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Cell. 2018 Dec 13;175(7):1731-1743.e13. doi: 10.1016/j.cell.2018.10.014. Epub 2018 Nov 29.

Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells.

Author information

1
Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France. Electronic address: pascale.andre@innate-pharma.fr.
2
Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France.
3
Aix Marseille Université, INSERM, CNRS, Centre d'Immunologie de Marseille-Luminy, 13009 Marseille, France.
4
Unité INSERM U932, Immunité et Cancer, Institut Curie, 75248 Paris Cedex 5, France.
5
Unité INSERM U932, Immunité et Cancer, Institut Curie, 75248 Paris Cedex 5, France; Service ORL et Chirurgie cervico-faciale, Institut Curie, 75248 Paris Cedex 5, France.
6
Centre Léon Bérard, 69008 Lyon, France.
7
MedImmune, Ltd., Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, UK.
8
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
9
Abramson Cancer Center, 3400 Civic Center Boulevard West Pavilion, Philadelphia, PA, USA.
10
Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France; Aix Marseille Université, INSERM, CNRS, Centre d'Immunologie de Marseille-Luminy, 13009 Marseille, France; Service d'Immunologie, Marseille Immunopole, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, 13005 Marseille, France. Electronic address: vivier@ciml.univ-mrs.fr.

Abstract

Checkpoint inhibitors have revolutionized cancer treatment. However, only a minority of patients respond to these immunotherapies. Here, we report that blocking the inhibitory NKG2A receptor enhances tumor immunity by promoting both natural killer (NK) and CD8+ T cell effector functions in mice and humans. Monalizumab, a humanized anti-NKG2A antibody, enhanced NK cell activity against various tumor cells and rescued CD8+ T cell function in combination with PD-x axis blockade. Monalizumab also stimulated NK cell activity against antibody-coated target cells. Interim results of a phase II trial of monalizumab plus cetuximab in previously treated squamous cell carcinoma of the head and neck showed a 31% objective response rate. Most common adverse events were fatigue (17%), pyrexia (13%), and headache (10%). NKG2A targeting with monalizumab is thus a novel checkpoint inhibitory mechanism promoting anti-tumor immunity by enhancing the activity of both T and NK cells, which may complement first-generation immunotherapies against cancer.

KEYWORDS:

CD8(+) T cells; cancer immunotherapy; immunce checkpoint inhibitor; inhibitory receptors; lymphocytes; natural killer cells; therapeutic monoclonal antibodies

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