EpCAM/CD3-Bispecific T-cell Engaging Antibody MT110 Eliminates Primary Human Pancreatic Cancer Stem Cells

• Published in: Clinical cancer research Vol. 18; no. 2; pp. 465 - 474
• Main Authors: CIOFFI, Michele, DORADO, Jorge, BAEUERLE, Patrick A, HEESCHEN, Christopher
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.01.2012
• Subjects: Animal models; Animals; Antibody-Dependent Cell Cytotoxicity - drug effects; Antigens, Neoplasm - immunology; Antigens, Neoplasm - metabolism; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Biological and medical sciences; Bispecific antibodies; Bites; CD3 Complex - immunology; CD3 Complex - metabolism; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Adhesion Molecules - immunology; Cell Adhesion Molecules - metabolism; Cell Survival - drug effects; Chemotherapy; Coculture Techniques; Cytotoxicity; Epithelial Cell Adhesion Molecule; Female; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Immunotherapy; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Lymphocytes T; Medical sciences; Metastases; Mice; Mice, Nude; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - immunology; Neoplastic Stem Cells - metabolism; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pharmacology. Drug treatments; Primary Cell Culture; Single-Chain Antibodies - pharmacology; Single-Chain Antibodies - therapeutic use; Spheroids, Cellular - drug effects; Stem cells; Tumor Cells, Cultured; Tumorigenicity; Tumors; Xenograft Model Antitumor Assays; Human; Antibody; Stem cell; Pancreas cancer; T-Lymphocyte; Digestive diseases; Malignant tumor; Tumor cell; Cancer; Pancreatic disease; Primary cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-1270

Tumor-initiating cells with stem-like properties, also termed cancer stem cells (CSC), have been shown to sustain tumor growth as well as metastasis and are highly resistant to chemotherapy. Because pancreatic CSCs have been isolated on the basis of EpCAM expression, we investigated whether a targeted immunotherapy to EpCAM using the bispecific T-cell-engaging antibody MT110 is capable of eradicating CSCs. We studied in vitro and in vivo the effects of MT110 on CSCs using both established cell lines as well as primary cells of human pancreatic cancer. Although established cell lines were more responsive to MT110-engaged T cells, also primary cells showed a time- and dose-dependent response to treatment with the bispecific antibody. In addition, the population of highly tumorigenic CSCs was efficiently targeted by the EpCAM/CD3-bispecific antibody MT110 in vitro and in vivo using a mouse model of established primary pancreatic cancer. Pancreatic cancer cells derived from metastases were slightly more resistant to MT110 treatment on the basis of in vivo tumorigenicity studies. This appeared to be related to a higher frequency of an EpCAM-negative subpopulation of CSCs. Cytotoxic T cells can be effectively redirected against primary human pancreatic cancer cells by T-cell-engaging BiTE antibody MT110 including a subpopulation of highly tumorigenic CSCs.