STEM CELL Immunotherapeutic aspects of stem cell transplantation

Initially, the treatment of haematological malignancies predominantly made use of the antimetabolites (methotrexate, hydroxyurea) or alkylating agents (cyclophosphamide, busulphan) that achieved a normalization of the white blood cells count but were associated with serious side effects (such as marrow aplasia). The introduction of a-interferon (IFN-a) in the early 1980s contributed to an increase of overall survival compared to chemotherapy of about 20 months. Furthermore, the complete response in some patients treated in chronic phase was ascribed to its immunomodulatory effect, i.e., upregulation of HLA class I and II and of adhesion molecules. Allogeneic haematopoietic stem cell transplantation (HSCT), in addition to the diminution and eradication of some of the tumour burden by high dose pretransplant chemo and radiotherapy regimens, provides an allogeneic antitumour effect or graftversus-leukaemia (GVL) effect and truly constitutes the only current curative treatment for chronic myeloid leukemia (CML). Thus, the major curative effect of allogeneic HSCT is due to immune responses directed against malignant cells, either targeting specific tumour markers (antigens) or, more likely, individual-to-individual antigenic differences between the donor and recipient. Donor lymphocyte infusion (DLI) has been shown to cure 20 /80% of the patients with relapsed leukaemia or lymphoma depending on the type and extent of the disease. However, graft-verses-host disease (GVHD) often accompanies treatment using unmodified DLI. In vitro selection and expansion of cytotoxic T lymphocytes (CTL) with relative specificity for the malignant cells may separate the anti leukemic responses from GVHD. Although ‘‘proof of principle’’ for this approach has been demonstrated in a number of patients by successful eradiation of the relapsed haematological malignancy by infusion of leukaemia reactive CTL, therapeutic numbers of Tcells with the desired antigen specificities are difficult to obtain and process in vitro. Moreover, with a very small number of exceptions, such as the minor Histocompatibility antigens HA-1 and HA-2, the differences between individuals that are capable of giving rise to these beneficial immune antitumour responses and not to a detrimental anti-host reaction, GVHD, have not been characterized. In consequence, this potentially immunotherapeutic effect of allogeneic transplantation has so far been an untargeted and unpredictable property of stem cell transplantation (SCT). Suitable targets for tumour immunotherapy fall into a number of discrete classes.