CD3 bispecific antibodies are a very potent means to re-activate the immune system against tumour cells targeting cancer-associated antigens and CD3 on T cells and acting as direct immune activators. The aim of this study was to investigate the early changes occurring in the tumour and peripheral blood in tumour bearing mice treated with a T cell Bispecific (TCB) antibody designed to elicit T cell activation upon simultaneously binding to T cells and to a tumour-specific target.
C57Bl/6 mice bearing a B16 metastatic lung murine melanoma were treated with a single dose iv of a TCB targeting murine CD3 and an antigen highly expressed in the B16 tumour. At 2h, 4h, 7h, 24h, 48h after treatment blood was collected for hematology, serum chemistry, cytokines, flow cytometry and pharmacokinetic analysis and the tumour-bearing lung was collected and analyzed for cytokines, flow cytometry and histopathology.
Treatment with the targeted TCB induced, starting from two hours post single dose administration, a transient marked drop in lymphocytes, an increase in neutrophils and monocytes and an increase in acute phase proteins (haptoglobin, SAA1, a1-AGP and SAP) in the peripheral blood, correlating with the histopathological changes at the tumour site. Histopathology, immunohistochemistry and flow cytometry of the tumour showed that acute inflammation was already present at two to four hours after treatment in the form of neutrophilic infiltrate, while CD3+ T lymphocytes started to accumulate in the tumour 24h after treatment. These changes were accompanied by an increase of some cytokines in the tumour (e.g. IL-6, MCP1, IL-1b) and in the peripheral blood.
Changes observed in tumour bearing mice upon treatment with a tumour-targeted TCB suggest an early engagement of tumour resident T cells resulting in cytokine release locally and systemically within 2h after treatment, with homing and extravasation of inflammatory cells into the tumour progressively increasing 24h to 48h after treatment. This course of events is believed to be translatable to patients treated with TCBs.
Roche Glycart AG.
Roche Glycart AG.
A.M. Giusti: Full / Part-time employment: Roche Glycart AG. J. Sam: Full / Part-time employment: Roche Glycart AG. M. Karagianni: Full / Part-time employment: Roche Glycart AG. A. Schneider: Full / Part-time employment: Roche Glycart AG.