Autologous hematopoietic cell transplantation (AHCT) is the standard treatment for the mostcommon type of non-Hodgkin's lymphoma, diffuse large B-cell (DLBCL), that recurs or is primarily refractoryto induction therapy, and the application of AHCT following induction therapy for mantle cell lymphoma(MCL) has been shown to prolong diseas'e remission. Despite excellent cytoreduction, relapse occurscontinuously in MCL and in about half of DLBCL cases. The idiotype unique to each B-cell lymphoma is aspecific target that we have successfully pursued for vaccination.
In Aim 1, we plan to vaccinate withidiotype-pulsed dendritic cells after AHCT in MCL, building upon our experience in developing and usingthese cells after transplantation (IND #11227), together with administration of primed T-cells, in order tooptimize the likelihood of an effective, durable immune response. We will measure the effects of vaccinationby molecular assessment of tumor burden in the peripheral blood and by determination of the immuneresponse.
In Aim 2, we will take advantage of advances in functional imaging with FDG-PET that allow thedistinction of DLBCL patients with a very high rate of relapse after standard AHCT. Utilizing existing systemsfor central PET review at Stanford University, we will define very high risk DLBCL patients on the basis ofPET-positive disease after salvage chemotherapy and plan post-AHCT immunotherapy on the basis ofgenetic randomization. In high risk DLBCL patients with HLA matched donors (Aim 2.1), we will pursue non-myeloablative allogeneic HCT utilizing a novel conditioning regimen consisting of total lymphoid irradiation(TLI) and anti-thymocyte globulin (ATG) developed in Project 4 and translated in Project 1 of this ProgramProject Grant. Our experience with this regimen suggests that graft versus tumor effects are retained but theincidence of acute graft versus host disease (GVHD) and treatment-related mortality is reduced. For thosePET-positive patients without an available donor (Aim 2.2), we plan to study cytokine-induced killer (CIK)cells as a post-AHCT immunotherapy, building on our previous experience with CIK cells in Project 3, whichhas been translated in the autologous setting in this Project. The unifying hypothesis in Project 2 is thatlymphoma-specific immunotherapy applied after cytoreduction and tumor control is established withconventional AHCT will improve event-free survival in patients with lymphoma at high risk of recurrence. Ourgoals are to develop such immune-based strategies to reduce the risk of disease relapse after AHCT thatcould be broadly applied to non-Hodgkin's lymphoma patients. Project 2 interacts with Projects 1, 3, 4, 6,and 8 and is supported by all of the Cores of this Program Project Grant.
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