Abstract
Current strategies in cellular immunotherapy of cancer and viral infections include the adoptive transfer of T cell receptor (TCR) and chimeric antigen receptor engineered T cells. When using transient RNA expression systems in clinical studies, multiple infusions with receptor-redirected T cells appear necessary. However, in allogeneic hematopoietic stem-cell transplantation, repeated transfer ...
Abstract
Current strategies in cellular immunotherapy of cancer and viral infections include the adoptive transfer of T cell receptor (TCR) and chimeric antigen receptor engineered T cells. When using transient RNA expression systems in clinical studies, multiple infusions with receptor-redirected T cells appear necessary. However, in allogeneic hematopoietic stem-cell transplantation, repeated transfer of donor-derived T cells increases the risk of alloreactive graft-versus-host disease. We investigated naive-derived (T-N), memory-derived (T-M), and Epstein Barr virus-specific (T-EBV) CD8(+) T cell subsets for alloreactivity upon redirection with RNA encoding a cytomegalovirus-specific model TCR. We observed that alloreactivity to human leukocyte antigen (HLA)-mismatched hematopoietic cells developed at much stronger levels in T-N compared with T-M or T-EBV populations in cytokine-release and cytotoxicity assays. Cytomegalovirus-specific effector function was higher in TCR-transfected T-EBV and T-M over T-N cells. To measure alloreactivity in vivo, we reconstituted NOD/SCBD/IL-2R gamma c(null) mice with human CD34(+) stem cells and adoptively transferred them with CD8(+) T cell subsets previously stimulated against cells of the HLA-mismatched stem-cell donor. T-N cells showed a significant ability to eliminate CD34-derived hematopoietic cells, which was not found with T-M and TEBv cells. This reduced alloreactive potential along with strong effector function upon receptor RNA engineering makes CD8(+) memory and EBV-specific T cells advantageous tools in adoptive immunotherapy after allogeneic transplantation. (C) 2014 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.
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