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The effect of dexamethasone on polyclonal T cell activation and redirected target cell lysis as induced by a CD19/CD3-bispecific single-chain antibody construct
- Source :
- Cancer Immunology, Immunotherapy. 56:1551-1563
- Publication Year :
- 2007
- Publisher :
- Springer Science and Business Media LLC, 2007.
-
Abstract
- BiTE molecules comprise a new class of bispecific single-chain antibodies redirecting previously unstimulated CD8+ and CD4+ T cells for the elimination of target cells. One example is MT103 (MEDI-538; bscCD19xCD3), a CD19-specific BiTE that can induce lysis of normal and malignant B cells at low picomolar concentrations, which is accompanied by T cell activation. Here, we explored in cell culture the impact of the glucocorticoid derivative dexamethasone on various activation parameters of human T cells in response to MT103. In case cytokine-related side effects should occur with BiTE molecules and other T cell-based approaches during cancer therapy it is important to understand whether glucocorticoids do interfere with the cytotoxic potential of T cells. We found that MT103 induced in the presence of target cells secretion by peripheral T cells of interleukin (IL)-2, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), IL-6, IL-10 and IL-4 into the cell culture medium. Production of all studied cytokines was effectively reduced by dexamethasone at a concentration between 1 and 3x10(-7) M. In contrast, upregulation of activation markers CD69, CD25, CD2 and LFA-1 on both CD4+ and CD8+ T cells, and T cell proliferation were barely affected by the steroid hormone analogue. Most importantly, dexamethasone did not detectably inhibit the cytotoxic activity of MT103-activated T cells against a human B lymphoma line as investigated with lymphocytes from 12 human donors. Glucocorticoids thus qualify as a potential co-medication for therapeutic BiTE molecules and other cytotoxic T cell therapies for treatment of cancer.
- Subjects :
- CD4-Positive T-Lymphocytes
Cytotoxicity, Immunologic
Cancer Research
CD3 Complex
T cell
Antigens, CD19
Immunology
CD8-Positive T-Lymphocytes
Biology
Lymphocyte Activation
Dexamethasone
Interleukin 21
Antigens, CD
Cell Line, Tumor
Neoplasms
Antibodies, Bispecific
medicine
Humans
Immunology and Allergy
Cytotoxic T cell
IL-2 receptor
Antigen-presenting cell
Glucocorticoids
Interleukin 3
Natural killer T cell
Molecular biology
Lymphocyte Function-Associated Antigen-1
medicine.anatomical_structure
Oncology
Interleukin 12
Cytokines
Subjects
Details
- ISSN :
- 14320851 and 03407004
- Volume :
- 56
- Database :
- OpenAIRE
- Journal :
- Cancer Immunology, Immunotherapy
- Accession number :
- edsair.doi.dedup.....b318b4feeca343b16d915702cf52416a