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

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      1 , , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 2 , 3 , 3 , 4 , 3 , 5 , 1 , 1 , 1 , 6 , 7 , 1 , 7 , 2 , 8 , 1 , 2 , 9 , 10 , ∗∗
      Cell
      Cell Press
      immunce checkpoint inhibitor, cancer immunotherapy, inhibitory receptors, therapeutic monoclonal antibodies, lymphocytes, natural killer cells, CD8+ T cells

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          Summary

          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.

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          Highlights

          • Blocking NKG2A unleashes both T and NK cell effector functions

          • Combined blocking of the NKG2A and the PD-1 axis promotes anti-tumor immunity

          • Blocking NKG2A and triggering CD16 illustrates the efficacy of dual checkpoint therapy

          Abstract

          Blocking of the NKG2A inhibitory receptor unleashes both T and NK cells, and demonstrates anti-tumor efficacy in combination with anti-EGFR or with anti-PD-x antibodies.

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          Most cited references42

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          Natural killer cells and other innate lymphoid cells in cancer

          Immuno-oncology is an emerging field that has revolutionized cancer treatment. Most immunomodulatory strategies focus on enhancing T cell responses, but there has been a recent surge of interest in harnessing the relatively underexplored natural killer (NK) cell compartment for therapeutic interventions. NK cells show cytotoxic activity against diverse tumour cell types, and some of the clinical approaches originally developed to increase T cell cytotoxicity may also activate NK cells. Moreover, increasing numbers of studies have identified novel methods for increasing NK cell antitumour immunity and expanding NK cell populations ex vivo, thereby paving the way for a new generation of anticancer immunotherapies. The role of other innate lymphoid cells (group 1 innate lymphoid cell (ILC1), ILC2 and ILC3 subsets) in tumours is also being actively explored. This Review provides an overview of the field and summarizes current immunotherapeutic approaches for solid tumours and haematological malignancies.
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            Coinhibitory Pathways in Immunotherapy for Cancer.

            The immune system is capable of recognizing tumors and eliminates many early malignant cells. However, tumors evolve to evade immune attack, and the tumor microenvironment is immunosuppressive. Immune responses are regulated by a number of immunological checkpoints that promote protective immunity and maintain tolerance. T cell coinhibitory pathways restrict the strength and duration of immune responses, thereby limiting immune-mediated tissue damage, controlling resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors exploit these coinhibitory pathways to evade immune eradication. Blockade of the PD-1 and CTLA-4 checkpoints is proving to be an effective and durable cancer immunotherapy in a subset of patients with a variety of tumor types, and additional combinations are further improving response rates. In this review we discuss the immunoregulatory functions of coinhibitory pathways and their translation to effective immunotherapies for cancer.
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              Targeting natural killer cells and natural killer T cells in cancer.

              Natural killer (NK) cells and natural killer T (NKT) cells are subsets of lymphocytes that share some phenotypical and functional similarities. Both cell types can rapidly respond to the presence of tumour cells and participate in antitumour immune responses. This has prompted interest in the development of innovative cancer therapies that are based on the manipulation of NK and NKT cells. Recent studies have highlighted how the immune reactivity of NK and NKT cells is shaped by the environment in which they develop. The rational use of these cells in cancer immunotherapies awaits a better understanding of their effector functions, migratory patterns and survival properties in humans.
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                Author and article information

                Contributors
                Journal
                Cell
                Cell
                Cell
                Cell Press
                0092-8674
                1097-4172
                13 December 2018
                13 December 2018
                : 175
                : 7
                : 1731-1743.e13
                Affiliations
                [1 ]Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France
                [2 ]Aix Marseille Université, INSERM, CNRS, Centre d’Immunologie de Marseille-Luminy, 13009 Marseille, France
                [3 ]Unité INSERM U932, Immunité et Cancer, Institut Curie, 75248 Paris Cedex 5, France
                [4 ]Service ORL et Chirurgie cervico-faciale, Institut Curie, 75248 Paris Cedex 5, France
                [5 ]Centre Léon Bérard, 69008 Lyon, France
                [6 ]MedImmune, Ltd., Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, UK
                [7 ]MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA
                [8 ]Abramson Cancer Center, 3400 Civic Center Boulevard West Pavilion, Philadelphia, PA, USA
                [9 ]Service d’Immunologie, Marseille Immunopole, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, 13005 Marseille, France
                Author notes
                []Corresponding author pascale.andre@ 123456innate-pharma.fr
                [∗∗ ]Corresponding author vivier@ 123456ciml.univ-mrs.fr
                [10]

                Lead Contact

                Article
                S0092-8674(18)31322-9
                10.1016/j.cell.2018.10.014
                6292840
                30503213
                f353cb6b-f83e-4142-8c4b-377aaaeaa17d
                © 2018 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 13 June 2018
                : 3 August 2018
                : 2 October 2018
                Categories
                Article

                Cell biology
                immunce checkpoint inhibitor,cancer immunotherapy,inhibitory receptors,therapeutic monoclonal antibodies,lymphocytes,natural killer cells,cd8+ t cells

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