Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm

• Type of Material: Article
• Authors: Nicki Panoskaltsis, Emory University; Neil E. McCarthy, Imperial College London; Andrew J. Stagg, Imperial College London; Catherine J. Mummery, Northwick Park Hospital; Mariwan Husni, Northwick Park Hospital; Naila Arebi, St. Mark's Hospital; David Greenstein, North West London Hospital; Claire L. Price, Imperial College London; Hafid O. Al-Hassi, Imperial College London; Michalis Koutinas, Imperial College London; Athanasios Mantalaris, Imperial College London; Stella C. Knight, Imperial College London
• Language: English
• Date: 2020-10-08
• Publisher: SPRINGER
• Publication Version: Final Published Version
• Copyright Statement: © Springer-Verlag GmbH Germany, part of Springer Nature 2020
• Final Published Version (URL): http://dx.doi.org/10.1007/s00262-020-02725-2
• Title of Journal or Parent Work: CANCER IMMUNOLOGY IMMUNOTHERAPY
• Volume: 70
• Issue: 4
• Start Page: 1127
• End Page: 1142
• Grant/Funding Information: The North West London Hospitals NHS Trust; Cancer Research UK; The Northwick Park Hospital Leukemia Research Trust Fund.; NEM is supported by a Career Development Award from The Medical Research Council (Grant Ref: MR/R008302/1) and is in receipt of a project grant from Bart’s and The London Charity (MGU0465). He has also received consultancy fees and funding for research from ImCheck Therapeutics SAS. AJS research is supported by grants from Gilead Sciences AbbVie, The Medical College of St Bartholomew's Hospital Trust, Bowel & Cancer Research and Bart's Charity. CLM has received consultancy fees from Roche and Biogen for clinical trials in Alzheimer's disease, not relevant to the work presented here. NA has received honoraria from Janssen and Pfizer and also consulting for Janssen. She also has an affiliation with Imperial College London. SCK, NEM and AJS have done contract work for Parexel pre-dating the work described in this report. At the time of this work and report, Parexel Clinical Trials Unit had a short-term contract with the Antigen Presentation Research Group (APRG) to use a Class II cabinet within the laboratory. The APRG has also been contracted to perform immunological studies by a pharmaceutical company, the tissue specimens for which were supplied on behalf of that company via Parexel which is located adjacent to the APRG department.
• Keywords: SUBSET; RELEASE SYNDROME; CD8(+); T-CELL THERAPY; Life Sciences & Biomedicine; Immunology; Science & Technology; Immunotherapy; NEUROTOXICITY; Cytokine storm; Immune-related adverse events (irAEs); TGN1412; CANCER IMMUNOTHERAPIES; EFFECTOR; BIOMARKERS; Oncology; Immune monitoring; BLOCKADE; DISRUPTION; Cytokine release syndrome
• Research Categories: Health Sciences, Oncology; Biology, Cell; Health Sciences, Immunology

Abstract

Cytokine storm can result from cancer immunotherapy or certain infections, including COVID-19. Though short-term immune-related adverse events are routinely described, longer-term immune consequences and sequential immune monitoring are not as well defined. In 2006, six healthy volunteers received TGN1412, a CD28 superagonist antibody, in a first-in-man clinical trial and suffered from cytokine storm. After the initial cytokine release, antibody effect-specific immune monitoring started on Day + 10 and consisted mainly of evaluation of dendritic cell and T-cell subsets and 15 serum cytokines at 21 time-points over 2 years. All patients developed problems with concentration and memory; three patients were diagnosed with mild-to-moderate depression. Mild neutropenia and autoantibody production was observed intermittently. One patient suffered from peripheral dry gangrene, required amputations, and had persistent Raynaud’s phenomenon. Gastrointestinal irritability was noted in three patients and coincided with elevated γδT-cells. One had pruritus associated with elevated IgE levels, also found in three other asymptomatic patients. Dendritic cells, initially undetectable, rose to normal within a month. Naïve CD8+ T-cells were maintained at high levels, whereas naïve CD4+ and memory CD4+ and CD8+ T-cells started high but declined over 2 years. T-regulatory cells cycled circannually and were normal in number. Cytokine dysregulation was especially noted in one patient with systemic symptoms. Over a 2-year follow-up, cognitive deficits were observed in all patients following TGN1412 infusion. Some also had signs or symptoms of psychological, mucosal or immune dysregulation. These observations may discern immunopathology, treatment targets, and long-term monitoring strategies for other patients undergoing immunotherapy or with cytokine storm.