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

Iris de Weerdt, Tom Hofland, Roeland Lameris, Sanne Endstra, Aldo Jongejan, Perry D Moerland, Renee C G de Bruin, Ester B M Remmerswaal, Ineke J M Ten Berge, Nora Liu, Mario van der Stelt, Laura M Faber, Mark-David Levin, Eric Eldering, Sanne H Tonino, Tanja D de Gruijl, Hans J van der Vliet, Arnon P Kater

Research output: Contribution to journalArticleAcademicpeer-review

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 memory phenotype. Furthermore, ibrutinib treatment promoted an antitumor T helper 1 (TH1) phenotype in Vγ9Vδ2-T cells, and we demonstrated binding of ibrutinib to IL-2-inducible kinase (ITK) in Vγ9Vδ2-T cells. Taken together, CLL-mediated dysfunction of autologous Vγ9Vδ2-T cells is fully reversible, resulting in potent cytotoxicity toward CLL cells. Our data support the potential use of Vγ9Vδ2-T cells as effector T cells in CLL immunotherapy and favor further exploration of combining Vγ9Vδ2-T-cell-based therapy with ibrutinib.

Original languageEnglish
Pages (from-to)2260-2272
Number of pages13
JournalBlood
Volume132
Issue number21
DOIs
Publication statusPublished - 22 Nov 2018

Cite this

de Weerdt, Iris ; Hofland, Tom ; Lameris, Roeland ; Endstra, Sanne ; Jongejan, Aldo ; Moerland, Perry D ; de Bruin, Renee C G ; Remmerswaal, Ester B M ; Ten Berge, Ineke J M ; Liu, Nora ; van der Stelt, Mario ; Faber, Laura M ; Levin, Mark-David ; Eldering, Eric ; Tonino, Sanne H ; de Gruijl, Tanja D ; van der Vliet, Hans J ; Kater, Arnon P. / Improving CLL Vγ9Vδ2-T-cell fitness for cellular therapy by ex vivo activation and ibrutinib. In: Blood. 2018 ; Vol. 132, No. 21. pp. 2260-2272.
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title = "Improving CLL Vγ9Vδ2-T-cell fitness for cellular therapy by ex vivo activation and ibrutinib",
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 memory phenotype. Furthermore, ibrutinib treatment promoted an antitumor T helper 1 (TH1) phenotype in Vγ9Vδ2-T cells, and we demonstrated binding of ibrutinib to IL-2-inducible kinase (ITK) in Vγ9Vδ2-T cells. Taken together, CLL-mediated dysfunction of autologous Vγ9Vδ2-T cells is fully reversible, resulting in potent cytotoxicity toward CLL cells. Our data support the potential use of Vγ9Vδ2-T cells as effector T cells in CLL immunotherapy and favor further exploration of combining Vγ9Vδ2-T-cell-based therapy with ibrutinib.",
author = "{de Weerdt}, Iris and Tom Hofland and Roeland Lameris and Sanne Endstra and Aldo Jongejan and Moerland, {Perry D} and {de Bruin}, {Renee C G} and Remmerswaal, {Ester B M} and {Ten Berge}, {Ineke J M} and Nora Liu and {van der Stelt}, Mario and Faber, {Laura M} and Mark-David Levin and Eric Eldering and Tonino, {Sanne H} and {de Gruijl}, {Tanja D} and {van der Vliet}, {Hans J} and Kater, {Arnon P}",
note = "{\circledC} 2018 by The American Society of Hematology.",
year = "2018",
month = "11",
day = "22",
doi = "10.1182/blood-2017-12-822569",
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de Weerdt, I, Hofland, T, Lameris, R, Endstra, S, Jongejan, A, Moerland, PD, de Bruin, RCG, Remmerswaal, EBM, Ten Berge, IJM, Liu, N, van der Stelt, M, Faber, LM, Levin, M-D, Eldering, E, Tonino, SH, de Gruijl, TD, van der Vliet, HJ & Kater, AP 2018, 'Improving CLL Vγ9Vδ2-T-cell fitness for cellular therapy by ex vivo activation and ibrutinib' Blood, vol. 132, no. 21, pp. 2260-2272. https://doi.org/10.1182/blood-2017-12-822569

Improving CLL Vγ9Vδ2-T-cell fitness for cellular therapy by ex vivo activation and ibrutinib. / de Weerdt, Iris; Hofland, Tom; Lameris, Roeland; Endstra, Sanne; Jongejan, Aldo; Moerland, Perry D; de Bruin, Renee C G; Remmerswaal, Ester B M; Ten Berge, Ineke J M; Liu, Nora; van der Stelt, Mario; Faber, Laura M; Levin, Mark-David; Eldering, Eric; Tonino, Sanne H; de Gruijl, Tanja D; van der Vliet, Hans J; Kater, Arnon P.

In: Blood, Vol. 132, No. 21, 22.11.2018, p. 2260-2272.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Improving CLL Vγ9Vδ2-T-cell fitness for cellular therapy by ex vivo activation and ibrutinib

AU - de Weerdt, Iris

AU - Hofland, Tom

AU - Lameris, Roeland

AU - Endstra, Sanne

AU - Jongejan, Aldo

AU - Moerland, Perry D

AU - de Bruin, Renee C G

AU - Remmerswaal, Ester B M

AU - Ten Berge, Ineke J M

AU - Liu, Nora

AU - van der Stelt, Mario

AU - Faber, Laura M

AU - Levin, Mark-David

AU - Eldering, Eric

AU - Tonino, Sanne H

AU - de Gruijl, Tanja D

AU - van der Vliet, Hans J

AU - Kater, Arnon P

N1 - © 2018 by The American Society of Hematology.

PY - 2018/11/22

Y1 - 2018/11/22

N2 - 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 memory phenotype. Furthermore, ibrutinib treatment promoted an antitumor T helper 1 (TH1) phenotype in Vγ9Vδ2-T cells, and we demonstrated binding of ibrutinib to IL-2-inducible kinase (ITK) in Vγ9Vδ2-T cells. Taken together, CLL-mediated dysfunction of autologous Vγ9Vδ2-T cells is fully reversible, resulting in potent cytotoxicity toward CLL cells. Our data support the potential use of Vγ9Vδ2-T cells as effector T cells in CLL immunotherapy and favor further exploration of combining Vγ9Vδ2-T-cell-based therapy with ibrutinib.

AB - 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 memory phenotype. Furthermore, ibrutinib treatment promoted an antitumor T helper 1 (TH1) phenotype in Vγ9Vδ2-T cells, and we demonstrated binding of ibrutinib to IL-2-inducible kinase (ITK) in Vγ9Vδ2-T cells. Taken together, CLL-mediated dysfunction of autologous Vγ9Vδ2-T cells is fully reversible, resulting in potent cytotoxicity toward CLL cells. Our data support the potential use of Vγ9Vδ2-T cells as effector T cells in CLL immunotherapy and favor further exploration of combining Vγ9Vδ2-T-cell-based therapy with ibrutinib.

U2 - 10.1182/blood-2017-12-822569

DO - 10.1182/blood-2017-12-822569

M3 - Article

VL - 132

SP - 2260

EP - 2272

JO - Blood

JF - Blood

SN - 0006-4971

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ER -