Graft-versus-leukemia effects of transplantation and donor lymphocytes

Abstract

Allogeneic transplantation of hematopoietic cells is an effective treatment of leukemia, even in advanced stages. Allogeneic lymphocytes produce a strong graftversus-leukemia (GVL) effect, but the beneficial effect is limited by graft-versushost disease (GVHD). Depletion of T cells abrogates GVHD and GVL effects. Delayed transfusion of donor lymphocytes into chimeras after T cell-depleted stem cell transplantation produces a GVL effect without necessarily producing GVHD. Chimerism and tolerance provide a platform for immunotherapy using donor lymphocytes. The allogeneic GVL effects vary from one disease to another, the stage of the disease, donor histocompatibility, the degree of chimerism, and additional treat- IntroductionTreatment of leukemia and other malignancies of the hematopoietic system with total body irradiation (TBI) and transplantation of bone marrow from healthy persons was developed from studies on radiation protection in the 1950s. However, it was evident from bioassays of murine leukemia that radiation could not eliminate leukemia in doses tolerated clinically. 1 In contrast, TBI followed by allogeneic marrow transplantation could cure leukemia in some murine models. 2 The term adoptive immunotherapy by allogeneic marrow transplantation was coined by Mathé 3 in the early 1960s when little was known about donor selection, appropriate conditioning treatment, and prevention of graft-versus-host disease (GVHD). Selection of sibling donors by human leukocyte antigen (HLA) typing, the combination of TBI with cyclophosphamide for conditioning treatment, and postgrafting immunosuppressive treatment with methotrexate provided the basis of success in the treatment of acute leukemia with allogeneic marrow transplantation. 4,5 In these patients, Weiden et al described the beneficial effect of GVHD on the incidence of leukemia relapse. 6 In patients with chronic GVHD, this reduced relapse was even associated with a survival benefit. 7 The role of T cells became evident when depletion of T cells from the graft was introduced into the clinical practice for prevention of GVHD. 8,9 In chronic myelogenous leukemia (CML), the beneficial effect of T-cell depletion on GVHD was negated because of an increased relapse rate. 10 Increased relapse after T-cell depletion was most pronounced in CML, less in acute myeloid leukemia (AML), and lowest in acute lymphoblastic leukemia (ALL). 11 The challenge of allogeneic stem cell transplantation for treatment of leukemia and other malignancies of the hematopoietic system is the prevention of GVHD without losing the graft-versusleukemia (GVL) effect. One possible approach has been is to apply a delayed transfusion of T cells after T cell-depleted marrow transplantation. Previous experiments in stable canine chimeras showed that graft-versus-host tolerance was not abrogated by donor lymphocyte transfusions (DLTs). 12 In DLA-identical littermate chimeras, we analyzed at which time after T cell-depleted marrow transplantation we could transfuse donor lymphocytes without p...

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Subsequent Neoplasms Working Group Report

“…107–111 Finally, research into the allogeneic graft-versus-leukemia effect reveals donor T-cell responses to tumor antigens and minor antigens, and that disease relapse can be provoked by immunosuppressive therapy. 112 …”

Progress and prospects: graft-versus-host disease

“…The potency of cellular adoptive immunotherapy against cancer has been shown by persistent and complete clinical responses obtained with allo-HSCT, followed by the adoptive transfer of donor T lymphocytes. 72 This has been reinforced by the encouraging clinical responses observed with adoptive transfer of tumour-specific CTLs in cancer patients. 73,74 Major hurdles limiting adoptive T-cell therapy relate to toxicity (that is, GvHD in allo-HSCT) and efficacy (that is, difficulty in expanding rare, high-avidity tumour-specific CTLs).…”

Recent advances in T‐cell immunotherapy for haematological malignancies

“…(Horowitz et al 1990, Kolb 2008) Studies showed associations of clinical responses with circulating T cells that recognized not only allo-antigens but also tumour antigens, such as PR1(Molldrem et al 2000) or WT1(Bellantuono et al 2002), stimulating interest in adoptive transfer of tumour-specific T-cells. Studies of melanoma patients at the National Cancer Institute (NCI) initially illustrated T cells could recognize tumour antigens by showing that patient-derived TILs, generated by expansion in recombinant interleukin 2, could kill autologous tumour cells in a major histocompatibily complex (MHC)-restricted manner.…”