Abstract
Catumaxomab (CatmAb), a trifunctional bispecific antibody directed against the epithelial cell adhesion molecule (EpCAM) and the T-cell antigen CD3, is approved as intraperitoneal therapy for the treatment of malignant ascites in patients with EpCAM-positive carcinomas. The immunomonitoring results of a phase II/III study using CatmAb revealed a tumoricidal effect associated with reduced VEGF levels, CD69-expressing T cells, and the release of T-helper cell (TH)-1 cytokines. We comprehensively dissected the immunomodulatory effects of the CatmAb on the major subsets of malignant ascites-infiltrating leukocytes and the molecular fingerprint of tumor cell death. Herein we show that in the presence of EpCAM-positive tumor targets, CatmAb markedly enhanced T-cell activation [CD69, CD107A (LAMP1), HLA-DR and PD-1(PDCD1) expression] and stimulated inflammatory CD4(+) TH1 and CD8(+) TH1 to release IFN-γ but failed to trigger TH17 cells. Engagement of CD16-expressing cells caused upregulation of TRAIL (TNFSF10) and costimulatory CD40 and CD80 molecules. CatmAb promoted tumor cell death associated with ATP release and strongly synergized with oxaliplatin for the exposure of the three hallmarks of immunogenic cell death (calreticulin, HMGB1, and ATP). These findings warrant validation as potential biomarkers of efficacy of CatmAb.
Highlights
The trifunctional bispecific monoclonal antibody catumaxomab (CatmAb) has two binding specificities directed at epithelial cell adhesion molecule [EpCAM (through a mouse immunoglobulin G (IgG)-2a] and CD3]
CatmAb-mediated T-cell triggering Ascitic fluids harvested from 12 patients bearing EpCAMþ/À
Similar findings were achieved in cocultures of peripheral blood mononuclear cells (PBMC) and allogeneic EpCAMþ tumor cells modulated by CatmAb (Supplementary Fig. S3) in that NK cells became CD69þ TRAILþ while expressing low levels of CD107A and IFN-g in the presence of the trifunctional Ab
Summary
The trifunctional bispecific monoclonal antibody catumaxomab (CatmAb) has two binding specificities directed at epithelial cell adhesion molecule [EpCAM (through a mouse immunoglobulin G (IgG)-2a] and CD3 (through a rat IgG2b)]. Pilot and phase I/II studies showed that intraperitoneal administration of CatmAb reduced tumor cell accumulation in ascitic fluids in a sustained manner [10, 11]. An open label, multicenter, randomized phase II/III trial in patients with malignant ascites due to epithelial cancer compared the effects of CatmAb with control paracentesis. Ascites concentrations of VEGF and CD133þEpCAMþ cancer stem cells significantly dropped following CatmAb treatment, whereas 20% to 30% of CD4þ and CD8þ T cells acquired CD69 expression [14]. We undertook a comprehensive phenotypic analysis of the immune infiltrates and the tumor cell death fingerprint in ascitic fluids incubated ex vivo with CatmAb. Our findings indicate that CatmAb skews the T-cell cytokine www.aacrjournals.org. When combined with oxaliplatin, CatmAb imprinted an immunogenic cell death pathway to tumor cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
