Potent Immunomodulatory Effects of the Trifunctional Antibody Catumaxomab

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 (T H )-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 CD4þ T H 1 and CD8 þ T H 1 to release IFN-g but failed to trigger T H 17 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. Cancer Res; 73(15); 4663-73. Ó2013 AACR.

Expression of inhibitory receptors on intratumoral T cells modulates the activity of a T cell-bispecific antibody targeting folate receptor

“…Furthermore, and in line with our own findings, the lack of T-cell activation was not related to the T-cell to tumor cell ratio or the level of tumor-antigen expression on tumor cells. 38 Sustained expression of immune checkpoints is a hallmark of exhausted T-cells and co-regulates their dysfunctional state. [31][32][33] We documented the expression of the inhibitory receptors PD-1, Tim-3, CTLA-4, Lag-3, and BTLA on intratumoral CD8 C T-cells.…”

The Role of Relative Lymphocyte Count as a Biomarker for the Effect of Catumaxomab on Survival in Malignant Ascites Patients: Results from a Phase II/III Study

“…Different immunologic mechanisms are induced after intraperitoneal administration of catumaxomab, for example, immediate T-cell-mediated cytotoxicity is involved in the reduction of malignant ascites (22). Complex immunologic mechanisms in addition to the direct and local effects of catumaxomab may be involved in its mode of action (23). Cellular and humoral immune responses to antigens other than EpCAM [e.g.…”

Antitumor Immunity: Easy as 1, 2, 3 with Monoclonal Bispecific Trifunctional Antibodies?

“…who have received this agent (16) or using biologic material derived from patients with EpCAM þ -malignancy (21). In both cases, it was shown that catumaxomab promotes the activation of both ascitic CD4 þ and CD8 þ T cells in addition to CD16 (low affinity Fc receptor)-expressing accessory cells in a strictly EpCAM-dependent manner (21).…”

“…In both cases, it was shown that catumaxomab promotes the activation of both ascitic CD4 þ and CD8 þ T cells in addition to CD16 (low affinity Fc receptor)-expressing accessory cells in a strictly EpCAM-dependent manner (21). Immune cellactivation was accompanied by release of prototypic type 1 T-cell cytokines [interferon (IFN)-g, interleukin (IL)-2] and the inflammatory cytokines, tumor necrosis factor-a and IL-6, despite the presence of regulatory T cells at that site (16,21). Accessory cells comprised NK cells, which upregulated the cytolytic effector TRAIL, in addition to monocytes, which upregulated the expression of costimulatory ligands (CD40 and CD80).…”

“…This question was studied using catumaxomab alone or in combination with oxaliplatin, a chemotherapeutic agent that is known to promote immunogenic cell death in its own right. When these agents were combined, tumor cells exhibited an increase in three cardinal hallmarks of immunogenic cell death, namely translocation of calreticulin from endoplasmic reticulum to cell surface, accompanied by release of high mobility group box 1 (HMGB1), and adenosine triphosphate (21). Respectively, these provide a combination of "eat me," danger signals, and inflammasome activating/chemotactic signals to monocytes and dendritic cells that together favor the crosspriming of tumor-reactive T-cell responses (22).…”