Improving CLL Vγ9Vδ2-T--cell fitness for cellular therapy by ex vivo activation and ibrutinib.

The efficacy of autologous (αβ) T-cell--based treatment strategies in chronic lymphocytic leukemia (CLL) has been modest. The Vγ9Vδ2-T cell subset consists of cytotoxic T lymphocytes with potent antilymphoma activity via a major histocompatibility complex--independent mechanism. We studied whether Vγ9Vδ2 cells can be exploited as autologous effector lymphocytes in CLL. Healthy control Vγ9Vδ2 cells were activated by and had potent cytolytic activity against CLL cells. However, CLL-derived Vγ9Vδ2 cells proved dysfunctional with respect to effector cytokine production and degranulation, despite an increased frequency of the effector-type subset. Consequently, cytotoxicity against malignant B cells was hampered. A comparable dysfunctional phenotype was observed in healthy Vγ9Vδ2 cells after coculture with CLL cells, indicating a leukemia-induced mechanism. Gene-expression profiling implicated alterations in synapse formation as a conceivable contributor to compromised Vγ9Vδ2--cell function in CLL patients. Dysfunction of Vγ9Vδ2 cells was fully reversible upon activation with autologous monocyte-derived dendritic cells (moDCs). moDC activation resulted in efficient expansion and predominantly yielded Vγ9Vδ2 cells with a memory phenotype. Furthermore, ibrutinib treatment promoted an antitumor T helper 1 (TH1) phenotype in Vγ9Vδ2 cells, and we demonstrated binding of ibrutinib to IL-2-inducible kinase (ITK) in Vγ9Vδ2 cells. Taken together, CLL-mediated dysfunction of autologous Vγ9Vδ2 cells is fully reversible, resulting in potent cytotoxicity toward CLL cells. Our data support the potential use of Vγ9Vδ2 cells as effector T cells in CLL immunotherapy and favor further exploration of combining Vγ9Vδ2-cell--based therapy with ibrutinib. [ABSTRACT FROM AUTHOR]