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

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.

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

“…We observed (data not shown) that the T cells reach their maximal cell size after 72 h of incubation, assuming that this time is needed for the T cells to prepare for progressing through the cell cycle. This finding is in line with published data showing T-cell proliferation after 5 days, whereas cell lysis was already seen after 24 h. 29 BMSCs are known to protect MM cells from apoptosis and can be involved in drug resistance, 23 therefore we tested BI 836909 in in vitro assays where we co-cultured BMSCs with two different MM 3 . Then mice were injected with activated and ex vivo expanded human T cells into the peritoneal cavity.…”

Redirected T-Cell Killing of Solid Cancers Targeted with an Anti-CD3/Trop-2–Bispecific Antibody Is Enhanced in Combination with Interferon-α

“…However, we were able to compare the relative cytokine-inducing potency between the (X)-3s and BiTE formats, using a CD19XCD3 BiTE (identical sequence as blinatumomab) and (19)-3s made by DNL. The 19-3 BiTE induced similar cytokine levels as reported by Brandl and colleagues under similar conditions (38). The levels of the five cytokines measured were 7-to 13-fold higher for 19-3 BiTE, compared with those of (19)-3s.…”

“…However, not all bsAb formats necessarily have the same risk. Brandl and colleagues reported cytokine induction with blinatumomab, in which response levels of IL2, IL6, IFNg, and TNFa were variable among donors and typically peaked at >1 ng/mL, with some donors reaching levels as high as 5 ng/mL (38). We lacked a suitable BiTE, or equivalent construct, for direct comparison with (E1)-3s.…”

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

“…In vitro experiments were conducted to determine the impact of dexamethasone pretreatment on cytokine secretion, cytotoxicity, and proliferation. In fact, dexamethasone at clinically relevant concentrations could blunt the increase in cytokine levels with minimal impact on proliferation or killing of ALL cells 46. This provided a rationale for coadministering blinatumomab with dexamethasone in clinical trials, a practice that has continued with other BiTE® antibody constructs 47, 48.…”