Immunomonitoring Results Of A Pivotal Phase Ii/Iii Study With The Trifunctional Antibody Catumaxomab (Anti-Epcam X Anti-Cd3) In Ovarian Cancer Patients With Malignant Ascites

3020 Background: Malignant ascites is a symptom of late-stage tumor disease and associated with a poor prognosis. The trifunctional antibody catumaxomab specifically binds to EpCAM+ tumor cells and redirects CD3+ T lymphocytes and FcγR I/III+ accessory cells simultaneously to the tumor site. Methods: 129 (85 catumaxomab; 44 control paracentesis) EpCAM-positive ovarian cancer patients with symptomatic malignant ascites were compared in an open-label, multicenter, randomized study for efficacy and tolerability of intraperitoneally given catumaxomab. Various in vivo and in vitro immunological and pharmacodynamic parameters were measured directly from ascites cell preparations. Results: During the course of catumaxomab treatment in the ascites fluid tumor cells dramatically decreased and leukocytes increased. Accordingly, the in vivo effector/target ratio (CD45+/EpCAM+) showed an drastic increase from a baseline of 6:1 to 10,000:1 already after the first 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 ascites fluid and an increase of IL-6 in serum at 24 hours after each infusion indicating systemic effects of catumaxomab. In vitro pharmacodynamic studies were carried out with screening samples to further validate the in vivo results. Similarly, the in vitro experiments showed efficient EpCAM+ tumor cell elimination, leukocyte expansion, drastical improvement of the effector/target ratio and activation of T cells. Additionally, a strong upregulation of activating cytokines IL-2 and IFN-γ (TH1 cytokine profile) and proliferation of CD4+, CD8+ T cells and CD11c+ accessory cells were demonstrated in the samples with catumaxomab compared to controls. Conclusions: Intraperitoneal catumaxomab treatment triggers activation and proliferation of different immune cells and leads to elimination of tumor cells within malignant ascites. These data confirm the postulated mode of action of trifunctional catumaxomab in vivo and correlate with clinical efficacy in patients with malignant ascites. [Table: see text]