Journal
CANCER
Volume 121, Issue 3, Pages 403-412Publisher
WILEY
DOI: 10.1002/cncr.29062
Keywords
epithelial cell adhesion molecule; CD3; T-lymphocyte; bispecific antibody; ovarian cancer
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Funding
- National Institutes of Health [R01 CA154460-01A1, U01 CA17606701A1]
- Honorable Tina Brozman Foundation
- Deborah Bunn Alley Ovarian Cancer Research Foundation
- Guido Berlucchi Research Foundation
- National Institutes of Health from the National Cancer Institute [CA-16359]
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BACKGROUND: Solitomab is a novel, bispecific, single-chain antibody that targets epithelial cell adhesion molecule (EpCAM) on tumor cells and also contains a cluster of differentiation 3 (CD3) (T-cell coreceptor) binding region. The authors evaluated the in vitro activity of solitomab against primary chemotherapy-resistant epithelial ovarian carcinoma cell lines as well as malignant cells in ascites. METHODS: EpCAM expression was evaluated by flow cytometry in 5 primary ovarian cancer cell lines and in 42 fresh ovarian tumor cell cultures in ascites from patients with mainly advanced or recurrent, chemotherapy-resistant disease. The potential activity of solitomab against EpCAM-positive tumor cells was evaluated by flow cytometry, proliferation, and 4-hour chromium-release, cell-mediated cytotoxicity assays. RESULTS: EpCAM expression was detected by flow cytometry in approximately 80% of the fresh ovarian tumors and primary ovarian tumor cell lines tested. EpCAM-positive, chemotherapy-resistant cell lines were identified as resistant to natural killer cell-mediated or T-cell-mediated killing after exposure to peripheral blood lymphocytes in 4-hour chromium-release assays (mean +/- standard error of the mean, 3.6% 60.7% of cells killed after incubation of EpCAM-positive cell lines with control bispecific antibody). In contrast, after incubation with solitomab, EpCAM-positive, chemotherapy-resistant cells became highly sensitive to T-cell cytotoxicity (mean +/- standard error of the mean, 28.2% 62.05% of cells killed; P<.0001) after exposure to peripheral blood lymphocytes. Ex vivo incubation of autologous tumor-associated lymphocytes with EpCAM-expressing malignant cells in ascites with solitomab resulted in a significant increase in T-cell activation markers and a reduction in the number of viable ovarian tumor cells in ascites (P<.001). CONCLUSIONS: Solitomab may represent a novel, potentially effective agent for the treatment of chemotherapy-resistant ovarian cancers that overexpress EpCAM. (C) 2014 American Cancer Society.
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