Novel bispecific antibodies increase γδ T-cell cytotoxicity against pancreatic cancer cells.

Abstract

The ability of human γδ T cells from healthy donors to kill pancreatic ductal adenocarcinoma (PDAC) in vitro and in vivo in immunocompromised mice requires the addition of γδ T-cell-stimulating antigens. In this study, we demonstrate that γδ T cells isolated from patients with PDAC tumor infiltrates lyse pancreatic tumor cells after selective stimulation with phosphorylated antigens. We determined the absolute numbers of γδ T-cell subsets in patient whole blood and applied a real-time cell analyzer to measure their cytotoxic effector function over prolonged time periods. Because phosphorylated antigens did not optimally enhance γδ T-cell cytotoxicity, we designed bispecific antibodies that bind CD3 or Vγ9 on γδ T cells and Her2/neu (ERBB2) expressed by pancreatic tumor cells. Both antibodies enhanced γδ T-cell cytotoxicity with the Her2/Vγ9 antibody also selectively enhancing release of granzyme B and perforin. Supporting these observations, adoptive transfer of γδ T cells with the Her2/Vγ9 antibody reduced growth of pancreatic tumors grafted into SCID-Beige immunocompromised mice. Taken together, our results show how bispecific antibodies that selectively recruit γδ T cells to tumor antigens expressed by cancer cells illustrate the tractable use of endogenous γδ T cells for immunotherapy.

• Authors: Hans-Heinrich Oberg, Matthias Peipp, Christian Kellner, Susanne Sebens, Sarah Krause, Domantas Petrick, Sabine Adam-Klages, Christoph Röcken, Thomas Becker, Ilka Vogel, Dietrich Weisner, Sandra Freitag-Wolf, Martin Gramatzki, Dieter Kabelitz, Daniela Wesch
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 5 Pg. 1349-60 (Mar 01 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 24448235 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 AACR

Chemical References

• Antibodies
• Receptors, Antigen, T-Cell, gamma-delta
• Receptor, ErbB-2

Topics

• Adenocarcinoma (immunology)
• Animals
• Antibodies (immunology)
• Carcinoma, Pancreatic Ductal (immunology)
• Cell Line
• Cell Line, Tumor
• Cytotoxicity, Immunologic (immunology)
• Female
• HEK293 Cells
• Humans
• Immunotherapy (methods)
• Mice
• Mice, SCID
• Pancreatic Neoplasms (immunology)
• Receptor, ErbB-2 (immunology)
• Receptors, Antigen, T-Cell, gamma-delta (immunology)
• T-Lymphocyte Subsets (immunology)
• T-Lymphocytes, Cytotoxic (immunology)