Project 2. Advancing Stem Cell Transplantation for CML- Chemosensitization and Enhancing Graft-vs.-Leukemia Effects, Richard Champlin, M.D., Project Leader Allogeneic stem cell transplantafion is a potentially curative treatment for CML, and remains the only effective treatment for pafients resistant to tyrosine kinase inhibitors. This project advances therapeutic concepts and preclinical studies from the projects into human clinical trials involving stem cell transplantafion. The goal of this project is to improve the safety and effectiveness of reduced intensity preparafive regimens and cellular therapy involving NK cells or antigen specific T-cells, post transplant therapy with hypomethylating agents (collaboration with project 6), and chemosensitization of the leukemia by interference with supportive interactions with the bone marrow microenvironment (collaborafion with Project 3). The primary goal is to enhance the rate of molecular complete remission induced by nonmyeloablative stem cell transplantation which is a prerequisite for cure ofthe disease.
The Specific Aims are the following: 1. Test the hypothesis that addition of haploidentical alloreactive NK cells to the busulfan fludarabine nonmyeloablative preparative regimen will increase the rate of molecular complete remission. Correlative studies will examine KIR:KIR ligand expression and NK cell cytotoxicity against CML cells in vitro. 2. Test the hypothesis that post transplant hypomethylating therapy with 5-azacitidine can increase the rate of molecular complete remission in patients with CML in collaboration with Dr. Issa in project 6. Correlative studies include pharmacodynamic studies of hypomethylation and effects on immune reconstitution. 3. Test the hypothesis that PRI speciflc cytotoxic T-cells can induce molecular complete remission in pafients with CML and residual or recurrent disease post transplant. Correlafive studies will examine anfileukemic immune response and persistence ofthe transferred cells. 4. Test the hypothesis that interference with CXCR4-SDF-1 interacfions using systemic G-CSF and plerixafor treatment will enhance antileukemia effects of busulfan-fludarabine and stem cell transplantafion, in collaboration with Drs. Andreeff and Konopleva in Project 3. Correlative studies will examine the biologic effects on leukemia cells.
Despite treatment with tyrosine kinase inhibitors, most patients have detectable disease and overt resistance may develop. Allogeneic stem cell transplant Is a potenfially curafive option. This project evaluates innovative strategies to Increase the efficacy and reduce the risks of non-myeloablative allogeneic stem cell transplantafion.
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