) This is an application for a K23 award. The candidate, Dr. John Levine, is a junior faculty member in the Blood and Marrow Stem Cell Transplantation Program at the University of Michigan. Dr. Levine's long-term goal is to conduct clinical research in cellular immunotherapy for hematologic disorders. Dr. Levine's research project will focus on the potential role of adoptive cellular immunotherapy to prevent relapse after allogeneic stem cell transplantation. Unfortunately, conventional myeloablative allogeneic stem cell transplantation fails in many high-risk patients, particularly those who are older or have more advanced leukemia. In high-risk patients with diseases such as advanced CML or multiply relapsed or refractory acute leukemia, two to three year disease-free survival after sibling HSCT ranges from 0-29 percent. Treatment failures are often due to regimen-related toxicity, GVHD, or relapse. The candidate proposes a strategy of a low intensity conditioned transplant followed by prophylactic adoptive immunotherapy as a means of preventing relapse through GVL while minimizing risk of GVHD or regimen-related toxicity. Dr. Levine will be actively mentored by an advisory committee consisting of Dr. James Ferrara, Director of Blood and Marrow Stem Cell Transplantation, Dr. Voravit Ratanatharathorn, and Dr. Jeremy Taylor, Director of UMCC Biostatistics Core. Starting with a basic strategy of low intensity conditioning followed by prophylactic adoptive immunotherapy, samples from patients will be prospectively collected and analyzed for both leukemia and host markers of toxicity. The information gained from the prospective collection and analysis of these samples will be used to determine reasons for treatment failure, when it occurs, and thus may be helpful in the design of future treatment strategies intended to increase relapse-free survival and decrease treatment- related toxicity, especially GVHD. An especially important aspect to this project is that the approach will be adjusted based on both clinical observations of relapse and GVHD and their laboratory correlates.
The specific aims are: 1. To conduct a phase I-II trial of prophylactic cellular immunotherapy after allogeneic hematopoietic stem cell therapy using low intensity conditioning for high-risk hematological malignancies. 2A. To evaluate a panel of cytokines as surrogate markers for GVHD and correlate these with clinical outcomes during the above trial. 2B. To correlate changes in minimal residual disease with clinical outcomes during the above trial.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Study Section
Subcommittee G - Education (NCI)
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Gorelic, Lester S
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Uberti, Joseph P; Ayash, Lois; Ratanatharathorn, Voravit et al. (2005) Pilot trial on the use of etanercept and methylprednisolone as primary treatment for acute graft-versus-host disease. Biol Blood Marrow Transplant 11:680-7
Levine, John E; Uberti, Joseph P; Ayash, Lois et al. (2003) Lowered-intensity preparative regimen for allogeneic stem cell transplantation delays acute graft-versus-host disease but does not improve outcome for advanced hematologic malignancy. Biol Blood Marrow Transplant 9:189-97