Graft-versus-host disease, the graft-versus-leukemia effect, and mixed chimerism following nonmyeloablative stem cell transplantation.

Allogeneic bone marrow or blood stem cell transplantation represents an important therapeutic tool for the treatment of otherwise incurable cancer and a large spectrum of nonmalignant diseases. Until recently, bone marrow transplantation was used primarily to eliminate malignant, genetically abnormal, or otherwise deficient stem cells; hence, highly toxic myeloablative regimens were considered mandatory for the eradication of undesirable cells of host origin. Recent data suggest that high-dose chemoradiotherapy may be successively replaced by nonmyeloablative stem cell transplantation (NST), which represents a safer biologic tool that involves the induction of host-versus-graft transplantation tolerance. NST thus provides allogeneic donor lymphocytes with the capacity to induce immune-mediated graft-versus-malignancy effects, either against mismatched minor or major histocompatibility alloantigens or against tumor-specific or tumor-associated antigens expressed by tumor or other hematologic cells of host origin. The future goals of the wider and safer clinical application of NST for the treatment of a larger number of indications and larger numbers of patients in need depend, on the one hand, on the development of more effective and safer modalities for maximizing the antitumor potential of donor lymphocytes (T-cells as well as natural killer and natural killer T-cells). On the other hand, these goals depend on using more selective approaches for targeting anticancer effector cells to their target cells. Such changes will thus set the stage for smarter rather than stronger modalities for the treatment of malignant and life-threatening nonmalignant diseases.