The GVL effect in donor lymphocyte transfusion

The existence of an immunologic antileukemia effect mediated by donor cells after bone marrow transplantation (BMT) was first found more than four decades ago in murine transplant models [1]. However, it was only in the 1980s that the presence of an antitumor effect, also referred to as the graft-versus-leukemia effect (GVL), in human bone marrow grafting was first shown from the statistical analyses of large cohorts of patients transplanted at single institutions or reported to the International Bone Marrow Transplant Registry (IBMTR) [2-4]. These studies found that absence of graft-versus-host disease (GVHD) after BMT or removal of immunocompetent lymphoid cells from the marrow inoculum increased leukemia relapse rates. The first attempts to induce immunological effects in bone marrow graft recipients by transfusing lymphocytes from the donor were carried out in the early 1980s. The purpose of these studies was to prevent graft rejection in aplastic anemia and to reduce the relapse rate in advanced hematological malignancies [5-7]. These studies were abandoned due to an increased incidence of GVHD attributed to the fact that donor lymphocyte transfusions (DLTs) were given at or shortly after BMT. Animal studies demonstrated that delayed transfusion of donor cells resulted in considerably less GVHD [8]. Several investigators provided the first clear evidence that transfused donor lymphoid cells exert a direct antileukemic effect in patients with relapse of leukemia after BMT with acceptable toxicity. Komori et al. [9] described a patient with frank relapse of acute lymphoblastic leukemia (ALL) 18 months after an HLA-identical transplant who responded to transfusions of donor lymphocytes activated with IL-2. However, the response proved transient, and this patient eventually succumbed to leukemia. Kolb et al. [10] first induced lasting, complete remissions in three patients with clinical relapse of CML after allografting by transfusing donor lymphocytes and administering interferon-alpha (IFN-α). Slavin et al. [11] reported a patient with persistent ALL, treated in the 1980s, who obtained a remission with DLT given between 1 and 3 months post-DLT. Several other investigators have since reported similar results with lymphocyte therapy for relapse after transplant [12-17]. This chapter describes the clinical results and complications of DLT therapy for relapse of hematological malignancies after allografting. It seeks to determine the overall place of DLT in the management of relapse and addresses the role of adjuvant therapies such as chemotherapy, IL-2, and IFN-α. DLT is not only a important new addition to our therapeutic arsenal but also serves as an in vivo model of adoptive immunotherapy that can be used to test new strategies for inducing leukemia-specific T-cell responses. The final section of the chapter discusses some of the current clinical and preclinical efforts to develop specific anti-leukemic T-cell immunotherapy.