New gene-immunotherapy combining TRAIL-lymphocytes and EpCAMxCD3 Bispecific antibody for tumor targeting.
OBJECTIVE
To enhance T-cell responsiveness toward cancer cells, we overexpressed TRAIL in lymphocytes, as this death ligand induces tumor-specific apoptosis. To increase contact time of lymphocytes with tumor cells and thereby of TRAIL with its death receptors, lymphocytes were linked to the CD3 arm of bispecific antibody EpCAMxCD3, to guide the lymphocytes to tumor cells positive for the cancer stem cell marker EpCAM/ESA.


METHODS
Lymphocytes were transduced with TRAIL lentivirus and the antitumor effect in presence and absence of EpCAMxCD3 was evaluated in vitro and in xenograft studies using epithelial cell adhesion molecule (EpCAM)-positive pancreatic and prostate cancer cells.


RESULTS
Compared with control lymphocytes, TRAIL-lymphocytes increased cytotoxicity and further induced expression of several apoptosis-related molecules. Cotransplantation of TRAIL-lymphocytes and tumor cells in mice or peritumoral injection of TRAIL-lymphocytes in larger xenografts retarded growth and induced apoptosis. Combination of TRAIL-lymphocytes with EpCAMxCD3 potentiated tumor eradication by enhancing antiapoptotic and antiproliferative signaling and by decreasing tumor vasculature. Intratumoral cyst formation was involved and associated with enhanced chemokine secretion and infiltration of mouse macrophages, suggesting contribution of an inflammatory host response. Most importantly, tumorigenicity of pancreatic cancer cells with cancer stem cell features resistant to conventional chemotherapy was strongly reduced.


CONCLUSIONS
This gene-immunotherapeutic approach may be a new tool to support endogenous immune responses toward cancer even in its advanced stages.
Molecular OncoSurgery Group, Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
Ariane
A
Groth
Alexei V
AV
Salnikov
Sabine
S
Ottinger
Jury
J
Gladkich
Li
L
Liu
Georgios
G
Kallifatidis
Olga
O
Salnikova
Eduard
E
Ryschich
Nathalia
N
Giese
Thomas
T
Giese
Frank
F
Momburg
Markus W
MW
Büchler
Gerhard
G
Moldenhauer
Ingrid
I
Herr
D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000276:immunology*; D002460:Cell Line; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D000071858:Epithelial Cell Adhesion Molecule; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000276:immunology; D009389:Neovascularization, Pathologic / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000628:therapy*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D017252:CD3 Complex; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D053221:TNF-Related Apoptosis-Inducing Ligand