A bispecific nanobody approach to leverage the potent and widely applicable tumor cytolytic capacity of Vγ9Vδ2-T cells

Renée C.G. de Bruin, John P. Veluchamy, Sinéad M. Lougheed, Famke L. Schneiders, Silvia Lopez-Lastra, Roeland Lameris, Anita G. Stam, Zsolt Sebestyen, Jürgen Kuball, Carla F.M. Molthoff, Erik Hooijberg, Rob C. Roovers, James P.Di Santo, Paul M.P. van Bergen en Henegouwen, Henk M.W. Verheul, Tanja D. de Gruijl, Hans J. van der Vliet

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Though Vγ9Vδ2-T cells constitute only a small fraction of the total T cell population in human peripheral blood, they play a vital role in tumor defense and are therefore of major interest to explore for cancer immunotherapy. Vγ9Vδ2-T cell-based cancer immunotherapeutic approaches developed so far have been generally well tolerated and were able to induce significant clinical responses. However, overall results were inconsistent, possibly due to the fact that these strategies induced systemic activation of Vγ9Vδ2-T cells without preferential accumulation and targeted activation in the tumor. Here we show that a novel bispecific nanobody-based construct targeting both Vγ9Vδ2-T cells and EGFR induced potent Vγ9Vδ2-T cell activation and subsequent tumor cell lysis both in vitro and in an in vivo mouse xenograft model. Tumor cell lysis was independent of KRAS and BRAF tumor mutation status and common Vγ9Vδ2-T cell receptor sequence variations. In combination with the conserved monomorphic nature of the Vγ9Vδ2-TCR and the facile replacement of the tumor-specific nanobody, this immunotherapeutic approach can be applied to a large group of cancer patients.

Original languageEnglish
JournalOncoImmunology
DOIs
Publication statusAccepted/In press - 17 Oct 2017

Cite this

de Bruin, Renée C.G. ; Veluchamy, John P. ; Lougheed, Sinéad M. ; Schneiders, Famke L. ; Lopez-Lastra, Silvia ; Lameris, Roeland ; Stam, Anita G. ; Sebestyen, Zsolt ; Kuball, Jürgen ; Molthoff, Carla F.M. ; Hooijberg, Erik ; Roovers, Rob C. ; Santo, James P.Di ; van Bergen en Henegouwen, Paul M.P. ; Verheul, Henk M.W. ; de Gruijl, Tanja D. ; van der Vliet, Hans J. / A bispecific nanobody approach to leverage the potent and widely applicable tumor cytolytic capacity of Vγ9Vδ2-T cells. In: OncoImmunology. 2017.
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title = "A bispecific nanobody approach to leverage the potent and widely applicable tumor cytolytic capacity of Vγ9Vδ2-T cells",
abstract = "Though Vγ9Vδ2-T cells constitute only a small fraction of the total T cell population in human peripheral blood, they play a vital role in tumor defense and are therefore of major interest to explore for cancer immunotherapy. Vγ9Vδ2-T cell-based cancer immunotherapeutic approaches developed so far have been generally well tolerated and were able to induce significant clinical responses. However, overall results were inconsistent, possibly due to the fact that these strategies induced systemic activation of Vγ9Vδ2-T cells without preferential accumulation and targeted activation in the tumor. Here we show that a novel bispecific nanobody-based construct targeting both Vγ9Vδ2-T cells and EGFR induced potent Vγ9Vδ2-T cell activation and subsequent tumor cell lysis both in vitro and in an in vivo mouse xenograft model. Tumor cell lysis was independent of KRAS and BRAF tumor mutation status and common Vγ9Vδ2-T cell receptor sequence variations. In combination with the conserved monomorphic nature of the Vγ9Vδ2-TCR and the facile replacement of the tumor-specific nanobody, this immunotherapeutic approach can be applied to a large group of cancer patients.",
keywords = "cancer, EGFR, gamma delta T cells, immunotherapy, nanobody, single-domain antibody fragment, tumor, VHH",
author = "{de Bruin}, {Ren{\'e}e C.G.} and Veluchamy, {John P.} and Lougheed, {Sin{\'e}ad M.} and Schneiders, {Famke L.} and Silvia Lopez-Lastra and Roeland Lameris and Stam, {Anita G.} and Zsolt Sebestyen and J{\"u}rgen Kuball and Molthoff, {Carla F.M.} and Erik Hooijberg and Roovers, {Rob C.} and Santo, {James P.Di} and {van Bergen en Henegouwen}, {Paul M.P.} and Verheul, {Henk M.W.} and {de Gruijl}, {Tanja D.} and {van der Vliet}, {Hans J.}",
year = "2017",
month = "10",
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A bispecific nanobody approach to leverage the potent and widely applicable tumor cytolytic capacity of Vγ9Vδ2-T cells. / de Bruin, Renée C.G.; Veluchamy, John P.; Lougheed, Sinéad M.; Schneiders, Famke L.; Lopez-Lastra, Silvia; Lameris, Roeland; Stam, Anita G.; Sebestyen, Zsolt; Kuball, Jürgen; Molthoff, Carla F.M.; Hooijberg, Erik; Roovers, Rob C.; Santo, James P.Di; van Bergen en Henegouwen, Paul M.P.; Verheul, Henk M.W.; de Gruijl, Tanja D.; van der Vliet, Hans J.

In: OncoImmunology, 17.10.2017.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - A bispecific nanobody approach to leverage the potent and widely applicable tumor cytolytic capacity of Vγ9Vδ2-T cells

AU - de Bruin, Renée C.G.

AU - Veluchamy, John P.

AU - Lougheed, Sinéad M.

AU - Schneiders, Famke L.

AU - Lopez-Lastra, Silvia

AU - Lameris, Roeland

AU - Stam, Anita G.

AU - Sebestyen, Zsolt

AU - Kuball, Jürgen

AU - Molthoff, Carla F.M.

AU - Hooijberg, Erik

AU - Roovers, Rob C.

AU - Santo, James P.Di

AU - van Bergen en Henegouwen, Paul M.P.

AU - Verheul, Henk M.W.

AU - de Gruijl, Tanja D.

AU - van der Vliet, Hans J.

PY - 2017/10/17

Y1 - 2017/10/17

N2 - Though Vγ9Vδ2-T cells constitute only a small fraction of the total T cell population in human peripheral blood, they play a vital role in tumor defense and are therefore of major interest to explore for cancer immunotherapy. Vγ9Vδ2-T cell-based cancer immunotherapeutic approaches developed so far have been generally well tolerated and were able to induce significant clinical responses. However, overall results were inconsistent, possibly due to the fact that these strategies induced systemic activation of Vγ9Vδ2-T cells without preferential accumulation and targeted activation in the tumor. Here we show that a novel bispecific nanobody-based construct targeting both Vγ9Vδ2-T cells and EGFR induced potent Vγ9Vδ2-T cell activation and subsequent tumor cell lysis both in vitro and in an in vivo mouse xenograft model. Tumor cell lysis was independent of KRAS and BRAF tumor mutation status and common Vγ9Vδ2-T cell receptor sequence variations. In combination with the conserved monomorphic nature of the Vγ9Vδ2-TCR and the facile replacement of the tumor-specific nanobody, this immunotherapeutic approach can be applied to a large group of cancer patients.

AB - Though Vγ9Vδ2-T cells constitute only a small fraction of the total T cell population in human peripheral blood, they play a vital role in tumor defense and are therefore of major interest to explore for cancer immunotherapy. Vγ9Vδ2-T cell-based cancer immunotherapeutic approaches developed so far have been generally well tolerated and were able to induce significant clinical responses. However, overall results were inconsistent, possibly due to the fact that these strategies induced systemic activation of Vγ9Vδ2-T cells without preferential accumulation and targeted activation in the tumor. Here we show that a novel bispecific nanobody-based construct targeting both Vγ9Vδ2-T cells and EGFR induced potent Vγ9Vδ2-T cell activation and subsequent tumor cell lysis both in vitro and in an in vivo mouse xenograft model. Tumor cell lysis was independent of KRAS and BRAF tumor mutation status and common Vγ9Vδ2-T cell receptor sequence variations. In combination with the conserved monomorphic nature of the Vγ9Vδ2-TCR and the facile replacement of the tumor-specific nanobody, this immunotherapeutic approach can be applied to a large group of cancer patients.

KW - cancer

KW - EGFR

KW - gamma delta T cells

KW - immunotherapy

KW - nanobody

KW - single-domain antibody fragment

KW - tumor

KW - VHH

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U2 - 10.1080/2162402X.2017.1375641

DO - 10.1080/2162402X.2017.1375641

M3 - Article

JO - OncoImmunology

JF - OncoImmunology

SN - 2162-4011

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