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

Blood
Iris de WeerdtArnon P Kater

Abstract

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-T cells can be exploited as autologous effector lymphocytes in CLL. Healthy control Vγ9Vδ2-T cells were activated by and had potent cytolytic activity against CLL cells. However, CLL-derived Vγ9Vδ2-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 Vγ9Vδ2-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 Vγ9Vδ2-T-cell function in CLL patients. Dysfunction of Vγ9Vδ2-T cells was fully reversible upon activation with autologous monocyte-derived dendritic cells (moDCs). moDC activation resulted in efficient expansion and predominantly yielded Vγ9Vδ2-T cells with a m...Continue Reading

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Citations

Sep 8, 2019·Nature Reviews. Drug Discovery·Zsolt SebestyenJurgen Kuball
May 8, 2020·Blood·Arnon P Kater, J Joseph Melenhorst
Nov 24, 2018·Blood·Meixiao Long
Jun 19, 2019·Nature Reviews. Cancer·Bruno Silva-SantosSeth B Coffelt
Jul 24, 2020·Cellular & Molecular Immunology·Dieter KabelitzShirin Kalyan
Apr 21, 2020·Leukemia & Lymphoma·Denise RisnikRomina Gamberale
Nov 9, 2019·Blood Reviews·Rossana MaffeiRoberto Marasca
Dec 15, 2020·Frontiers in Immunology·Valentina GriggioMarta Coscia
Jan 17, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Iris de WeerdtHans J van der Vliet
May 21, 2021·Journal for Immunotherapy of Cancer·Lingling OuXiaowei Xu
Apr 23, 2021·Haematologica·Rebecka SvanbergCarsten U Niemann
Oct 17, 2021·Journal of Experimental & Clinical Cancer Research : CR·Carol MorenoMiguel Villanueva

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