Improving CLL V{gamma}9V{delta}2-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 V9V2-T cell subset consists of cytotoxic T lymphocytes with potent antilymphoma activity via a major histocompatibility complex–independent mechanism. We studied whether V9V2-T cells can be exploited as autologous effector lymphocytes in CLL. Healthy control V9V2-T cells were activated by and had potent cytolytic activity against CLL cells. However, CLL-derived V9V2-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 V9V2-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 V9V2-T–cell function in CLL patients. Dysfunction of V9V2-T cells was fully reversible upon activation with autologous monocyte-derived dendritic cells (moDCs). moDC activation resulted in efficient expansion and predominantly yielded V9V2-T cells with a memory phenotype. Furthermore, ibrutinib treatment promoted an antitumor T helper 1 (TH1) phenotype in V9V2-T cells, and we demonstrated binding of ibrutinib to IL-2-inducible kinase (ITK) in V9V2-T cells. Taken together, CLL-mediated dysfun...

Source: Blood - November 22, 2018 Category: Hematology Authors: de Weerdt, I., Hofland, T., Lameris, R., Endstra, S., Jongejan, A., Moerland, P. D., de Bruin, R. C. G., Remmerswaal, E. B. M., ten Berge, I. J. M., Liu, N., van der Stelt, M., Faber, L. M., Levin, M.-D., Eldering, E., Tonino, S. H., de Gruijl, T. D., van Tags: Immunobiology and Immunotherapy, Lymphoid Neoplasia Source Type: research