Patients with pancreatic cancer have a poor survival rate, and new therapeutic strategies are needed. Epithelial cell adhesion molecule (EpCAM), suggested as a marker for cancer stem cells, is over-expressed on most pancreatic tumour cells but not on normal cells and may be an ideal therapeutic target. We evaluated the anti-tumour efficiency of bispecific EpCAMxCD3 antibody linking tumour cells and T lymphocytes. In NOD SCID mice, EpCAMxCD3 had a long serum half-life (t(1/2) approximately 7 days). EpCAMxCD3 significantly retarded growth of BxPC-3 pancreatic carcinoma xenografts. For mimicking a pancreatic cancer microenvironment in vitro, we used a three-dimensional tumour reconstruct system, in which lymphocytes were co-cultured with tumour cells and fibroblasts in a collagen matrix. In this in vivo-like system, EpCAMxCD3 potently stimulated production of the effector cytokines IFN-gamma and TNF-alpha by extracorporally pre-activated lymphocytes. Moreover, compared with a bivalent anti-CD3 antibody, EpCAMxCD3 more efficiently activated the production of TNF-alpha and IFN-gamma by non-stimulated peripheral blood mononuclear cells. Most excitingly, we demonstrate for the first time that EpCAMxCD3 induces prolonged contacts between lymphocytes and tumour cells, which may be the main reason for the observed anti-tumour effects. As an important prerequisite for future use in patients, EpCAMxCD3 did not alter lymphocyte migration as measured by time-lapse video microscopy. Our data may open a way to improve the immune response and treatment outcome in patients with pancreatic cancer.
Metastatic thymic lymphosarcoma was diagnosed in a 16-month-old mixed-breed heifer with a history of progressive weight loss. Physical examination revealed cachexia, pale mucous membranes, large peripheral lymph nodes, and a 15 X 40-cm mass in the ventral portion of the neck, extending cranially from the thoracic inlet. Neoplastic lymphocytes were identified in aspirates of pleural effusion and bone marrow. Histologic examination of necropsy specimens substantiated metastatic dispersal of the tumor into lymphoid tissue, liver, intestine, heart, and kidney. This case differs from other reported cases of thymic lymphosarcoma because of the involvement of organs other than the thymus and lymph nodes. Analytical flow cytometry was performed on mononuclear leukocytes obtained from blood by use of density gradient centrifugation. The majority of cells (65%) appeared to be of an immature, poorly differentiated phenotype, on the basis of the small numbers of cells stained with monoclonal antibodies specific for the following cell surface markers: 8% BoCD2 (IL-A26; sheep erythrocyte receptor on T-lymphocytes); less than 10% B-lymphocytes as determined by expression of MHC class II proteins and surface immunoglobulin; 12% monocytes (IL-A24); and 5% null cells (IL-A29). Although the leukemic cell population did not express traditional surface markers for T-lymphocytes, we hypothesize that the leukemic cell population represents an early stage of T-cell maturation that has failed to differentiate and express characteristic cell surface antigens.
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