Two of the major obstacles to further improvement in allogeneic haematopoietic stem cell transplantation (HSCT) outcomes are the toxicity associated with the development of graft–versus-host disease (GvHD) and the propensity for malignant disease to relapse, which are both influenced by a number of transplant- and disease-related factors. To some degree, the two are interlinked. The immune-mediated allogeneic effect that is responsible for GvHD also appears to be responsible, at least in part, for the graft-versus-tumour activity of HSCT that is most notably demonstrated by the ability of donor lymphocyte infusions (DLIs) to mediate anti-tumour responses in patients relapsing following transplantation . In accordance with the theory that the effectors causing GvHD are the donor T cells, the most efficient method for prevention of GvHD following HSCT is T-cell depletion of the graft. This can be achieved by a number of techniques falling within three broad categories: physical methods (e.g. counterflow centrifugal elutriation, E-rosette depletion), immunological methods (e.g. monoclonal antibody (anti-CD6, -CD8, or -TCRαβ) and rabbit complement, Campath-1 antibodies in vitro or in vivo, immunotoxins), and combined physical/immunologic methods (selection for cells expressing CD34 by immunoadsorption columns, immunomagnetic beads). The concurrent T-cell depletion of the recipient that can be achieved with in vivo Campath antibodies that activate antibody-dependent cell-mediated cytotoxicity (ADCC) facilitates engraftment and limits the requirement for escalation of the intensity of conditioning that is otherwise often required to prevent an increased incidence of graft rejection (Figure 17.1). However, donor lymphocytes contribute an anti-leukaemia effect and lymphocyte depletion may exacerbate problems with immune reconstitution resulting in increased risks of both infection and relapse. Thus there is a fine balance between the risks of GvHD and host-versus-graft reactions, relapse and infection.
The balance of host and donor immunity determines the outcome of opposing host-versus-graft (HvG) and graft-versus-host (GvH) reactions. In the unconditioned host (a) the graft will be rejected. Conditioning with chemo-radiotherapy (b) reduces host immunity sufficiently to allow donor engraftment, but immune cells in the graft can now mediate graft-versus-host disease (GvHD). T-cell depletion of the graft with monoclonal antibody in vitro (c) is an effective means of reducing GvHD. The opposing immunological processes will be more balanced, leading to an increased risk of graft failure. Further immune suppression of the host will reduce this risk. This can be achieved by increasing the intensity/immunosuppressive capacity of the chemo-radiotherapy or by depleting the host of T cells with in vivo monoclonal antibodies (d). This can be combined with in vitro T-cell depletion of the graft but the long half-life of alemtuzumab obviates this requirement.
Although initially developed as T-cell depleting antibodies that would activate human effector systems (such as complement), and that could be used to reduce GvHD following allogeneic transplantation, the more widespread distribution of the target antigen on haematopoietic cells led to another potential application, which ...