Combining dasatinib with dexamethasone long-term leads to maintenance of antiviral and antileukemia specific cytotoxic T cell responses in vitro

Maintaining graft versus leukemia (GvL) and antivirus responses of cytotoxic T cells (CTLs) while suppressing graft-versus-host disease (GvHD) remains a challenge after allogeneic bone marrow transplantation. Clinical observations indicate that combining glucocorticoids with multi-tyrosine-kinase inhibitors could be a successful therapeutic approach. We and others have shown that the BCR-ABL/SRC kinase inhibitor dasatinib may enhance or suppress T cells in vitro. In this report, we evaluated combination effects of dasatinib and dexamethasone on CD3(+) and virus-specific CD8(+) T cells directly ex vivo and on antigen-specific leukemia-reactive and alloreactive CD8(+) T cell clones. Functional outcomes assessed included cytokine production (IL-2, IFN-gamma, TNF-alpha), degranulation (CD107a/b), activation (CD69 upregulation), proliferation, apoptosis and necrosis induction, and signal transduction. Overall, helper CD4(+) T cells were more sensitive to inhibitory effects of the drug combination than cytotoxic CD8(+) T cells and were more naive than memory T cell subsets. Of note, synergistic inhibitory effects occurred in different memory but not in naive T cell subsets. The drug combination inhibited virus-specific CD8(+) T cell proliferation, but left cytokine production and degranulation unaltered, which may be due to the viral memory subset composition. Dasatinib rather hampered IFN-gamma secretion and cytotoxic activity of human leukocyte antigen (HLA)-reactive CTLs, whereas effector functions of leukemia-reactive CTLs were maintained or enhanced when applied long term. Our data suggest that dasatinib might modulate GvL-differently than GvHD-promoting CTLs and provide a rationale to explore the drug combination further to treat GvHD while preserving GvL and antiviral CTL responses. (C) 2013 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.