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      Immunotherapy for Merkel cell carcinoma: a turning point in patient care

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          Abstract

          Merkel Cell carcinoma (MCC) is a rare but aggressive cancer, with an estimated disease-associated mortality as high as 46%. MCC has proven to be an immunologically responsive disease and the advent of immune checkpoint inhibitors has changed the treatment landscape for patients with advanced MCC. In this review, we discuss the rationale for the use of immune checkpoint inhibition, review current single agent therapies tested in and approved for MCC, and discuss emerging immunotherapeutic options for these patients.

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          Most cited references24

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features.

            Merkel cell carcinoma (MCC) is an aggressive skin cancer with a mortality of 33%. Advanced disease at diagnosis is a poor prognostic factor, suggesting that earlier detection may improve outcome. No systematic analysis has been published to define the clinical features that are characteristic of MCC. We sought to define the clinical characteristics present at diagnosis to identify features that may aid clinicians in recognizing MCC. We conducted a cohort study of 195 patients given the diagnosis of MCC between 1980 and 2007. Data were collected prospectively in the majority of cases, and medical records were reviewed. An important finding was that 88% of MCCs were asymptomatic (nontender) despite rapid growth in the prior 3 months (63% of lesions) and being red or pink (56%). A majority of MCC lesions (56%) were presumed at biopsy to be benign, with a cyst/acneiform lesion being the single most common diagnosis (32%) given. The median delay from lesion appearance to biopsy was 3 months (range 1-54 months), and median tumor diameter was 1.8 cm. Similar to earlier studies, 81% of primary MCCs occurred on ultraviolet-exposed sites, and our cohort was elderly (90% >50 years), predominantly white (98%), and often profoundly immune suppressed (7.8%). An additional novel finding was that chronic lymphocytic leukemia was more than 30-fold overrepresented among patients with MCC. The study was limited to patients seen at a tertiary care center. Complete clinical data could not be obtained on all patients. This study could not assess the specificity of the clinical characteristics of MCC. To our knowledge, this study is the first to define clinical features that may serve as clues in the diagnosis of MCC. The most significant features can be summarized in an acronym: AEIOU (asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, and ultraviolet-exposed site on a person with fair skin). In our series, 89% of primary MCCs had 3 or more of these findings. Although MCC is uncommon, when present in combination, these features may indicate a concerning process that would warrant biopsy. In particular, a lesion that is red and expanding rapidly yet asymptomatic should be of concern.
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              PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival.

              Merkel cell carcinoma (MCC) is a lethal, virus-associated cancer that lacks effective therapies for advanced disease. Agents blocking the PD-1/PD-L1 pathway have demonstrated objective, durable tumor regressions in patients with advanced solid malignancies and efficacy has been linked to PD-L1 expression in the tumor microenvironment. To investigate whether MCC might be a target for PD-1/PD-L1 blockade, we examined MCC PD-L1 expression, its association with tumor-infiltrating lymphocytes (TILs), Merkel cell polyomavirus (MCPyV), and overall survival. Sixty-seven MCC specimens from 49 patients were assessed with immunohistochemistry for PD-L1 expression by tumor cells and TILs, and immune infiltrates were characterized phenotypically. Tumor cell and TIL PD-L1 expression were observed in 49% and 55% of patients, respectively. In specimens with PD-L1(+) tumor cells, 97% (28/29) demonstrated a geographic association with immune infiltrates. Among specimens with moderate-severe TIL intensities, 100% (29/29) demonstrated PD-L1 expression by tumor cells. Significant associations were also observed between the presence of MCPyV DNA, a brisk inflammatory response, and tumor cell PD-L1 expression: MCPyV(-) tumor cells were uniformly PD-L1(-). Taken together, these findings suggest that a local tumor-specific and potentially MCPyV-specific immune response drives tumor PD-L1 expression, similar to previous observations in melanoma and head and neck squamous cell carcinomas. In multivariate analyses, PD-L1(-) MCCs were independently associated with worse overall survival (hazard ratio 3.12; 95% CI, 1.28-7.61; p=0.012). These findings suggest that an endogenous immune response promotes PD-L1 expression in the MCC microenvironment when MCPyV is present, and provide a rationale for investigating therapies blocking PD-1/PD-L1 for patients with MCC.
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                Author and article information

                Contributors
                isaac@jhmi.edu
                sbhatia@uw.edu
                howard.kaufman@rutgers.edu
                410-502-5977 , evanlipson@jhmi.edu
                Journal
                J Immunother Cancer
                J Immunother Cancer
                Journal for Immunotherapy of Cancer
                BioMed Central (London )
                2051-1426
                23 March 2018
                23 March 2018
                2018
                : 6
                : 23
                Affiliations
                [1 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Oncology, , Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, and Bloomberg-Kimmel Institute for Cancer Immunotherapy, ; Baltimore, MD USA
                [2 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Medicine/Medical Oncology, , University of Washington and Fred Hutchinson Cancer Research Center, ; Seattle, Washington, USA
                [3 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Department of Surgery, , Massachusetts General Hospital, ; Boston, MA USA
                [4 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Melanoma and Cancer Immunology Programs, , Johns Hopkins University School of Medicine, ; 1550 Orleans Street, Room 507, Baltimore, MD 21287 USA
                Article
                335
                10.1186/s40425-018-0335-9
                5865292
                29566749
                bbd0c86a-0df3-48d5-86da-ca9a3d3ad0cb
                © The Author(s). 2018

                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
                : 24 October 2017
                : 7 March 2018
                Categories
                Research Article
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                © The Author(s) 2018

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