[Frontiers in Bioscience E3, 1500-1508, June 1, 2011]

Novel mobilization strategies to enhance autologous immune effector cells in multiple myeloma

Laleh Talebian1, Jia Yan Wu 1, Dawn A. Fischer1, John M. Hill1, Zbigniew M. Szczepiorkowski 2, Marc S. Ernstoff2, Charles L. Sentman4, Kenneth R. Meehan1

1Blood and Marrow Transplant Program, 2Section of Hematology and Oncology, 3Cellular Therapy Center and Transfusion Medicine Service, and the 4Department of Microbiology and Immunology, Dartmouth Hitchcock Medical Center, Dartmouth Medical School and the Norris Cotton Cancer Center, One Medical Center Drive, Lebanon, NH 03756

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Materials and methods
3.1. Immune mobilization treatment regimen
3.2. Cell lines
3.3. Flow cytometry analyses
3.4. Cytotoxicity assays
3.5. Ex vivo expansion of myeloma patients' peripheral blood mononuclear cells (pbmc): a method to enrich for NKG2D+CD8+ T Cells
3.6. CD107A expression on CD8+ T cells
3.7. Statistical analyses
4. Results
4.1. Summary of clinical results
4.2. Immune mobilization results in ample CD34+ cells and effector cell numbers
4.3. Functional abilities of the immune mobilized NKG2D+CD8+ T Cells
4.3.1. Cytotoxicity of the mobilized cells
4.3.2. Degranulation of the mobilized cells
5. Discussion
6. Acknowledgments
7. References

1. ABSTRACT

The immune system plays a critical role determining the outcomes in transplanted multiple myeloma patients, since enhanced lymphocyte recovery results in improved survival. Since mobilization regimens influence the cellular subsets collected and infused for transplant, these regimens may determine immune recovery following transplant. We hypothesized that a mobilized stem cell product harboring an increased number of lymphocytes would enhance immune recovery following autologous stem cell infusion, increase lymphocyte recovery, and improve clinical outcomes. We designed a phase I immune mobilization trial using IL-2 and growth factors to increase the number of lymphocytes within the stem cell product. This regimen efficiently mobilized CD34+ progenitor cells (median: 3.6 x 106 cells/kg; range 1.9-6.6 x 106 cells/kg) and improved the immune properties of the mobilized stem cells, including an increase in CD8+ T cells expressing an NK activating receptor called NKG2D (P< 0.004), cells that are extremely potent at killing myeloma cells using non-MHC-I restricted and TCR-independent mechanisms. Novel mobilization techniques can improve the mobilized graft and may improve clinical outcomes in myeloma patients.