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      Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies

      research-article
      1 , 2 , 11 , 1 , 2 , 3 , 11 , 4 , 1 , 2 , 3 , 5 , 6 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 3 , 1 , 2 , 1 , 2 , 1 , 2 , 3 , 3 , 3 , 3 , 7 , 8 , 8 , 8 , 8 , TRACERx Melanoma, TRACERx Renal, TRACERx Lung consortia, 2 , 9 , 3 , 3 , 3 , 4 , 4 , 6 , 10 , 1 , 2 , , 1 , 2 , 12 , ∗∗
      Cancer Cell
      Cell Press
      CTLA-4, regulatory T cell depletion, ipilimumab, tremelimumab, antibody-dependent cell-mediated cytotoxicity, Fc-gamma receptors, IgG subclass, immune checkpoints, tumor immunotherapy, immune regulatory antibodies

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          Summary

          With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8 + to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.

          Graphical Abstract

          Highlights

          • Anti-CTLA-4 of hIgG1 and hIgG2 isotypes promote depletion of intra-tumoral Treg cells

          • hIgG2 antibodies mediate in vivo depletion of intra-tumoral Treg cells via CD32a

          • Anti-CTLA-4 with enhanced Fc effector function improves therapeutic outcomes

          • The CD16-V158F SNP is associated with response to ipilimumab in inflamed tumors

          Abstract

          Arce Vargas et al. use a mouse model expressing human FcγRs to show that antibodies with isotypes equivalent to ipilimumab increase the CD8 + to Treg ratio by depleting intra-tumoral Tregs to promote tumor rejection. In melanoma patients, response to ipilimumab is associated with a high affinity FcγR polymorphism.

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          Most cited references61

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          Signatures of mutational processes in human cancer

          All cancers are caused by somatic mutations. However, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here, we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, kataegis, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer with potential implications for understanding of cancer etiology, prevention and therapy.
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            Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

            An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)
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              Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma

              New England Journal of Medicine, 373(1), 23-34
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                Author and article information

                Contributors
                Journal
                Cancer Cell
                Cancer Cell
                Cancer Cell
                Cell Press
                1535-6108
                1878-3686
                09 April 2018
                09 April 2018
                : 33
                : 4
                : 649-663.e4
                Affiliations
                [1 ]Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK
                [2 ]Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK
                [3 ]The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK
                [4 ]Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London NW1 1AT, UK
                [5 ]Bill Lyons Informatics Centre, UCL Cancer Institute, London WC1E 6DD, UK
                [6 ]Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6DD, UK
                [7 ]Guy's and St Thomas' NHS Foundation Trust, London SE1 9RT, UK
                [8 ]BioInvent International AB, 223 70 Lund, Sweden
                [9 ]Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK
                [10 ]Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, London WC1E 6DD, UK
                Author notes
                []Corresponding author k.peggs@ 123456ucl.ac.uk
                [∗∗ ]Corresponding author s.quezada@ 123456ucl.ac.uk
                [11]

                These authors contributed equally

                [12]

                Lead Contact

                Article
                S1535-6108(18)30063-1
                10.1016/j.ccell.2018.02.010
                5904288
                29576375
                5363a606-1014-434a-a7a6-7157a4f10e5c
                © 2018 The Author(s)

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

                History
                : 22 June 2017
                : 13 December 2017
                : 15 February 2018
                Categories
                Article

                Oncology & Radiotherapy
                ctla-4,regulatory t cell depletion,ipilimumab,tremelimumab,antibody-dependent cell-mediated cytotoxicity,fc-gamma receptors,igg subclass,immune checkpoints,tumor immunotherapy,immune regulatory antibodies

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