EpCAM/CD3-Bispecific T-cell Engaging Antibody MT110 Eliminates Primary Human Pancreatic Cancer Stem Cells
EpCAM/CD3-Bispecific T-cell Engaging Antibody MT110 Eliminates Primary Human Pancreatic Cancer Stem Cells
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DOI：
10.1158/1078-0432.ccr-11-1270
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发表时间：
2012-01-15
影响因子：
11.5
通讯作者：
Heeschen, Christopher
中科院分区：
文献类型：
--
作者：
Cioffi, Michele;Dorado, Jorge;Heeschen, Christopher
目的：具有干细胞样特性的肿瘤起始细胞，也称为癌症干细胞（CSC），已被证明可维持肿瘤生长以及转移，并且对化疗具有高度抗性。由于胰腺CSC是在EpCAM表达的基础上分离出来的，因此我们研究了使用双特异性T细胞接合抗体MT 110对EpCAM进行靶向免疫治疗是否能够根除CSC。实验设计：我们使用已建立的细胞系以及人胰腺癌的原代细胞，在体外和体内研究了MT 110对CSC的影响。尽管建立的细胞系对MT 110接合的T细胞更有应答，但原代细胞也显示对用双特异性抗体处理的时间和剂量依赖性应答。此外，使用建立的原发性胰腺癌的小鼠模型，EpCAM/CD 3双特异性抗体MT 110在体外和体内有效靶向高度致瘤性CSC的群体。基于体内致瘤性研究，源自转移的胰腺癌细胞对MT 110治疗的抗性略高。这似乎与更高频率的EpCAM阴性CSCs.Conclusions亚群相关：细胞毒性T细胞可以有效地重定向对原代人胰腺癌细胞的T细胞接合BiTE抗体MT 110，包括高度致瘤性CSCs的亚群。Clin Cancer Res; 18（2）; 465-74. (C)2011年AACR。
Purpose: 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.Experimental Design: 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.Results: 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.Conclusions: 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. Clin Cancer Res; 18(2); 465-74. (C) 2011 AACR.