Ex Vivo Tcell Depletion

A series of experimental and clinical observations have shown that GVHD can be effectively prevented by infusing less than 1-5 X 105 T cells/kg of recipient body weight.43 44 Early enthusiasm for the ex vivo removal of immunocompetent T cells from the marrow graft, however, was tempered by an increased risk of engraftment failure and relapse of the underlying malig-nancy.45-47 This increased relapse risk was somewhat disease-specific. In chronic myelogenous leukemia (CML), for example, an increase in relapse risk from approximately 10-20% following HLA-matched donor non-T-cell-depleted transplantation to 60-80% following T-cell-depleted transplantation was observed.47 In acute myelogenous leukemia (AML) in first remission, on the other hand, an effect of T-cell depletion on probability of relapse was not apparent.48

Given the limitations of ex vivo T-cell depletion, this strategy has not reached widespread acceptance for the prevention of GVHD following HLA genotypically identical donor HSCT for hematologic malignancies, particularly CML. However, given the more profound impact of GVHD on mortality risk following HLA nongeno-typically identical donor transplants, T-cell-depletion strategies are being reevaluated.

In an effort to diminish the problems of engraftment failure and relapse following ex vivo T-cell depletion, recent investigations have focused on the depletion of selective T-cell subsets. Ex vivo depletion of CD8+ T cells has been shown to result in an apparent reduction of GVHD with no increase in relapse probability following HLA-matched sibling donor HSCT for CML.49 An increased risk of engraftment failure, however, has further demonstrated the importance of T cells in overcoming host alloresistance to engraftment.

Recently, adoptive cellular immunotherapy via DLI has been increasingly utilized for its capacity to enhance GVH alloreactivity and to impart a potent GVM effect.50 51 In CML, for example, a cytogenetic and molecular remission is achieved with DLI for the treatment of relapse following allogeneic HSCT in the majority of cases, demonstrating that a potent antitumor effect, with at least a several log tumor cell cytore-duction, is achievable.50-53 In a nonrandomized comparison of non-T-cell-depleted transplants and CD6+ T-cell-depleted transplants for CML (followed by DLI at time of relapse), similar survival probabilities were realized.54 Not surprisingly an increased probability of relapse occurred in the T-cell-depleted transplant recipients, but the majority of these patients achieved a second remission with DLI, which in most cases appeared to be durable. This suggests that for at least selected patients who are at high risk for transplant-related morbidity or mortality an ex vivo T-cell-depleted HSCT followed by DLI for posttransplant relapse may be a rational treatment strategy.

Given the potent antitumor potential of DLI and experimental evidence suggesting that delayed DLI may be associated with a substantially lower risk of GVHD than with early T-cell infusion(s), clinical trials evaluating ex vivo T-cell-depleted bone marrow or peripheral blood progenitor cell (PBPC) transplants followed by delayed T-cell infusions have been con-ducted.55-57 Preliminary results suggest that this strategy is feasible and that delayed DLI can be performed without a prohibitive risk of GVHD.56 The optimal dosing and timing of delayed T-cell infusion(s) remain to be determined.

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