495P - Contribution of immunogenic cell death (ICD) to the anti-tumor activity of catumaxomab (anti-EPCAM x anti-CD3)

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Anticancer agents
Immunotherapy
Therapy
Biological therapy
Presenter Diane Goéré
Authors D. Goéré1, C. Flament2, N. Chaput-Gras2, L. Zitvogel3
  • 1Surgery, Institut Gustave Roussy, 94805 - Villejuif/FR
  • 2Surgical Oncology, Institut Gustave Roussy, 94805 - Villejuif/FR
  • 3Institut Gustave Roussy, 94805 - Villejuif/FR

Abstract

Background

The trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3) is approved (EU) for the intraperitoneal treatment of malignant ascites. Catumaxomab is a trifunctional antibody targeting EpCAM on tumor cells, CD3 on T lymphocytes and binding to FcγR positive accessory cells thereby leading to the elimination of EpCAM+ tumor cells by different immune-mediated mechanisms. It has been reported that tumor cell death triggered by some immunogenic compounds or drugs used in the oncological armamentarium participates in the long term protection of patients treated with chemotherapy. The present nonclinical study investigated whether catumaxomab promotes immunogenic cell death (ICD) mechanisms which may contribute to its mode of action and its pharmacological activity in vivo.

Methods

Either co-cultures of peripheral blood mononuclear cells from healthy volunteers and EpCAM+ tumor cells (allogeneic system) or ascites cells from patients with malignant ascites (autologous system) were incubated in the presence of catumaxomab for 24-48 hours. Analysis of T, NK, DC/monocyte cell activation and measurement of cytokine release in cell culture supernatants was performed. Subsequent analyses included investigation of cell death of EpCAM+ tumor cells and evaluation of ICD parameters (calreticulin, HMGB1, ATP).

Results

The trifunctional antibody catumaxomab, in the presence of EpCAM+ tumor cells, induces activation of T lymphocytes, both CD4, CD8, with induction of Th1 and Th17 polarization accompanied by a by-stander NK cell triggering. In the absence of ICD chemotherapy (oxaliplatin, doxorubicin), no ICD markers (calreticulin, HMGB1, ATP) can be detected on EpCAM+ tumor cells. However, following a pre-sensitization by suboptimal doses of oxaliplatin, catumaxomab could promote enhanced exposure of calreticulin, HMGB1 and ATP release from EpCAM+ tumor cells (allogeneic system).

Conclusions

Activation of T cells and induction of inflammatory lymphocytes mainly contributes to the catumaxomab-mediated elimination of EpCAM+ tumor target cells. ICD mechanisms including release of HMGB1 and ATP, exposure of calreticulin by targeted tumor cells may further promote the anti-tumor activity of catumaxomab.

Disclosure

All authors have declared no conflicts of interest.