title: An epithelial cell adhesion molecule- and CD3-bispecific antibody plus activated T-cells can eradicate chemoresistant cancer stem-like pancreatic carcinoma cells in vitro.
abstract: Cancer stem-like properties of various types of cancer, including pancreatic cancer, one of the most aggressive types, correlate with metastasis, invasion, and therapeutic resistance. More importantly, chemoresistance in cancer stem-like cells (CSLCs) is a critical problem for eradication of pancreatic cancer. Several cell surface markers, such as CD44 and epithelial cell adhesion molecule (EpCAM), are molecular targets on CSLCs of pancreatic carcinoma. In this study, we investigated whether catumaxomab, a clinical-grade bi-specific antibody that binds to both EpCAM on tumor cells and CD3 on T-cells, combined with activated T-cells can eliminate chemoresistant pancreatic CSLCs in vitro. Firstly, we established a CSLC line (MU-PK1) from human pancreatic carcinoma cells derived from a patient with chemoresistant and disseminated pancreatic cancer. These CSLCs were almost completely resistant to gemcitabine-mediated cytotoxicity up to a concentration of 10 μg/ml. The cells expressed high levels of CSLC markers (CD44 and EpCAM) and had significantly higher capacities for sphere formation, invasion, and aldehyde dehydrogenase-1 expression, which are associated with cancer stemness properties. We found that pre-treatment with catumaxomab and subsequent addition of interleukin-2/OKT3 activated autologous T-cells eliminated CSLCs during a short incubation period. Moreover, when MU-PK1 cells were cultured under hypoxic conditions, the CSLCs became more aggressive. However, the combination of cytokine-activated killer T-cells with catumaxomab successfully lysed almost all these cells. In conclusion, catumaxomab combined with activated T-cells may be a potent therapeutic modality to eradicate chemoresistant pancreatic CSLCs.
authors: Fukuoka General Cancer Clinic, Fukuoka, Japan.
authors: Masayo
authors: M
authors: Umebayashi
authors: Fukuoka General Cancer Clinic, Fukuoka, Japan.
authors: Akifumi
authors: A
authors: Kiyota
authors: Fukuoka General Cancer Clinic, Fukuoka, Japan.
authors: Norihiro
authors: N
authors: Koya
authors: Fukuoka General Cancer Clinic, Fukuoka, Japan.
authors: Hiroto
authors: H
authors: Tanaka
authors: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Hideya
authors: H
authors: Onishi
authors: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Mitsuo
authors: M
authors: Katano
authors: Fukuoka General Cancer Clinic, Fukuoka, Japan tmorisaki@cancer-clinic.jp.
authors: Takashi
authors: T
authors: Morisaki
mesh_terms: D018033:Antibodies, Bispecific / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000276:immunology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D000071858:Epithelial Cell Adhesion Molecule; D006801:Humans; D008213:Lymphocyte Activation; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D017252:CD3 Complex; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C522419:catumaxomab
keywords: Cancer stem-like cells; EpCAM; catumaxomab; chemoresistance; cytokine-activated T-cells