Novel bispecific antibodies increase γδ T-cell cytotoxicity against pancreatic cancer cells.
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' Affiliations: Institute of Immunology; Division of Stem Cell Transplantation and Immunotherapy; Institute for Experimental Medicine; Institute of Pathology; Clinic of General and Thoracic Surgery; Institute for Medical Informatics and Statistic, Christian-Albrechts-University Kiel; Municipal Hospital, Department of Surgery; and Clinic of Gynaecology and Obstetrics, Kiel, Germany.
Hans-Heinrich
HH
Oberg
Matthias
M
Peipp
Christian
C
Kellner
Susanne
S
Sebens
Sarah
S
Krause
Domantas
D
Petrick
Sabine
S
Adam-Klages
Christoph
C
Röcken
Thomas
T
Becker
Ilka
I
Vogel
Dietrich
D
Weisner
Sandra
S
Freitag-Wolf
Martin
M
Gramatzki
Dieter
D
Kabelitz
Daniela
D
Wesch
D000230:Adenocarcinoma / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000276:immunology; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000276:immunology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000906:Antibodies; D018719:Erb-b2 Receptor Tyrosine Kinases; D016692:Receptors, Antigen, T-Cell, gamma-delta