ADOPTIVE CELLULAR THERAPY AFTER ALLOGENEIC BMT

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It is now generally recognized that success of allogeneic BMT can be attributed to both anti-neoplastic effects of the ablative regimen and immunologic control of residual leukemia mediated by the donor graft. In an attempt to exploit the allogeneic immune system's ability to eradicate or suppress malignant cells, studies in Project 1 have examined the ability of IL-2 to enhance anti-leukemia immunity when administered soon after engraftment with donor marrow. There have been several recent reports of donor leukocyte infusions inducing remissions with re- establishment of donor hematopoiesis in patients with relapsed CML after allogeneic BMT. However, almost all patients who achieved remission following infusion of unseparated allogeneic lymphocytes also developed severe GVHD. The relationship between the anti-leukemic effects of donor lymphocyte infusions and GVHD as well as the mechanisms whereby donor lymphocytes induce regression of leukemia have not yet been established. These two issues will be the major focus of future studies in this project. To develop new approaches for adoptive cellular therapy, we have initiated clinical trials utilizing infusion of selected populations of donor lymphocytes. Preliminary results following infusion of CD8 depleted lymphocytes (3x10(7) CD4+ cells/kg) have demonstrated responses in patients with relapsed stable phase CML after allogeneic BMT. Responses occurred 8-12 weeks post infusion, but no patients have developed acute or chronic GVHD. One responding patient that has been fully evaluated, converted from a state of hematologic relapse to molecular remission (PCR negative) over a 2 week period. These preliminary results support the hypothesis that it will be possible to selectively induce graft vs. leukemia (GVL) without GVHD. Further studies will be undertaken to define the cellular immune mechanisms whereby donor lymphocytes mediate GVL in vivo. In conjunction with these studies we will develop methods for both selecting and expanding these immune effector cells in vivo and in vitro for use in adoptive cellular therapy. In addition to CML, these studies will also include patients with CLL. These represent biologically distinct myeloid and lymphoid malignancies but both are diseases in which sensitive PCR techniques can be used to identify patients with persistent residual disease and to monitor the effects of immune therapy. Moreover, as progress is made in the treatment of patients with relapsed disease, further studies will be initiated in patients with minimal residual disease prior to the development of clinical relapse. 3 Specific Aims are proposed: 1. Development of clinical trials of adoptive cellular therapy after allogeneic BMT. 2. Characterization of the graft versus leukemia (GVL) response in patients receiving donor lymphocyte infusions after allogeneic BMT. 3. Development of new approaches for in vitro selection and expansion of anti-leukemia effector cells for adoptive cellular therapy.