OBJECTIVE: To explore the effects of intraperitoneal (i.p.) infusion of catumaxomab, a bispecific monoclonal antibody (anti-EpCAM×anti-CD3), on T cells, NK cells and macrophages in ascites of cancer patients and to understand how ascitic immune cells can be activated despite the pervasive immunosuppressive ability of ascites microenvironment. METHODS: Six patients with malignant ascites received i.p. catumaxomab infusion. Ascitic immune cells were profiled by flow cytometry and gene expression at baseline and after i.p. catumaxomab infusion. In vitro experiments enabled investigations on the adverse effect of ascites microenvironment on catumaxomab-stimulated immune cells. RESULTS: I.p. catumaxomab infusion enhanced the expression of the CD69 and CD38 activation molecules in CD4(+) and CD8(+) T cells, NK cells and macrophages, and favoured CD8(+) T cell accumulation into the peritoneal cavity. An analogous immune cell activation as well as IFN-γ and IL-2 production were induced by catumaxomab in vitro. In vitro experiments showed that the immunosuppressive milieu of ascites abrogated all the immunostimulatory activities of catumaxomab. Adding EpCAM(+) tumour cells to the culture permitted both catumaxomab Fab regions to engage cognate antigens and restored immunostimulatory catumaxomab activity. CONCLUSIONS: This is the first demonstration in a clinical setting that i.p. catumaxomab infusion activates NK cells and macrophages in addition to T cells in ascites and favours CD8(+) T cell accumulation into the peritoneal cavity. Moreover, our findings indicate that the concomitant binding of both catumaxomab Fab regions delivers an activation signal that is strong enough to activate immune cells despite the prevailing immunosuppressive environment of malignant ascites.

Fossati, M., Buzzonetti, A., Monego, G., Catzola, V., Scambia, G., Fattorossi, A., Battaglia, A., Immunological changes in the ascites of cancer patients after intraperitoneal administration of the bispecific antibody catumaxomab (anti-EpCAM x anti-CD3), <<GYNECOLOGIC ONCOLOGY>>, 2015; 138 (2): 343-351. [doi:10.1016/j.ygyno.2015.06.003] [http://hdl.handle.net/10807/70312]

Immunological changes in the ascites of cancer patients after intraperitoneal administration of the bispecific antibody catumaxomab (anti-EpCAM x anti-CD3)

Monego, G;Scambia, Giovanni;Fattorossi, A;
2015

Abstract

OBJECTIVE: To explore the effects of intraperitoneal (i.p.) infusion of catumaxomab, a bispecific monoclonal antibody (anti-EpCAM×anti-CD3), on T cells, NK cells and macrophages in ascites of cancer patients and to understand how ascitic immune cells can be activated despite the pervasive immunosuppressive ability of ascites microenvironment. METHODS: Six patients with malignant ascites received i.p. catumaxomab infusion. Ascitic immune cells were profiled by flow cytometry and gene expression at baseline and after i.p. catumaxomab infusion. In vitro experiments enabled investigations on the adverse effect of ascites microenvironment on catumaxomab-stimulated immune cells. RESULTS: I.p. catumaxomab infusion enhanced the expression of the CD69 and CD38 activation molecules in CD4(+) and CD8(+) T cells, NK cells and macrophages, and favoured CD8(+) T cell accumulation into the peritoneal cavity. An analogous immune cell activation as well as IFN-γ and IL-2 production were induced by catumaxomab in vitro. In vitro experiments showed that the immunosuppressive milieu of ascites abrogated all the immunostimulatory activities of catumaxomab. Adding EpCAM(+) tumour cells to the culture permitted both catumaxomab Fab regions to engage cognate antigens and restored immunostimulatory catumaxomab activity. CONCLUSIONS: This is the first demonstration in a clinical setting that i.p. catumaxomab infusion activates NK cells and macrophages in addition to T cells in ascites and favours CD8(+) T cell accumulation into the peritoneal cavity. Moreover, our findings indicate that the concomitant binding of both catumaxomab Fab regions delivers an activation signal that is strong enough to activate immune cells despite the prevailing immunosuppressive environment of malignant ascites.
Inglese
Fossati, M., Buzzonetti, A., Monego, G., Catzola, V., Scambia, G., Fattorossi, A., Battaglia, A., Immunological changes in the ascites of cancer patients after intraperitoneal administration of the bispecific antibody catumaxomab (anti-EpCAM x anti-CD3), <<GYNECOLOGIC ONCOLOGY>>, 2015; 138 (2): 343-351. [doi:10.1016/j.ygyno.2015.06.003] [http://hdl.handle.net/10807/70312]
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