Abstract 3481: Establishment of preclinical models to identify clinically useful combinations of trifunctional antibodies with chemotherapy

Abstract

The trifunctional bispecific antibodies catumaxomab (anti-EpCAM x anti-CD3) and ertumaxomab (anti-HER-2/neu x anti-CD3) exert their mechanism of action by simultaneous recruitment and activation of two different types of immune effector cells at the tumor site. The interaction of different immune effector cells results in efficient elimination of tumor cells by several killing mechanisms including T-cell cytotoxic responses and direct effects mediated by accessory cells. Effective treatment of cancer is essentially based on cytotoxic drugs that kill tumor cells or inhibit their proliferation. However, the commonly observed hematotoxicity of chemotherapeutics is regularly associated with some degree of immunosuppression. On the other hand, some of these chemotherapeutic agents are reported to support or even enhance the anti-tumoral effect of immunotherapeutic drugs in certain doses. A largely intact immune system is the key for trifunctional antibodies to exhibit their full mode of action. Since chemotherapy might impact the number and function of immune effector cells, we evaluated in different preclinical in vitro models whether the efficacy of trifunctional bispecific antibodies would be influenced when combined with chemotherapeutic drugs (5-FU and cisplatin). The preclinical studies performed included in vitro cytotoxicity assays with established tumor cell lines evaluating potential synergy by using the method of Chou and Talalay. Furthermore, results from 3D tumor spheroids and from an autologous human ex vivo setting are presented. In addition, immune cells from cancer patients were obtained at different time points during and after chemotherapy and were assessed for their in vitro cytotoxicity mediated by trifunctional antibodies. So far the results from the different in vitro assay systems used indicate synergy for the combination of the trifunctional antibodies with 5-FU and cisplatin. Furthermore, no negative influence of these chemotherapeutic drugs was observed on the trifunctional mode of action in vitro. These results provide a basis for the possible combination of these drugs with trifunctional antibodies in the clinical setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3481.

Humoral response to catumaxomab correlates with clinical outcome: Results of the pivotal phase II/III study in patients with malignant ascites

“…The short treatment duration of 10 days would allow for integration into existing treatment regimens. In vitro data indicate synergy of catumaxomab with chemotherapeutic drugs 26. Clinical studies investigating combinations of catumaxomab with chemotherapies are in development.…”

“…In vitro data indicate synergy of catumaxomab with chemotherapeutic drugs. 26 Clinical studies investigating combinations of catumaxomab with chemotherapies are in development. In this study, the HAMA response appeared to be associated with patients' clinical status and prognosis, as shown by the trend for HAMA-positive status to correlate with a better Karnofsky status.…”

Catumaxomab – trifunctional anti-EpCAM antibody used to treat malignant ascites

“…Infusion Cycle of Catumaxomab in Patients With Malignant Ascites (SECIMAS) [39]. The in vitro postulated potential synergistic effects of the combination/ sequence of catumaxomab and chemotherapy will be addressed in several study concepts [40].…”