New strategies in allogeneic stem cell transplantation: immunotherapy using irradiated allogeneic T cells

Recipients of T cell-depleted allogeneic bone marrow transplants have incre ased risks of relapse and graft rejection. The addition of donor T cells to the TCD allograft will decrease the risk of graft rejection but will incre ase the risk of graft-versus-host disease (GVHD). Relapse of leukemia or ly mphoma following allogeneic bone marrow transplantation can be successfully treated with post-transplant infusions of donor lymphocytes, A relatively small number of donor T cells can have a profound anti-tumor effect and fac ilitate engraftment, but has an unpredictable potential for severe GVHD. An alternative to using viable immunocompetent donor immune cells to facilita te engraftment and to treat relapsed patients are donor lymphocytes that ha ve been treated to limit their ability to proliferate and cause GVHD. T cel ls treated with irradiation retain cytotoxic activity against tumor cells a nd host immune cells. We have tested the hypothesis that allogeneic donor T cells treated with low-dose irradiation will facilitate engraftment and me diate an anti-leukemia effect in a mouse model of bone marrow transplantati on. Multiple infusions of irradiated allogeneic donor lymphocytes in the pe ri-transplant period had graft-enhancing activity without resulting in GVHD , Murine recipients of irradiated allogeneic splenocytes and allogeneic bon e marrow had stable donor-derived hematopoiesis without a significant contr ibution of irradiated donor cells to the T cell compartment. Removing T cel ls from the allogeneic splenocytes prior to irradiation largely eliminated their graft facilitating activity. Based upon the promising results of the pre-clinical murine studies, we initiated a phase I clinical trial of multi ple infusions of irradiated allogeneic lymphocytes in patients who had rela psed after allogeneic BMT, Of 12 patients treated to date on this study, th ree have shown objective responses of their leukemia or lymphoma to multipl e infusions of irradiated donor lymphocytes, We have initiated a new phase I clinical study to test the efficacy of multiple infusions of irradiated a llogeneic cytotoxic T cells to facilitate engraftment in allogeneic transpl antation. Successive cohorts of patients will be transplanted with allogene ic stem cells alone, or a combination of allogeneic stem cells and increasi ng numbers of irradiated allogeneic T cells. Irradiated allogeneic lymphocy tes that retain short-term allo-specific cytotoxicity and lack the potentia l for clonal expansion in vivo can be considered as a novel form of immunot herapy with defined pharmacokinetics.