Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors.

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2019-12

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Abstract

Immune checkpoint inhibitors are novel biologic agents to treat cancer by inhibiting the regulatory interactions that limit T cell cytotoxicity to tumours. Current agents target either CTLA-4 or the PD-1/PD-L1 axis. Because checkpoints may also regulate autoreactivity, immune checkpoint inhibitor therapy is complicated by side effects known as immune-related adverse events (irAEs). The aim of this article is to review the mechanisms of these events. irAEs can involve different tissues and include arthritis and other rheumatic manifestations. The frequency of irAEs is related to the checkpoint inhibited, with the combination of agents more toxic. Because of their severity, irAEs can limit therapy and require immunosuppressive treatment. The mechanisms leading to irAEs are likely similar to those promoting anti-tumour responses and involve expansion of the T cell repertoire; furthermore, immune checkpoint inhibitors can affect B cell responses and induce autoantibody production. Better understanding of the mechanisms of irAEs will be important to improve patient outcome as well as quality of life during treatment.

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10.1093/rheumatology/kez308

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Weinmann, Sophia C, and David S Pisetsky (2019). Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors. Rheumatology (Oxford, England), 58(Supplement_7). pp. vii59–vii67. 10.1093/rheumatology/kez308 Retrieved from https://hdl.handle.net/10161/20067.

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Scholars@Duke

Weinmann

Sophia Cenac Weinmann

Assistant Professor of Medicine
Pisetsky

David Stephen Pisetsky

Professor of Medicine

Studies in my laboratory concern the immunological properties of DNA as related to two main topics: 1) the induction of anti-DNA responses in systemic lupus erythematosus; and 2) the stimulation of innate immunity by bacterial DNA. These topics are closely linked since we have established novel disease models in which lupus-like illness can be induced in normal mice by bacterial DNA under conditions in which mammalian DNA is inactive. This model has been useful in elucidating mechanisms of DNA antigen drive in autoimmunity.

To pursue these studies, our laboratory conducts investigations in the following areas: 1) specificity of anti-DNA for epitopes on mammalian and bacterial DNA; 2) molecular analysis of murine monoclonal anti-DNA antibodies; 3) histopathological analyses of DNA-immunized mice; 4) in vitro analysis of proliferation, antibody production and cytokine expression in human and murine immune cells; and 5) analysis of DNA binding to cell surface molecules on B cells, T cells and macrophages. Results of these studies have allowed identification of at least two structural motifs that are immunoactive. We are also exploring the impact of chemical modifications of the DNA backbone.

In addition to work on the immunology of DNA, I am also involved in clinical trials related to new immunomodulatory agents in the treatment of rheumatoid arthritis as well as serological markers of disease activity.

The areas of research for which I am known nationally are anti-DNA antibodies, systemic lupus erythematosus and immunological properties of DNA. I have written textbook chapters and reviews on all these subjects.


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