Multiple myeloma remains an incurable cancer even with high dose chemotherapy and autologous transplantation. However, allogeneic transplantation (allotx) with a similar conditioning regimen as autotransplantation, appears curative in 25-30 percent of the patients. These data raise an important question: Is the cure rate in allotx due to a possible graft vs myeloma (GVM) effect? The infusion of allogeneic peripheral blood mononuclear cells appears curative in a proportion of patients with CML. The applicant has preliminary data showing that infusion of donor derived lymphocytes in patients with relapsed myeloma following T- cell depleted allogeneic marrow transplantation is successful in inducing sustained complete remissions. Based on these observations the applicant proposes to test the hypothesis that a GVM effect following allotx can be induced by the infusion of donor lymphocytes in refractory melanoma patients. Patients with relapsed or persistent myeloma following T-cell depleted allotx will be treated with an infusion of thymidine kinase (TK) gene- transduced lymphocytes. TK-transduction of the cells allows him to monitor the fate of the infused lymphocytes, provides him with an ability to control the lymphocyte population by ganciclovir infusion in the patient and also allows him to abrogate clinically significant GVHD making the procedure safer. Preliminary data presented show feasibility of selecting transduced primary lymphocytes which can be killed by ganciclovir in pharmacologically achievable concentrations. Patients will receive two lymphocyte infusions. The first infusion will be modulated by ganciclovir administration, on day 21 post- infusion, to test if GVM and GVHD are separable in time. There will be dose escalation if no response is seen with initial dose of lymphocytes. The applicant proposes to evaluate the clinical efficacy of lymphocyte infusion and study the biology of the GVM effect. Toward these goals the following aims will be pursued:
Specific Aim 1 : To evaluate the clinical effects of transduced-lymphocyte infusion by investigating a) anti-myeloma effects of donor T-lymphocytes, b) efficacy of ganciclovir to decrease or abrogate the clinical manifestations of severe acute and/or chronic GVHD and c) occurrence of bone marrow hypoplasia following transduced lymphocyte infusions and the role of donor lymphocyte removal with ganciclovir on its prevention.
Specific Aim 2 : To understand the biology of GVM effect by studying the phenotypic and functional characteristics of the lymphocytes involved in the process, the role of various cytokines and the relationship between GVHD and GVM effect.
