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Translational Cancer Mechanisms and Therapy

A Bispecific Single-Domain Antibody Boosts Autologous Vγ9Vδ2-T Cell Responses Toward CD1d in Chronic Lymphocytic Leukemia

Iris de Weerdt, Roeland Lameris, Jurjen M. Ruben, Renate de Boer, Jan Kloosterman, Lisa A. King, Mark-David Levin, Paul W.H.I. Parren, Tanja D. de Gruijl, Arnon P. Kater and Hans J. van der Vliet
Iris de Weerdt
1Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
2Department of Hematology, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
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Roeland Lameris
1Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
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Jurjen M. Ruben
1Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
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  • ORCID record for Jurjen M. Ruben
Renate de Boer
3Department of Experimental Immunology, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
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Jan Kloosterman
1Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
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Lisa A. King
1Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
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Mark-David Levin
4Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, the Netherlands.
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  • ORCID record for Mark-David Levin
Paul W.H.I. Parren
5Lava Therapeutics, Utrecht, the Netherlands.
6Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
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Tanja D. de Gruijl
1Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
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Arnon P. Kater
2Department of Hematology, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
7Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, the Netherlands.
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Hans J. van der Vliet
1Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
5Lava Therapeutics, Utrecht, the Netherlands.
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  • For correspondence: h.vandervliet@lavatherapeutics.com jj.vandervliet@amsterdamumc.nl
DOI: 10.1158/1078-0432.CCR-20-4576
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Abstract

Purpose: Although considerable progress has been made with autologous T cell–based therapy in B-cell malignancies, application in chronic lymphocytic leukemia (CLL) lags behind due to disappointing response rates as well as substantial toxicity that is of particular concern in the elderly CLL population. Vγ9Vδ2-T cells form a conserved T-cell subset with strong intrinsic immunotherapeutic potential, largely because of their capacity to be triggered by phosphoantigens that can be overproduced by CLL and other malignant cells. Specific activation of Vγ9Vδ2-T cells by a bispecific antibody may improve the efficacy and toxicity of autologous T-cell–based therapy in CLL.

Experimental Design: We evaluated CD1d expression in a cohort of 78 untreated patients with CLL and generated and functionally characterized a CD1d-specific Vγ9Vδ2-T cell engager based on single-domain antibodies (VHH).

Results: CD1d was expressed by CLL in the majority of patients, particularly in patients with advanced disease. The CD1d-specific Vγ9Vδ2-T cell engager induced robust activation and degranulation of Vγ9Vδ2-T cells, enabling Vγ9Vδ2-T cells from patients with CLL to lyse autologous leukemic cells at low effector-to-target ratios. Expression of CD1d on CLL cells is upregulated by all-trans retinoic acid, and sensitizes the malignant cells to bispecific VHH-induced lysis. Furthermore, we provide evidence that the Vγ9Vδ2-T cell receptor retains responsiveness to phosphoantigens when the bispecific VHH is bound, and aminobisphosphonates can therefore enhance bispecific Vγ9Vδ2-T cell engager–mediated tumor-specific killing.

Conclusions: Collectively, our data demonstrate the immunotherapeutic potential of this novel CD1d-specific Vγ9Vδ2-T cell engager in CLL.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2021;XX:XX–XX

  • Received November 24, 2020.
  • Revision received December 30, 2020.
  • Accepted January 13, 2021.
  • Published first January 15, 2021.
  • ©2021 American Association for Cancer Research.
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This OnlineFirst version was published on February 19, 2021
doi: 10.1158/1078-0432.CCR-20-4576

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A Bispecific Single-Domain Antibody Boosts Autologous Vγ9Vδ2-T Cell Responses Toward CD1d in Chronic Lymphocytic Leukemia
Iris de Weerdt, Roeland Lameris, Jurjen M. Ruben, Renate de Boer, Jan Kloosterman, Lisa A. King, Mark-David Levin, Paul W.H.I. Parren, Tanja D. de Gruijl, Arnon P. Kater and Hans J. van der Vliet
Clin Cancer Res February 19 2021 DOI: 10.1158/1078-0432.CCR-20-4576

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A Bispecific Single-Domain Antibody Boosts Autologous Vγ9Vδ2-T Cell Responses Toward CD1d in Chronic Lymphocytic Leukemia
Iris de Weerdt, Roeland Lameris, Jurjen M. Ruben, Renate de Boer, Jan Kloosterman, Lisa A. King, Mark-David Levin, Paul W.H.I. Parren, Tanja D. de Gruijl, Arnon P. Kater and Hans J. van der Vliet
Clin Cancer Res February 19 2021 DOI: 10.1158/1078-0432.CCR-20-4576
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