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The effect of the trifunctional anti-EpCAM antibody catumaxomab on the development of tumor-specific immune responses in patients with gastric cancer.

2601 Background: The abundant expression of the epithelial cell-adhesion molecule EpCAM on the surface of epithelial cancer cells renders it an attractive target for immunotherapy of gastric cancer (GC). The trifunctional antibody (Ab) catumaxomab targets EpCAM on malignant cells and CD3 on T cells while triggering antigen (Ag)-presenting cells via their Fcγ-receptor. Recently, catumaxomab has received approval for the treatment of malignant ascites; however, the exact immune mechanisms behind its clinical effects are unknown.


METHODS
In a phase II study, patients with operable GC received neoadjuvant chemotherapy followed by 1 dose of catumaxomab during surgery and 4 consecutive doses applied intraperitoneally in the adjuvant setting. We measured the immunomodulatory effects of catumaxomab in 6 patients at 3 time points: before surgery, after application of the first dose, and 1 month post treatment.


RESULTS
None of the patients had evidence of autologous EpCAM-specific Ab responses. However, the majority of patients developed Abs against different classes of Ags, namely cancer-testis Ags, after catumaxomab treatment. Monitoring T cell subsets, we observed a drastic decrease in peripheral CD4+ T cells carrying an effector and T-helper (Th)-1 phenotype (CXCR3+CCR4-) directly after Ab application, whereas the CD4+ Th2 population remained unchanged. At 4 weeks after catumaxomab, the number of CD4+ effector-type T cells in the peripheral blood (PB) had returned to baseline levels. Interestingly, we could demonstrate pre-existing EpCAM-specific CD4+ and/or CD8+ T cells in all patients. While these T cells seemed to disappear from the PB immediately after Ab exposure, we detected significantly increased numbers of peripheral EpCAM-specific cells 4 weeks after immunomodulatory treatment.


CONCLUSIONS
Our data suggest that catumaxomab might exert its clinical effects through at least 3 different immunological routes: (1) the spreading of humoral immune responses to other Ags apart from EpCAM, (2) the redistribution of effector and Th1-type cells from the PB into peripheral tissues, and (3) the expansion of pre-existing EpCAM-specific T cells.