Patients with gastrointestinal irritability after TGN1412-induced cytokine storm displayed selective expansion of gut-ho
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ORIGINAL ARTICLE
Patients with gastrointestinal irritability after TGN1412‑induced cytokine storm displayed selective expansion of gut‑homing αβ and γδT cells Neil E. McCarthy1,3 · Andrew J. Stagg1,3 · Claire L. Price1,4 · Elizabeth R. Mann1,5 · Nichola L. Gellatly1 · Hafid O. Al‑Hassi1,6 · Stella C. Knight1 · Nicki Panoskaltsis1,2,7,8 Received: 5 May 2020 / Accepted: 11 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Following infusion of the anti-CD28 superagonist monoclonal antibody TGN1412, three of six previously healthy, young male recipients developed gastrointestinal irritability associated with increased expression of ‘gut-homing’ integrin β7 on peripheral blood αβT cells. This subset of patients with intestinal symptoms also displayed a striking and persistent expansion of putative Vδ2+ γδT cells in the circulation which declined over a 2-year period following drug infusion, concordant with subsiding gut symptoms. These data demonstrate that TGN1412-induced gastrointestinal symptoms were associated with dysregulation of the ‘gut-homing’ pool of blood αβ and γδT cells, induced directly by the antibody and/or arising from the subsequent cytokine storm. Keywords Cytokine storm · Cytokine release syndrome · TGN1412 · Vδ2+ γδT cells · Immunotherapy · Immune-related adverse events (irAEs)
Introduction
The work was done at the Antigen Presentation Research Group and the Department of Hematology, Imperial College London, Northwick Park and St. Mark’s Campus, London UK. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02723-4) contains supplementary material, which is available to authorized users. * Neil E. McCarthy [email protected] * Nicki Panoskaltsis [email protected] 1
Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark’s Campus, London, UK
2
Department of Haematology, Imperial College London, Northwick Park and St. Mark’s Campus, London, UK
3
Centre for Immunobiology, The Blizard Institute, Bart’s and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
In higher primates, the blood T cell pool contains diverse αβT cells and semi-invariant ‘unconventional’ T cells that recognize either microbial peptides or metabolites, respectively [1]. In both cases, antigen activation can stimulate these cells to upregulate the gut-homing integrin α4β7 and traffic to the intestine [2–4]. Gut microbes, and the metabolic activities these perform, vary between host species. Consequently, the compounds generated and their conditioning effects on peripheral blood T cell responses 4
Lucid Group Communications, Buckinghamshire, UK
5
Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK
6
Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK
7
Department of Hematology and Medical Oncology, Winship
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