The trifunctional antibody catumaxomab (anti-EpCAM × anti-CD3) in patients with malignant ascites: Immunomonitoring results of a pivotal phase II/III study (pooled population).

Abstract

2521 Background: Malignant ascites (MA) is a symptom of late-stage tumor disease and associated with a poor prognosis. The trifunctional antibody catumaxomab is approved for treatment of MA. Methods: 258 EpCAM-positive ovarian (n=129) and nonovarian cancer (n=129) patients with MA were compared in an open-label, multicenter, randomized study for efficacy and tolerability of intraperitoneally administered catumaxomab. Various immunological and pharmacodynamical parameters were measured from ascites cell preparations. Results: In 170 patients randomized to catumaxomabtumor cells strongly decreased from a median of 6510 to 0 (after the last infusion). The in vivo target/effector ratio (EpCAM+/CD45+) showed a pronounced decrease from a baseline of 0.4404 at screening to 0.000 after the last infusion (all median). Leukocyte expansion was accompanied by in vivo upregulation of T-cell activation marker CD69 on CD4+ and CD8+ T cells in the MA samples. Concentration of the vascular endothelial growth factor (VEGF) was significantly decreased from screening (147 × 10-9) to after therapy (55 × 10-9) in MA samples (median; VEGF compared to total protein). Interestingly, at re-puncture visit catumaxomab patients (re- puncture at day 77, median) had a 9-fold lower and statistically significant (p=0.0012) tumor cell load compared to control patients (re-puncture at day 13, median). In vitro studies were carried out with screening samples to further validate the in vivo results. Similarly, the in vitro experiments showed EpCAM+ tumor cell elimination, leukocyte expansion, and activation of T cells. A strong upregulation of activating cytokines IL2, IL6, TNFα, and IFNγ (TH1 cytokine profile) was observed compared to control samples without catumaxomab. Conclusions: Intraperitoneal catumaxomab treatment triggers activation and proliferation of different types of immune cells and leads to long-lasting elimination of EpCAM+ tumor cells within malignant ascites. These data confirm the postulated trifunctional mode of action of catumaxomab in vivo and are in line with clinical efficacy in patients with MA. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Fresenius Biotech, TRION Research, TRION Pharma TRION Pharma TRION Pharma, TRION Research