Minitransplants and cell-based therapies for malignant and nonmalignant disorders

Considering the role of alloreactive donor lymphocytes in mediating graft-versus-leukemia and graft-versus-tumor effects, including in patients who are resistant to conventional anticancer modalities, we have introduced the concept of using the bone marrow transplantation procedure as a platform for induction of host-versus-graft transplantation tolerance rather than as a means of eradicating all tumor cells. Safe and stable transplantation tolerance can best be accomplished by induction of mixed chimerism, which can be achieved using nonmyeloablative conditioning. Once host-versus-graft tolerance allows consistent and durable engraftment of donor immunohematopoietic cells, donor lymphocytes can be added if needed for induction of graft-versus-leukemia and graft-versus-tumor effects to displace residual malignant or genetically abnormal host cells. In principle, a similar approach can be used for induction of transplantation tolerance to all donor tissues and perfused organ allografts. Our preliminary data in nearly 100 patients are reviewed here. The conclusion of our working hypothesis, supported by many studies in animal models and a growing clinical experience, suggests that well-tolerated, safer nonmyeloablative stem cell transplantation may replace the use of myeloablative chemoradiotherapy for most patients in need of allogeneic bone marrow transplantation, toward a general goal of replacing aggressive and ineffective anticancer modalities with improved immunotherapy that is to become more selective and less hazardous as the experience accumulates.