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      A First-in-Human Dose Finding Study of Camrelizumab in Patients with Advanced or Metastatic Cancer in Australia

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          Camrelizumab inhibits PD-1 in non-clinical models and showed typical non-clinical pharmacokinetic (PK) and safety profiles for an IgG4 monoclonal antibody. We report results from the First-in-Human Phase 1 trial of camrelizumab in Australian population.


          Camrelizumab was administered to patients with advanced solid tumors who had failed standard therapies. In the dose-escalation phase (n=23), camrelizumab was administered intravenously at 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg every 2 weeks. In dose expansion (n=26), camrelizumab was given at 200 mg or 600 mg every 4 weeks.


          Two dose-limiting toxicities were observed during dose escalation: transaminase elevation and diarrhea (both grade 3). Overall, treatment-related adverse events were consistent with the expected toxicity profile of immune checkpoint inhibition, with the striking exception of the dose-related development of angiomatous skin lesions characterized as reactive cutaneous capillary endothelial proliferation. The PK profile showed a dose-progressive increase in half-life from 3 days at 1 mg/kg to 7 days at 10 mg/kg. Moreover, receptor occupancy assays showed a PD-1 occupancy of >50% in most patients out to 28 days post-dose. The objective response rate was 15.2% (95% CI 6.3–28.9).


          Camrelizumab has manageable toxicity and encouraging preliminary antitumor activity in advanced solid tumors in Australia.

          Clinical Trial Registration

          ClinicalTrials.gov Identifier: NCT02492789.

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          Most cited references 28

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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.

           Y Iwai,  M. Ishida,  Y. Tanaka (2002)
          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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            PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells.

            Since metastasis is the major cause of death for cancer patients, there is an urgent need to develop new therapies to control hematogenous dissemination of cancer cells. Previously we and others demonstrated a novel mechanism that allows tumors to escape from the host immune response by expressing PD-L1 which can negatively regulate immune response through the interaction with PD-1, an immunoinhibitory receptor belonging to the CD28 family. In this study, we report that hematogenous spread of poorly immunogenic B16 melanoma cells to the liver was inhibited in PD-1-deficient mice. After inoculation to spleen, PD-L1 was induced on tumor cells, which did not express PD-L1 in vitro. As compared with wild-type mice, intrasplenic injection of B16 cells into PD-1-deficient mice showed enhanced induction of effector T cells in spleen, prolonged T cell proliferation and cytokine production, and augmented homing of effector T cells to tumor sites in the liver, resulting in accumulation of effector T cells in the tumor sites. PD-1 blockade by genetic manipulation or antibody treatment inhibited not only hematogenous dissemination of B16 melanoma cells to the liver on the C57BL/6 background, but also dissemination of CT26 colon cancer cells to the lung on the BALB/c background. These results suggest that PD-1 blockade may be a powerful tool for treatment of hematogenous spread of various tumor cells.
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              Anti-PD-1 Antibody SHR-1210 Combined with Apatinib for Advanced Hepatocellular Carcinoma, Gastric, or Esophagogastric Junction Cancer: An Open-label, Dose Escalation and Expansion Study


                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                18 March 2020
                : 14
                : 1177-1189
                [1 ]Nucleus Network , Melbourne, Victoria, Australia
                [2 ]Department of Medicine, University of Melbourne , Heidelberg, Victoria, Australia
                [3 ]Olivia Newton-John Cancer Wellness and Research Centre, Austin Hospital , Melbourne, Victoria, Australia
                [4 ]Department of Medical Oncology, La Trobe University School of Cancer Medicine , Bundoora, Victoria, Australia
                [5 ]Department of Medical Oncology, Alfred Hospital , Melbourne, Victoria, Australia
                [6 ]Department of Medical Oncology, Monash University, Central Clinical School, Alfred Campus , Melbourne, Victoria, Australia
                [7 ]Blacktown Cancer and Haematology Centre, Blacktown Hospital, University of Sydney , Sydney, New South Wales, Australia
                [8 ]Department of Medical Oncology, Chris O’Brien Life House , Camperdown, New South Wales, Australia
                [9 ]Jiangsu Hengrui Medicine Co. Ltd , Shanghai, People’s Republic of China
                [10 ]Incyte Biosciences International Sarl , Geneva, Switzerland
                [11 ]Incyte Corporation , Wilmington, Delaware, USA
                [12 ]Department of Dermatology, The University of Sydney, Westmead Hospital , Westmead, New South Wales, Australia
                [13 ]Linear Clinical Research , Nedlands, Western Australia, Australia
                Author notes
                Correspondence: Jason D Lickliter Nucleus Network , Level 5, Burnet Tower, 89 Commercial Road, Melbourne, Victoria, AustraliaTel +61 3 9076 8900Fax +61 3 9076 8911 Email j.lickliter@nucleusnetwork.com.au
                © 2020 Lickliter et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 3, Tables: 3, References: 39, Pages: 13
                This study was sponsored by Jiangsu Hengrui Medicine Co. Ltd, Shanghai, China.
                Original Research


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