TY - JOUR
T1 - New gene-immunotherapy combining TRAIL-lymphocytes and EpCAMxCD3 bispecific antibody for tumor targeting
AU - Groth, Ariane
AU - Salnikov, Alexei V.
AU - Ottinger, Sabine
AU - Gladkich, Jury
AU - Liu, Li
AU - Kallifatidis, Georgios
AU - Salnikova, Olga
AU - Ryschich, Eduard
AU - Giese, Nathalia
AU - Giese, Thomas
AU - Momburg, Frank
AU - Büchler, Markus W.
AU - Moldenhauer, Gerhard
AU - Herr, Ingrid
PY - 2012/2/15
Y1 - 2012/2/15
N2 - Purpose: 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. Experimental Design: 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 immuneresponses toward cancer even in its advanced stages.
AB - Purpose: 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. Experimental Design: 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 immuneresponses toward cancer even in its advanced stages.
UR - http://www.scopus.com/inward/record.url?scp=84863132749&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863132749&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-11-2767
DO - 10.1158/1078-0432.CCR-11-2767
M3 - Article
C2 - 22228630
AN - SCOPUS:84863132749
SN - 1078-0432
VL - 18
SP - 1028
EP - 1038
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -