patients in published series of patients treated with T-cell depleted allogeneic HPCT, while relapse results in up to 50% additional mortality. Thus a long-standing goal in the field has been to develop strategies to enhance cellular immune reconstitution post-transplant without increasing the risk of graft versus host disease. One attractive approach has been to administer infusions of limited numbers of donor T-cells (donor lymphocyte infusions, abbreviated DLI) weeks to months after allogeneic HPCT at a time that the recipient has recovered from the effects of pre-transplant high dose radiation and chemotherapy conditioning and when lower levels of inflammation are predicted to result in less acute GvHD. While this approach works in mouse models of BMT [1], the strategy of delayed DLI has not abrogated the risk of transfusion-associated GvHD in human patients. Thus new strategies to enhance immune reconstitution while limiting GvHD are needed, particularly for HPCT recipients who are at very high risk for opportunistic infection and relapse. In order to translate novel approaches of graft engineering into clinical practice they should be technically simple, robust in their application across different types of transplants, and based upon established immunological mechanisms. A novel strategy to adoptively transfer antigen specific donor T-cells without inducing lethal graft-versus-host disease has been develop and validated in a murine model system. Donor T-cells treated ex vivo with fludarabine, an immunosuppressive nucleoside analog, have a markedly reduced ability to induce GvHD, yet confer protection against murine cytomegalovirus as well as residual leukemia cells [2,3]. The overall objective of the study proposed here is to translate this novel method of graft engineering, that improves immune reconstitution, enhances GvT and transfers antigen-specific immunity without increasing the risk of GvHD, into recipients of allogeneic transplants. This novel method of ex vivo fludarabine treatment is simple and can be broadly adopted in the blood bank and transplant communities. The result of the proposed studies will be a test of whether fludarabine DLI is safe and efficacious as a method of adoptive immunotherapy in a high-risk transplant population. Positive results from the proposed trial would set the ground-work for a larger randomized multi-center phase 2 clinical trial.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Emory University
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