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Toxicity Induced by a Bispecific T Cell-Redirecting Protein Is Mediated by Both T Cells and Myeloid Cells in Immunocompetent Mice.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2020 Jun 01; Vol. 204 (11), pp. 2973-2983. Date of Electronic Publication: 2020 Apr 15. - Publication Year :
- 2020
-
Abstract
- Bispecific T cell engagers have demonstrated clinical efficacy; however, their use can be accompanied by severe toxicity. Mechanistic understanding of these toxicities is limited by a lack of suitable immunocompetent preclinical models. In this study, we describe an immunocompetent mouse tumor model that exhibits bispecific T cell engager-induced toxicity and recapitulates key features similar to those in human cytokine release syndrome. In this study, toxicity occurred between the second and fourth injections of an NK Group 2D bispecific T cell engager protein. Symptoms were transient, peaking 3-4 h after treatment and resolving by 8 h. Mice developed weight loss, elevated plasma cytokines, a significant reduction in spleen white pulp, and lymphocyte infiltration in the liver. Systemic cellular immune changes also occurred; notably, an increase in CD8 <superscript>+</superscript> T cell activation, an increase in myeloid cells in the blood, and a population of Ly-6C <superscript>int</superscript> monocytes (CD11b <superscript>+</superscript> Ly-6G <superscript>-</superscript> F4/80 <superscript>-</superscript> ) emerged in the liver and spleens of bispecific protein-treated mice. IFN-γ was primarily produced by CD8 <superscript>+</superscript> T cells in the spleen and was required for the observed changes in both T cell and myeloid populations. Rag deficiency, IFN-γ deficiency, or depletion of either CD4 <superscript>+</superscript> or CD8 <superscript>+</superscript> T cells prevented toxicity, whereas perforin deficiency, GM-CSF deficiency, or modulation of the myeloid population through clodronate-mediated depletion showed a partial abrogation of toxicity. Together, these findings reveal that T cell activation by a bispecific T cell engager leads to changes in the host myeloid cell population, both of which contribute to treatment induced toxicity in immunocompetent mice.<br /> (Copyright © 2020 by The American Association of Immunologists, Inc.)
- Subjects :
- Animals
CD3 Complex
Cell Line, Tumor
Clodronic Acid metabolism
Colonic Neoplasms therapy
Cytokine Release Syndrome etiology
Disease Models, Animal
Drug-Related Side Effects and Adverse Reactions
Humans
Interferon-gamma metabolism
Lymphocyte Activation
Mice
Mice, Inbred C57BL
Mice, Knockout
Myeloid Cells immunology
NK Cell Lectin-Like Receptor Subfamily K genetics
Receptors, Chimeric Antigen genetics
T-Cell Antigen Receptor Specificity
CD4-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes immunology
Colonic Neoplasms immunology
NK Cell Lectin-Like Receptor Subfamily K metabolism
Receptors, Chimeric Antigen metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 204
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 32295875
- Full Text :
- https://doi.org/10.4049/jimmunol.1901401