EpCAM an immunotherapeutic target for gastrointestinal malignancy: current experience and future challenges

Abstract

Despite advances in surgery and adjuvant regimes, gastrointestinal malignancy remains a major cause of neoplastic mortality. Immunotherapy is an emerging and now successful treatment modality for numerous cancers that relies on the manipulation of the immune system and its effector functions to eradicate tumour cells. The discovery that the pan-epithelial homotypic cell adhesion molecule EpCAM is differentially expressed on gastrointestinal tumours has made this a viable target for immunotherapy. Clinical trials using naked anti EpCAM antibody, immunoconjugates, anti-idiotypic and dendritic cell vaccines have met variable success. The murine IgG2a Edrecolomab was shown to reduce mortality and morbidity at a level slightly lower than treatment with 5FU and Levamisole when administered to patients with advanced colorectal carcinoma in a large randomised controlled trial. Fully human and trifunctional antibodies that specifically recruit CD3-positive lymphocytes are now being tested clinically in the treatment of minimal residual disease and ascites. Although clinical trials are in their infancy, the future may bring forth an EpCAM mediated approach for the effective activation and harnessing of the immune system to destroy a pathological aberrance that has otherwise largely escaped its attention.

Lysis of cancer cells by autologous T cells in breast cancer pleural effusates treated with anti-EpCAM BiTE antibody MT110

“…The present study shows that breast cancer cells in pleural exudates frequently express the tumor-associated antigen EpCAM (CD326) providing a rationale for treatment of metastatic breast cancer with EpCAM-directed antibody-based therapeutic approaches [42,43] with the capacity of recruiting and activating T cells against EpCAM-expressing cancer cells [24] is here shown to redirect autologous T cells-as are found in the cellular milieu of malignant pleural effusions-for efficient lysis of carcinoma cells. This lysis was highly specific, dependent on the dose of MT110, similar as shown for the anti-Ep-CAM treatment of primary ovarian cells [44].…”

A genome-wide expression analysis identifies a network of EpCAM-induced cell cycle regulators

“…The application of EpCAM-specific antibodies as antineoplastic agents led to inconsistent results (reviewed in Baeuerle and Gires (2007) and Chaudry et al (2007)). The mechanisms by which anti-EpCAM antibodies exert tumour inhibition in vivo remain controversial.…”

EpCAM, a human tumor-associated antigen promotes Th2 development and tumor immune evasion

“…EpCAM is a panepithelial differentiation antigen that is restricted to normal epithelia in healthy subjects, but is typically overexpressed to various degrees in most human carcinomas, making it an attractive target for tumor therapy. 1 Several clinical trials with monoclonal 2 or bispecific antibodies and vaccination strategies directed against EpCAM showed variable success in the treatment of carcinomas. 1 Development of EpCAM-specific T cellbased strategies were suggested by in vitro studies with either chimeric T-cell receptor (TCR)-transduced primary T lymphocytes 3 or TAA-specific cytotoxic T lymphocytes (CTL), 4 showing cytolytic activity against EpCAM-expressing tumor cells.…”