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

The efficacy of autologous (ab) T-cell-based treatment strategies in chronic lymphocytic leukemia (CLL) has been modest. The V gamma 9V delta 2-T cell subset consists of cytotoxic T lymphocytes with potent antilymphoma activity via a major histocompatibility complex-independent mechanism. We studied whether V gamma 9V delta 2-T cells can be exploited as autologous effector lymphocytes in CLL. Healthy control V gamma 9V delta 2-T cells were activated by and had potent cytolytic activity against CLL cells. However, CLL-derived V gamma 9V delta 2-T 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 V gamma 9V delta 2-T 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 V gamma 9V delta 2-T-cell function in CLL patients. Dysfunction of V gamma 9V delta 2-T cells was fully reversible upon activation with autologous monocyte-derived dendritic cells (moDCs). moDC activation resulted in efficient expansion and predominantly yielded V gamma 9V delta 2-T cells with a memory phenotype. Furthermore, ibrutinib treatment promoted an antitumor T helper 1 (T(H)1) phenotype in V gamma 9V delta 2-T cells, and we demonstrated binding of ibrutinib to IL-2-inducible kinase (ITK) in V gamma 9V delta 2-T cells. Taken together, CLL-mediated dysfunction of autologous V gamma 9V delta 2-T cells is fully reversible, resulting in potent cytotoxicity toward CLL cells. Our data support the potential use of V gamma 9V delta 2-T cells as effector T cells in CLL immunotherapy and favor further exploration of combining V gamma 9V delta 2-T-cell-ased therapy with ibrutinib.