Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm
File(s)
Accepted version
OA Location
Author(s)
Type
Journal Article
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.
Date Issued
2021-04-01
Date Acceptance
2020-09-11
Citation
Cancer Immunology Immunotherapy, 2021, 70, pp.1127-1142
ISSN
0340-7004
Publisher
Springer
Start Page
1127
End Page
1142
Journal / Book Title
Cancer Immunology Immunotherapy
Volume
70
Copyright Statement
© Springer-Verlag GmbH Germany, part of Springer Nature 2020. The final publication is available at Springer via https://doi.org/10.1007/s00262-020-02725-2
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/33033851
PII: 10.1007/s00262-020-02725-2
Subjects
Cytokine release syndrome
Cytokine storm
Immune monitoring
Immune-related adverse events (irAEs)
Immunotherapy
TGN1412
Publication Status
Published
Coverage Spatial
Germany
Date Publish Online
2020-10-08