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      Risk of immune-related adverse events associated with ipilimumab-plus-nivolumab and nivolumab therapy in cancer patients

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          Abstract

          Purpose

          The aim of this study was to evaluate the risk of immune-related adverse events (irAEs) among cancer patients receiving nivolumab-plus-ipilimumab therapy and nivolumab monotherapy.

          Patients and methods

          PubMed and Web of Science were searched for related studies from inception to June 2018. Eligible studies included randomized controlled trials comparing nivolumab-plus-ipilimumab with nivolumab alone in cancer patients reporting on all-grade (grade 1–4) and high-grade (grade 3/4) irAEs. Paired reviewers selected studies for inclusion and extracted data. The odds risk and 95% CI were calculated.

          Results

          A total of 2,946 patients from four studies were included in the meta-analysis. The underlying malignancies included lung cancer (two trials) and melanoma (two trials). Compared with nivolumab monotherapy, the nivolumab-plus-ipilimumab therapy was associated with a significantly higher risk of all- and high-grade irAEs such as pruritus, rash, diarrhea, colitis, alanine aminotransferase elevation, and pneumonitis.

          Conclusion

          The combination therapy of nivolumab and ipilimumab increased the incidence of irAEs in patients with advanced cancer.

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          Most cited references 17

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          CTLA-4 is a second receptor for the B cell activation antigen B7

          Functional interactions between T and B lymphocytes are necessary for optimal activation of an immune response. Recently, the T lymphocyte receptor CD28 was shown to bind the B7 counter-receptor on activated B lymphocytes, and subsequently to costimulate interleukin 2 production and T cell proliferation. CTLA-4 is a predicted membrane receptor from cytotoxic T cells that is homologous to CD28 and whose gene maps to the same chromosomal band as the gene for CD28. It is not known, however, if CD28 and CTLA-4 also share functional properties. To investigate functional properties of CTLA-4, we have produced a soluble genetic fusion between the extracellular domain of CTLA-4 and an immunoglobulin C gamma chain. Here, we show that the fusion protein encoded by this construct, CTLA4Ig, bound specifically to B7-transfected Chinese hamster ovary cells and to lymphoblastoid cells. CTLA4Ig also immunoprecipitated B7 from cell surface 125I-labeled extracts of these cells. The avidity of 125I-labeled B7Ig fusion protein for immobilized CTLA4Ig was estimated (Kd approximately 12 nM). Finally, we show that CTLA4Ig was a potent inhibitor of in vitro immune responses dependent upon cellular interactions between T and B lymphocytes. These findings provide direct evidence that, like its structural homologue CD28, CTLA- 4 is able to bind the B7 counter-receptor on activated B cells. Lymphocyte interactions involving the B7 counter-receptor are functionally important for alloantigen responses in vitro.
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            The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation

            The immune system maintains a critically organized network to defend against foreign particles, while evading self-reactivity simultaneously. T lymphocytes function as effectors and play an important regulatory role to orchestrate the immune signals. Although central tolerance mechanism results in the removal of the most of the autoreactive T cells during thymic selection, a fraction of self-reactive lymphocytes escapes to the periphery and pose a threat to cause autoimmunity. The immune system evolved various mechanisms to constrain such autoreactive T cells and maintain peripheral tolerance, including T cell anergy, deletion, and suppression by regulatory T cells (TRegs). These effects are regulated by a complex network of stimulatory and inhibitory receptors expressed on T cells and their ligands, which deliver cell-to-cell signals that dictate the outcome of T cell encountering with cognate antigens. Among the inhibitory immune mediators, the pathway consisting of the programed cell death 1 (PD-1) receptor (CD279) and its ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273) plays an important role in the induction and maintenance of peripheral tolerance and for the maintenance of the stability and the integrity of T cells. However, the PD-1:PD-L1/L2 pathway also mediates potent inhibitory signals to hinder the proliferation and function of T effector cells and have inimical effects on antiviral and antitumor immunity. Therapeutic targeting of this pathway has resulted in successful enhancement of T cell immunity against viral pathogens and tumors. Here, we will provide a brief overview on the properties of the components of the PD-1 pathway, the signaling events regulated by PD-1 engagement, and their consequences on the function of T effector cells.
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              Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review

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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2019
                31 January 2019
                : 15
                : 211-221
                Affiliations
                Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu, People’s Republic of China, zhanghaijunseu@ 123456163.com
                Author notes
                Correspondence: Haijun Zhang, Department of Oncology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009 Jiangsu, People’s Republic of China, Tel/fax +86 25 8327 5418, Email zhanghaijunseu@ 123456163.com
                [*]

                These authors contributed equally to this work

                Article
                tcrm-15-211
                10.2147/TCRM.S193338
                6362938
                © 2019 Zhou 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.

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