Abstract
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.
Highlights
Pancreatic cancer is the fourth most frequent cause for cancer-related death [1] and is characterized by early metastasis and pronounced resistance to chemotherapy and radiation
On the basis of our previous work showing the existence of cancer stem cells (CSC) in pancreatic cancer and their strong resistance to standard chemotherapy, we provide multiple lines of evidence for the efficacy of a novel treatment regimen using the Epithelial cell adhesion molecule (EpCAM)/CD3-bispecific T-cell–engaging antibody MT110
Pancreatic cancer spheres were generated by placing pancreatic cancer cells in suspension (20,000 cells/mL) in serum-free Dulbecco’s Modified Eagle’s Medium (DMEM)/ F12 medium, supplemented with B27 (1:50; Invitrogen), 20 ng/mL basic fibroblast growth factor, and 50 units/mL penicillin/streptomycin
Summary
Pancreatic cancer is the fourth most frequent cause for cancer-related death [1] and is characterized by early metastasis and pronounced resistance to chemotherapy and radiation. The only currently available effective treatment modality for pancreatic cancer requires a very invasive and complex surgical procedure, known as Whipple procedure. These patients show an extended median survival of 20 months, only a minority of patients with local disease are suitable for surgical intervention For patients with advanced disease, the introduction of the Authors' Affiliations: 1Stem Cells & Cancer Group, Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; and 2Micromet, Inc., Rockville, Maryland. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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