Novel approaches to allogeneic stem cell therapy

Traditionally, allogeneic haematopoietic stem cell transplantation (SCT) ha s involved administration of myeloablative doses of chemotherapy and/or rad iation that may cure many patients with haematologic diseases. The high mor bidity and mortality associated with the intensive conditioning regimen lim its allogeneic SCT to younger and healthier patients. However, it is now kn own that successful allogeneic SCT is dependent, at least in part, on the a ntitumour properties of the donor graft independent of the conditioning reg imen. This potent 'graft versus tumour' (GVT) effect can now be exploited f or clinical benefit. The best evidence of a direct GVT reaction comes from the use of donor leukocyte infusions (DLI). For many patients with relapsed leukaemia after allogeneic SCT, DLI re-establishes complete and durable re missions. This has suggested a novel approach to allogeneic cell therapy (A CT) using non-myeloablative, but immunosuppressive conditioning regimens to permit engraftment of allogeneic stem cells and lymphocytes. Engrafted don or cells would then provide GVT activity in the setting of reduced conditio ning regimen toxicity. The ability to minimise toxicity and maximise the im munologic GVT effect will make allogeneic transplantation applicable to pat ients typically ineligible for conventional allogeneic SCT. Response rates with this strategy have been impressive, although toxicity related to graft versus host disease (GVHD) and other complications remains a concern. Curr ent trials have involved heterogeneous groups of patients using various con ditioning regimens. Many issues remain unsettled, including identification of the most appropriate tumour targets and definition of the most effective , least toxic conditioning regimen. In addition, the durability of response is unknown. Nevertheless, the use of non-myeloablative conditioning and AC T may provide a new paradigm for allogeneic cell transplantation and the im munotherapy of cancer.