Novel approaches to allogeneic stem cell therapy

Abstract

Traditionally, allogeneic haematopoietic stem cell transplantation (SCT) has involved administration of myeloablative doses of chemotherapy and/or radiation that may cure many patients with haematologic diseases. The high morbidity and mortality associated with the intensive conditioning regimen limits allogeneic SCT to younger and healthier patients. However, it is now known that successful allogeneic SCT is dependent, at least in part, on the antitumour properties of the donor graft independent of the conditioning regimen. This potent ‘graft versus tumour’ (GVT) effect can now be exploited for 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 remissions. This has suggested a novel approach to allogeneic cell therapy (ACT) using non-myeloablative, but immunosuppressive conditioning regimens to permit engraftment of allogeneic stem cells and lymphocytes. Engrafted donor cells would then provide GVT activity in the setting of reduced conditioning regimen toxicity. The ability to minimise toxicity and maximise the immunologic GVT effect will make allogeneic transplantation applicable to patients 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. Current trials have involved heterogeneous groups of patients using various conditioning 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 ACT may provide a new paradigm for allogeneic cell transplantation and the immunotherapy of cancer.