Allogeneic blood or marrow transplantation, or alloBMT, is a potentially curative therapy for a wide variety ofchemotherapy-incurable hematologic malignancies. However, the overall success of alloBMT remainsconstrained by procedure-related toxicity, which limits eligibility to relatively young patients withhistocompatible donors, and by lack of efficacy, manifested as post-transplantation progression of theunderlying disease. In the previous funding period, we had conducted clinical trials of post-transplantation,high dose cyclophosphamide (Cy) to reduce toxicity by promoting bi-directional transplantation tolerancewhile sparing stem cells and preserving immune responses to infection. A major goal of Aim 1 of the currentproposal is to characterize in detail the mechanisms of Cy-induced tolerance and the effect of post-transplantation Cy on regulatory T cells, antigen-presenting cells, and antigen-specific T cells. To increasethe anti-tumor efficacy of allogeneic T cell infusions, we will focus on inducing tumor-specific immunity by twodistinct approaches. The first approach is to administer cell-based tumor vaccines, with or without donorlymphocyte infusion, after nonmyeloablative allogeneic stem cell transplantation (Aim 2). The secondapproach will be to treat non-BMT candidates with Cy followed by transiently engrafting allogeneiclymphocytes so as to induce an 'allogeneic effect' that breaks tolerance in the patient's tumor-specific T cells(Aim 3). We will also study the capacity of tumor-targeted therapies to augment the effect of administeringallogeneic lymphocytes in this context (Aim 4). The ultimate goals of this project are to establish post-transplantation Cy as the gold standard of GVHD prophylaxis and to extend the application of adoptivecellular immunotherapy with allogeneic T cells outside of the context of alloBMT.Cancer is now the leading killer of Americans under the age of 85. Transfusions of white blood cells from ahealthy donor can actually make a cancer shrink, but this is a dangerous treatment that doesn't always work.The goal of this project is to find ways to make white blood cell transfusions safer and more effective in thetreatment of cancer.
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