Summary. Although it has been known for more than 40 years that allogeneic immune responses cure leukaemias after bone marrow transplantation, autologous leukaemiaspecific immunity remains controversial and its impact upon survival has not been established. Here we have tested 25 patients with de novo acute leukaemias, while in remission at completion of their anti-leukaemia therapy, for evidence of autologous cytolytic immunity to their leukaemic cells taken and cryopreserved at disease presentation. We have measured this degree of cell-mediated cytotoxicity in vitro and termed it Ôleukaemia cytolytic activityÕ (LCA). Patients whose disease ultimately relapsed had significantly lower LCA than those who remained in remission beyond 2 years (P < 0AE001); the absence of LCA when in remission predicted subsequent relapse within 2 years with a sensitivity of 100% and specificity of 77%. LCA was mediated in vitro by CD56 + /CD8a + /CD3 -natural killer cells. We propose that it is this immune response, rather than the chemotherapy per se, which is responsible for continued remission and that measurement of LCA in patients at completion of therapy may be used as an indicator of risk of subsequent relapse. Patients lacking this response will require further treatment, either with an allogeneic donor transplant or an alternative immunotherapeutic strategy.

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Summary:immune mediated. This is evidenced by the observations of a reduced risk of leukaemia relapse after allogeneic BMT Anti-leukaemia activity after allogeneic bone marrow when compared with autologous or syngeneic BMT. Furtransplantation has been studied extensively but its antithermore, an increased incidence of leukaemic relapse has gen specificity and effector cell phenotype remain been reported after aggressive GVHD prophylaxis with unknown. Here we report a study in three recipients of cyclosporin A, 1 or lymphocyte depletion. The association autologous bone marrow transplantation done as part between GVHD and the graft-versus-leukaemia activity of of the treatment for acute leukaemia, in whom we were allogeneic BMT is strong and has led to a number of workable to detect innate specific anti-leukaemia activity ers concluding that GVL might be inseparable from GVHD. post-transplant. One patient maintained selective cellHowever, the lymphocyte subsets responsible for GVHD mediated cytolytic activity against her autologous leuand GVL remain to be elucidated in man despite intensive kaemic cells in the absence of cytolysis of her normal efforts. leukaemia (M5). A second patient was trans-Studies of GVL in the allogeneic setting are beset with planted for acute lymphoblastic leukaemia and had the problem of alloreactivity against major and minor histodetectable anti-leukaemia activity up to 20 weeks postcompatibility antigens. A number of studies have been per-ABMT. At this point anti-leukaemia activity could no formed in the autologous setting but none have reported longer be demonstrated and the patient suffered a evidence of innate cytotoxic activity which is specific for relapse 2 weeks later. A third patient was transplanted autologous leukaemic cells. Lotzova and colleagues 6 demfor AML (M4 Eo) and lacked detectable leukaemiaonstrated that patients prior to chemotherapy had low sponspecific immune reactivity at 1, 3 and 6 months posttaneous NK activity against the erythroblastoid leukaemic ABMT. She relapsed 6 months after her ABMT and cell line K562 and no detectable activity against autologous returned to complete remission after further chemoleukaemic cells. However, both were enhanced following therapy. She commenced treatment with alpha interin vitro culture with IL-2, although the leukaemia-speciferon and regained NK function. Furthermore, she ficity of the activity remains unknown since cytotoxicity of developed high level cytolytic activity against her autoautologous normal myeloid cells by the IL-2 stimulated logous leukaemic cells in the absence of activity against cells was not studied. A recent study of CLL patients after her remission bone marrow samples. She remains in fludarabine treatment demonstrated recovery of NK cell complete remission 17 months after her initial relapse.killing of K562 targets to normal levels and, in three of This is the first report of an apparent association five patients, a specific lytic action against their autologous between in vitro leukaemia-specific cyt...

The prophylactic use of T cell depletion (TCD) strategies for the prevention of graft-versus-host disease (GVHD) following allogeneic stem cell transplantation remains widespread. Initial reports of high incidence of graft rejection after TCD BMT led to a move away from this approach but improved conditioning regimens have reduced this risk substantially. The use of TCD has also been associated with higher relapse risk post-BMT although the success of donor leukocyte infusion (DLI) as treatment for relapse has reduced this problem, especially in chronic myeloid leukaemia (CML). Currently the use of TCD BMT is increasing particularly due to the relative increase in BMT from non-related donors for whom TCD is the optimal GVHD prophylaxis. However, doubts remain over the long-term effect on the reconstituted immune system of recipients of TCD BMT, particularly in adult recipients. In this study we have undertaken a detailed sequential analysis in 23 patients who received allo-grafts from HLA-identical sibling donors after high-dose chemo/radiotherapy for acute or chronic leukaemia. Of these patients, 11 received non-manipulated grafts, five received 'partially TCD' (PTCD) and a further seven received 'fully TCD' (FTCD) bone marrow. T cell depletion was performed ex vivo by Campath-1M plus autologous serum as a source of complement. Partial TCD describes grafts with a T cell reduction of 1-2 log. Full TCD refers to grafts with a reduction of >2.5 log. The decision regarding the optimal degree of TCD was clinical and was based upon the perceived relative risk of relapse based upon the disease and remission status. All patients were monitored for up to 12 months post-BMT with regard to reconstitution of T and NK cell subsets. T cell depletion at either level was associated with a slower recovery of CD4 cells. This was most marked in the FTCD recipients and lasted throughout the period of study. CD8 cell recovery was also slower in the TCD recipients but this normalised throughout the 12 months post-BMT. The ratio of CD45RA+:CD45RO+ increased in all recipients after month 3. This suggests that a degree of extra-thymic T cell maturation can occur in recipients of allogeneic BMT. NK cell recovery was more rapid in the TCD recipients and these differences were maintained throughout the first year.

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.

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