Humoral tumor-associated immune responses induced by catumaxomab in patients with malignant ascites.

Abstract

2575 Background: Catumaxomab is the first EU approved bispecific (anti-EpCAM x anti-CD3) trifunctional antibody for the intraperitoneal (ip) treatment of malignant ascites (MA) in patients (pts) with EpCAM-positive tumors. Methods: In the ongoing phase IIIb study CASIMAS catumaxomab is investigated with/without prednisolone premedication in pts with MA due to epithelial cancer. Pts received four 3-hour infusions of 10, 20, 50 and 150 µg catumaxomab over 11 days. Plasma samples of 15 pts were quantified for autologous anti-EpCAM and anti-HER2 immunoglobulin (Ig) responses by ELISA. Additionally, MA samples were screened for EpCAM-positive tumor cells by immunocytochemistry and anti-drug antibody (ADA) responses were monitored. Results: At screening EpCAM-positive tumor cells were detected in the ascites fluid of all 15 pts. Thereof, 8 individuals (53%) showed a median 3-4 times increase of the initial anti-EpCAM Ig titer after treatment, whereas in 7/15 pts (47%) the titer did not increase. Although anti-EpCAM Ig screening values varied largely (2 -855 ng/ml) no significant distinction between the anti-EpCAM responder group (R) and non-responders (NR) was measured (p = 0.96; Mann Whitney test). However, there was a significant difference in the mean ADA concentrations of available samples determined 7 or 8 d after the last catumaxomab infusion (27,103 [R, n=5] vs. 910 ng/ml [NR, n=5]). Moreover, in 5/11evaluable pts (45%) HER2 -specific Ig could be quantified. In contrast to the augmented anti-EpCAM antibody levels which rapidly appeared (d 10) anti-HER2 responses developed de novo, started delayed (d 18) and peaked at the last sample collection (d 38, median=17 ng/ml). Interestingly, available samples of 2 pts who received a second treatment cycle after recurring MA displayed an anti-HER2 Ig booster reaction with peak levels of 48 and 209 ng/ml. Conclusions: The results indicate an active immunization induced by catumaxomab. Most importantly, the humoral immune response was not restricted to the EpCAM targeted but antigen spreading to the non-targeted HER2 tumor-associated antigen occurred. The impact of this immunization effect for the therapeutic benefit will be further investigated.