With the support of this Program Project we have undertaken a series of clinical trials and laboratory studies in patients undergoing allogeneic BMT. In over 250 patients who received CD6 depleted marrow, we have demonstrated that this method effectively prevents GVHD in >80% of patients with HLA matched sibling donors without compromising engraftment. This treatment eliminates the need for prophylactic immune suppressive agents in the great majority of patients and reduces the morbidity and mortality of allogeneic BMT. Although the risk of relapse after BMT has been very low in patients with acute leukemia transplanted in the early phases of their disease. the risk of relapse remains high in patients with GML and with advanced leukemia. The fact that patients can undergo allogeneic BMT without GVHD and without exogenous immune suppression has allowed us to carry out clinical trials to develop novel methods for enhancing and modulating immune function after BMT. These studies have focused on lL-2 and have demonstrated a dramatic and consistent expansion in the number and function of natural killer (Nk) cells in vivo during prolonged periods of lL-2 administration. IL-2 administration has not resulted in GVHD but does appear to have reduced the risk of relapse. These studies therefore suggest that it may be possible to selectively enhance graft-versus-leukemia immunity without enhancing GVHD. Future studies in this program project will continue to include both clinical and laboratory studies to evaluate the effects of treatment and to develop new strategies for further clinical trials. We will continue these efforts as an integrated team which includes both clinician-scientists and laboratory investigators in an effort to utilize the latest advances in basic immunology' to assist in the development of clinical trials. As in the past, clinical trials will focus on immune modulation in patients with leukemia, but our results will be applicable to other diseases and settings in which immune deficiency are critical problems and where interventions to enhance immune function are needed. In Project 1, we will continue to develop new strategies to enhance immune function following allogeneic BMT. We will also apply our previous results to patients undergoing allogeneic BMT from unrelated donors to test the hypothesis that selective T cell depletion combined with selective pre-transplant immune suppression will allow engraftment with a significantly lower incidence of GVHD. In Project 2, we will continue to define the cellular and molecular basis for the profound immune deficiency that occurs in all patients during immune reconstitution. Previous efforts in this project have identified several novel pathways with intrinsic functional defects and future studies will be directed to better characterize the biochemical and molecular nature of these defects. In Project 3, we have previously used sensitive molecular techniques to identify patients with minimal residual disease after BMT and have demonstrated that the vast majority of patients with CML have detectable leukemia in the first 6 months post BMT. In many of these patients, immunologic mechanisms are subsequently able to eliminate or suppress residual leukemia but others are at high risk for relapse. The ability to identify these individuals months to years before relapse will allow us to undertake clinical trials of adoptive cellular therapy in these individuals. Interesting preliminary results suggest that, as with cytokines such as lL-2, cellular therapy approaches will be able to selectively induce GVL without GVHD and further efforts will be made to develop a better understanding of the immunologic basis for this phenomenon.
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