Abstract
BackgroundUterine and ovarian carcinosarcomas (CS) are rare but highly aggressive gynecologic tumors which carry an extremely poor prognosis. We evaluated the expression levels of EpCAM and the in vitro activity of solitomab, a bispecific single-chain antibody construct which targets epithelial-cell-adhesion-molecule (EpCAM) on tumor cells and also contains a CD3 binding region, against primary uterine and ovarian CS cell lines.MethodsEpCAM expression was evaluated by flow cytometry in a total of 5 primary CS cell lines. Sensitivity to solitomab-dependent-cellular-cytotoxicity (ADCC) was tested against the panel of primary CS cell lines expressing different levels of EpCAM in standard 4 h 51Cr release-assays. The proliferative activity, activation, cytokine secretion (i.e., Type I vs Type II) and cytotoxicity of solitomab in autologous tumor-associated-T cells (TAL) in the pleural fluid of a CS patient were also evaluated by CFSE and flow-cytometry assays.ResultsSurface expression of EpCAM was found in 80.0 % (4 out of 5) of the CS cell lines tested by flow cytometry. EpCAM positive cell lines were found resistant to NK or T-cell-mediated killing after exposure to peripheral blood lymphocytes (PBL) in 4-h chromium-release assays (mean killing ± SEM = 1.1 ± 1.6 %, range 0–5.3 % after incubation of EpCAM positive cell lines with control BiTE®). In contrast, after incubation with solitomab, EpCAM positive CS cells became highly sensitive to T-cell-cytotoxicity (mean killing ± SEM of 19.7 ± 6.3 %; range 10.0-32.0 %; P < 0.0001). Ex vivo incubation of autologous TAL with EpCAM expressing malignant cells in pleural effusion with solitomab, resulted in a significant increase in T-cell proliferation in both CD4+ and CD8+ T cells, increase in T-cell activation markers (i.e., CD25 and HLA-DR), and a reduction in number of viable CS cells in the exudate (P < 0.001).ConclusionsSolitomab may represent an effective treatment for patients with recurrent/metastatic and/or chemo-resistant CS overexpressing EpCAM.
Highlights
Gynecological carcinosarcomas (CS), known as Malignant Mixed Mullerian Tumors (MMMT), are rare biphasic tumors that most commonly arise in the uterus and ovaries [1]
Both primary uterine carcinosarcoma cell lines were established from biopsies of the uterus of chemotherapy naïve patients at the time of the primary staging surgery, while all primary ovarian carcinosarcoma cell lines were obtained from the biopsy of metastatic sites of disease in patients harboring recurrent, chemotherapyresistant disease
Carcinosarcoma primary cell lines are resistant to natural killer (NK) cell activity but sensitive to solitomab-mediated T cell cytotoxicity We evaluated all five primary carcinosarcoma cancer cell lines for their sensitivity to NK and T-cells with a standard 4-h chromium (51Cr) release assay cytotoxicity using solitomab (EpCAM BiTE®) at a concentration of 1 μg/ml, as described previously [10]
Summary
Gynecological carcinosarcomas (CS), known as Malignant Mixed Mullerian Tumors (MMMT), are rare biphasic tumors that most commonly arise in the uterus and ovaries [1]. While the pathogenesis of CS remains under debate, an increasing body of evidence supports the origin of both elements from a common epithelial cell that undergoes sarcomatous dedifferentiation, rather than two independent progenitors [2,3,4,5]. The discovery of novel diagnostic and therapeutic markers against this aggressive subset of gynecological tumors remains a high priority. Uterine and ovarian carcinosarcomas (CS) are rare but highly aggressive gynecologic tumors which carry an extremely poor prognosis. We evaluated the expression levels of EpCAM and the in vitro activity of solitomab, a bispecific single-chain antibody construct which targets epithelial-cell-adhesion-molecule (EpCAM) on tumor cells and contains a CD3 binding region, against primary uterine and ovarian CS cell lines
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