ABSTRACT
Although there is considerable evidence to support a graft-versus-leukemia effect in allogeneic hematopoietic stem-cell transplantation (HSCT), the molecular basis for this effect remains unclear. It is likely that donor T-cell recognition of host alloantigens present on the tumor cells mediates a major component of the GVL effect. For HLA-matched sibling donors, these represent the minor histocompatibility antigens. With increasing mismatch between host and donor, this effect will potentially be increased. This type of GVL effect may be difficult to separate from GVHD, and most studies to date have demonstrated a close association between GVHD and GVL. However, the existence of immunogenic tumor antigens has now been well established [1-4]. These antigens represent targets for recognition by donor T lymphocytes. Importantly, this GVL effect will be distinct from GVHD and represents a mechanism that could be exploited for therapeutic purposes. Nevertheless, despite the documented presence of these tumor antigens, patients fail to mount clinically significant immune responses against tumor. This suggests either that tumor antigens are only very weakly immunogenic or that mechanisms exist whereby tumor cells are capable of escaping host-cell recognition. These mechanisms similarly will provide obstacles to
development of a maximal GVL effect against tumor-specific antigens. Maximization of this tumor-specific GVL will require manipulation of tumor cells and host T cells and will likely be based upon an understanding of the basic molecular and immunological mechanisms required for a maximal T cell-mediated effect against antigen.
