Novel Bispecific Antibodies Increase γδ T-Cell Cytotoxicity against Pancreatic Cancer Cells

The ability of human gamma delta T cells from healthy donors to kill pancreatic ductal adenocarcinoma (PDAC) in vitro and in vivo in immunocompromised mice requires the addition of gamma delta T-cell-stimulating antigens. In this study, we demonstrate that gamma delta 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 gamma delta 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 gamma delta T-cell cytotoxicity, we designed bispecific antibodies that bind CD3 or Vg9 on gamma delta T cells and Her2/neu (ERBB2) expressed by pancreatic tumor cells. Both antibodies enhanced gamma delta T-cell cytotoxicity with the Her2/Vg9 antibody also selectively enhancing release of granzyme B and perforin. Supporting these observations, adoptive transfer of gamma delta T cells with the Her2/Vg9 antibody reduced growth of pancreatic tumors grafted into SCID-Beige immunocompromised mice. Taken together, our results show how bispecific antibodies that selectively recruit gamma delta T cells to tumor antigens expressed by cancer cells illustrate the tractable use of endogenous gamma delta T cells for immunotherapy. (C) 2014 AACR.