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      Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease

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          Abstract

          The U.S. Food and Drug Administration (FDA) recently approved pembrolizumab, an anti- programmed cell death protein 1 cancer immunotherapeutic, for use in advanced solid tumors in patients with the microsatellite-high/DNA mismatch repair-deficient biomarker. This is the first example of a tissue-agnostic FDA approval of a treatment based on a patient’s tumor biomarker status, rather than on tumor histology. Here we discuss key issues and implications arising from the biomarker-based disease classification implied by this historic approval.

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          CTLA-4 and PD-1 Pathways

          Elizabeth I Buchbinder, Anupam Desai (2016)
          Supplemental Digital Content is available in the text.
          Article 0 comments Cited 843 times – based on 0 reviews     Review now
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            IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer

            K Abiko, N Matsumura, J Hamanishi … (2015)
            Background: PD-L1 (programmed cell death 1 ligand 1) on tumour cells suppresses host immunity through binding to its receptor PD-1 on lymphocytes, and promotes peritoneal dissemination in mouse models of ovarian cancer. However, how PD-L1 expression is regulated in ovarian cancer microenvironment remains unclear. Methods: The number of CD8-positive lymphocytes and PD-L1 expression in tumour cells was assessed in ovarian cancer clinical samples. PD-L1 expression and tumour progression in mouse models under conditions of altering IFN-γ signals was assessed. Results: The number of CD8-positive cells in cancer stroma was very high in peritoneally disseminated tumours, and was strongly correlated to PD-L1 expression on the tumour cells (P<0.001). In mouse models, depleting IFNGR1 (interferon-γ receptor 1) resulted in lower level of PD-L1 expression in tumour cells, increased the number of tumour-infiltrating CD8-positive lymphocytes, inhibition of peritoneal disseminated tumour growth and longer survival (P=0.02). The injection of IFN-γ into subcutaneous tumours induced PD-L1 expression and promoted tumour growth, and PD-L1 depletion completely abrogated tumour growth caused by IFN-γ injection (P=0.01). Conclusions: Interferon-γ secreted by CD8-positive lymphocytes upregulates PD-L1 on ovarian cancer cells and promotes tumour growth. The lymphocyte infiltration and the IFN-γ status may be the key to effective anti-PD-1 or anti-PD-L1 therapy in ovarian cancer.
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              A molecular portrait of microsatellite instability across multiple cancers

              Isidro Cortés-Ciriano, Sejoon Lee, Woong-Yang Park … (2017)
              Microsatellite instability (MSI) refers to the hypermutability of short repetitive sequences in the genome caused by impaired DNA mismatch repair. Although MSI has been studied for decades, large amounts of sequencing data now available allows us to examine the molecular fingerprints of MSI in greater detail. Here, we analyse ∼8,000 exomes and ∼1,000 whole genomes of cancer patients across 23 cancer types. Our analysis reveals that the frequency of MSI events is highly variable within and across tumour types. We also identify genes in DNA repair and oncogenic pathways recurrently subject to MSI and uncover non-coding loci that frequently display MSI. Finally, we propose a highly accurate exome-based predictive model for the MSI phenotype. These results advance our understanding of the genomic drivers and consequences of MSI, and our comprehensive catalogue of tumour-type-specific MSI loci will enable panel-based MSI testing to identify patients who are likely to benefit from immunotherapy.
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                Author and article information

                Contributors
                James L. Gulley: gulleyj@mail.nih.gov
                Journal
                Journal ID (nlm-ta): J Immunother Cancer
                Journal ID (iso-abbrev): J Immunother Cancer
                Title: Journal for Immunotherapy of Cancer
                Publisher: BioMed Central (London )
                ISSN (Electronic): 2051-1426
                Publication date (Electronic): 14 May 2018
                Publication date PMC-release: 14 May 2018
                Publication date Collection: 2018
                Volume: 6
                Electronic Location Identifier: 35
                Affiliations
                [1 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, University of Pittsburgh, ; Pittsburgh, PA USA
                [2 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, University of Pittsburgh Hillman Cancer Center, ; Pittsburgh, PA USA
                [3 ]ISNI 0000 0004 0461 3162, GRID grid.185006.a, Lombardi Cancer Research Center, ; Washington, D. C., USA
                [4 ]ISNI 0000000122986657, GRID grid.34477.33, University of Washington, ; Seattle, WA USA
                [5 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Johns Hopkins University, ; Baltimore, MD USA
                [6 ]ISNI 0000 0004 0483 9129, GRID grid.417768.b, Genitourinary Malignancies Branch, , Center for Cancer Research, National Cancer Institute, National Institutes of Health, ; Bethesda, MD USA
                Article
                Publisher ID: 342
                DOI: 10.1186/s40425-018-0342-x
                PMC ID: 5950135
                PubMed ID: 29754585
                SO-VID: c7c17e8f-f32a-4f3e-9267-89bdc0d0d358
                Copyright © © The Author(s). 2018
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 10 January 2018
                Date accepted : 19 April 2018
                Categories
                Subject: Review Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2018

                Keywords: dna mismatch repair,microsatellite instability,pembrolizumab,biomarker,immunotherapy
                Data availability:
                Keywords: dna mismatch repair, microsatellite instability, pembrolizumab, biomarker, immunotherapy

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