Understanding the Graft-Versus-Leukaemia Reaction

The role of the immune response in control and erradication of leukaemia remains controversial but there is increasing evidence that the principal mechanism of cure after intensive chemotherapy and allogeneic BMT is immune mediated. This is evidenced by the observations of a reduced risk of leukaemia relapse after allogeneic BMT when compared with autologous or syngeneic BMT. Furthermore, an increased incidence of leukaemic relapse has been reported after aggressive GvHD prophylaxis with cyclosporin or lymphocyte depletion. The association between GvHD and the graft-versus-leukaemia activity of allogeneic BMT is strong and has led to a number of workers concluding that GvL might be inseparable from GvHD although there is increasing evidence that this is not so. The lymphocyte subsets responsible for GvHD and GvL remain to be elucidated in man despite intensive efforts. Certainly T cells, natural killer cells and a population of in vivo activated killer cells are involved in GvL and an effective immune response probably requires a combined approach. The target antigens of GvL are also controversial. The majority of GvL studies have been conducted in the allogeneic transplant setting in which activity to leukaemia-specific peptides is easily masked by reactivity to undetected MHC mismatches and to minor histocompatibility antigens. Despite this the search for leukaemia-specific peptides has been fruitful in the case of the product of the BCR/ABL translocation in CML. The ultimate aim of a number of groups in all aspects of oncology is the development of effective and specific immunotherapy. A variety of approaches have been attempted over the last 80 years, including vaccination with irradiated leukaemic blasts and numerous trials of interleukin-2. We now know more about the mechanisms of induction of immunity than ever before and this knowledge, combined with sophisticated molecular biology and virology, promises to revolutionise the immunotherapy of leukaemia over the next ten years.