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

  • Cell. 2018 Dec 13;175(7):1731-1743.e13. doi: 10.1016/j.cell.2018.10.014.
Pascale André  1 ,  Caroline Denis  2 ,  Caroline Soulas  2 ,  Clarisse Bourbon-Caillet  2 ,  Julie Lopez  2 ,  Thomas Arnoux  2 ,  Mathieu Bléry  2 ,  Cécile Bonnafous  2 ,  Laurent Gauthier  2 ,  Ariane Morel  2 ,  Benjamin Rossi  2 ,  Romain Remark  2 ,  Violette Breso  2 ,  Elodie Bonnet  2 ,  Guillaume Habif  2 ,  Sophie Guia  3 ,  Ana Ines Lalanne  4 ,  Caroline Hoffmann  5 ,  Olivier Lantz  4 ,  Jérôme Fayette  6 ,  Agnès Boyer-Chammard  2 ,  Robert Zerbib  2 ,  Pierre Dodion  2 ,  Hormas Ghadially  7 ,  Maria Jure-Kunkel  8 ,  Yannis Morel  2 ,  Ronald Herbst  8 ,  Emilie Narni-Mancinelli  3 ,  Roger B Cohen  9 ,  Eric Vivier  10
Affiliations
  • 1. Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France. Electronic address: [email protected].
  • 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: [email protected].
PMID: 30503213 DOI: 10.1016/j.cell.2018.10.014
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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