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      A canine chimeric monoclonal antibody targeting PD-L1 and its clinical efficacy in canine oral malignant melanoma or undifferentiated sarcoma

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          Abstract

          Immunotherapy targeting immune checkpoint molecules, programmed cell death 1 (PD-1) and PD-ligand 1 (PD-L1), using therapeutic antibodies has been widely used for some human malignancies in the last 5 years. A costimulatory receptor, PD-1, is expressed on T cells and suppresses effector functions when it binds to its ligand, PD-L1. Aberrant PD-L1 expression is reported in various human cancers and is considered an immune escape mechanism. Antibodies blocking the PD-1/PD-L1 axis induce antitumour responses in patients with malignant melanoma and other cancers. In dogs, no such clinical studies have been performed to date because of the lack of therapeutic antibodies that can be used in dogs. In this study, the immunomodulatory effects of c4G12, a canine-chimerised anti-PD-L1 monoclonal antibody, were evaluated in vitro, demonstrating significantly enhanced cytokine production and proliferation of dog peripheral blood mononuclear cells. A pilot clinical study was performed on seven dogs with oral malignant melanoma (OMM) and two with undifferentiated sarcoma. Objective antitumour responses were observed in one dog with OMM (14.3%, 1/7) and one with undifferentiated sarcoma (50.0%, 1/2) when c4G12 was given at 2 or 5 mg/kg, every 2 weeks. c4G12 could be a safe and effective treatment option for canine cancers.

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          Most cited references23

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          Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

          PD-1 is a receptor of the Ig superfamily that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands (PD-L) and is suggested to play a role in the maintenance of self-tolerance. In the present study, we examined possible roles of the PD-1/PD-L system in tumor immunity. Transgenic expression of PD-L1, one of the PD-L, in P815 tumor cells rendered them less susceptible to the specific T cell antigen receptor-mediated lysis by cytotoxic T cells in vitro, and markedly enhanced their tumorigenesis and invasiveness in vivo in the syngeneic hosts as compared with the parental tumor cells that lacked endogenous PD-L. Both effects could be reversed by anti-PD-L1 Ab. Survey of murine tumor lines revealed that all of the myeloma cell lines examined naturally expressed PD-L1. Growth of the myeloma cells in normal syngeneic mice was inhibited significantly albeit transiently by the administration of anti-PD-L1 Ab in vivo and was suppressed completely in the syngeneic PD-1-deficient mice. These results suggest that the expression of PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses and that blockade of interaction between PD-1 and PD-L may provide a promising strategy for specific tumor immunotherapy.
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            Response evaluation criteria for solid tumours in dogs (v1.0): a Veterinary Cooperative Oncology Group (VCOG) consensus document.

            In veterinary medical oncology, there is currently no standardized protocol for assessing response to therapy in solid tumours. The lack of such a formalized guideline makes it challenging to critically compare outcome measures across various treatment protocols. The Veterinary Cooperative Oncology Group (VCOG) membership consensus document presented here is based on the recommendations of a subcommittee of American College of Veterinary Internal Medicine (ACVIM) board-certified veterinary oncologists. This consensus paper has used the human response evaluation criteria in solid tumours (RECIST v1.1) as a framework to establish standard procedures for response assessment in canine solid tumours that is meant to be easy to use, repeatable and applicable across a variety of clinical trial structures in veterinary oncology. It is hoped that this new canine RECIST (cRECIST v1.0) will be adopted within the veterinary oncology community and thereby facilitate the comparison of current and future treatment protocols used for companion animals with cancer.
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              Methods and mortality results of a health survey of purebred dogs in the UK.

              To collect information on the cause of death and longevity of dogs owned by members of the numerically largest breed clubs of 169 UK Kennel Club-recognised breeds. A cross-sectional study was carried out. Approximately 58,363 questionnaires were sent out to breed club members in 2004 (nine clubs failed to report the exact number of questionnaires sent out). Owners reported age at death and cause(s) of death for all dogs that had died within the previous 10 years. A total of 13,741 questionnaires (24% response rate) containing information on 15,881 deaths were included in the analysis. Breed-specific response rates ranged from 64·7 to 4·5%. The median age at death was 11 years and 3 months (minimum=2 months, maximum=23 years and 5 months) and it varied by breed. The most common causes of death were cancer (n=4282, 27%), "old age" (n=2830, 18%) and cardiac conditions (n=1770, 11%). This survey shows breed differences in lifespan and causes of death, and the results support previous evidence that smaller breeds tend to have longer lifespan compared with larger breeds. Although many of the breeds in the study may not be representative of the general pedigree dog population in the UK, the results do contribute to the limited information currently available. © 2010 British Small Animal Veterinary Association.
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                Author and article information

                Contributors
                konnai@vetmed.hokudai.ac.jp
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                21 August 2017
                21 August 2017
                2017
                : 7
                : 8951
                Affiliations
                [1 ]ISNI 0000 0001 2173 7691, GRID grid.39158.36, , Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, ; Sapporo, 060-0818 Japan
                [2 ]ISNI 0000 0001 2173 7691, GRID grid.39158.36, , Veterinary Teaching Hospital, Graduate School of Veterinary Medicine, Hokkaido University, ; Sapporo, 060-0819 Japan
                [3 ]North Lab, Sapporo, 003-0027 Japan
                [4 ]ISNI 0000 0001 2173 7691, GRID grid.39158.36, , Department of Diagnostic Pathology, Graduate School of Veterinary Medicine, Hokkaido University, ; Sapporo, 060-0818 Japan
                [5 ]ISNI 0000 0001 2173 7691, GRID grid.39158.36, , Research Center for Zoonosis Control, Hokkaido University, ; Sapporo, 001-0020 Japan
                [6 ]ISNI 0000 0001 2173 7691, GRID grid.39158.36, , Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, ; Sapporo, 001-0020 Japan
                [7 ]ISNI 0000 0001 2248 6943, GRID grid.69566.3a, , Department of Antibody Drug Development, Graduate School of Medicine, Tohoku University, ; Sendai, 980-8575 Japan
                [8 ]Project of Antibody Drug Development, New Industry Creation Hatchery Center, Sendai, 980-8575 Japan
                [9 ]Research and Development Center, Fuso Pharmaceutical Industries, Ltd, Osaka, 536-0025 Japan
                Article
                9444
                10.1038/s41598-017-09444-2
                5567082
                28827658
                44ce9808-f4ed-4a17-93e7-2ee962714797
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 27 February 2017
                : 27 July 2017
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