Abstract 1494: Combination of CEA TCB, a novel T-cell bispecific antibody for the treatment of solid tumors, with PD-L1 checkpoint blockade

Abstract

Abstract Recent results from clinical trials have shown that immune therapies, particularly immune checkpoint inhibitors, can extend the overall survival of cancer patients and lead to durable responses. Despite these promising results, current immune-based therapies are only effective in a proportion of patients and combination strategies are needed to improve therapeutic benefit. Programmed death-ligand 1(PD-L1) is found on the surface of immune and tumor cells and its expression is induced by interferon gamma (IFNg). It prevents the immune system from destroying cancer cells by interacting with the inhibitory programmed death-1 (PD-1) and B7.1 receptors on activated T cells, which results in a T-cell inhibitory signal. CEA TCB (RG7802, RO6958688) is a novel T cell bispecific antibody targeting the carcinoembryonic antigen (CEA) on tumor cells and CD3 on T cells, currently being investigated as single agent in a Phase I study in patients with advanced and/or metastatic CEA-expressing tumors. CEA TCB-mediated killing of tumor cells led to T cell activation, IFNg secretion and subsequent up-regulation of the PD-1/PD-L1 immune suppressive pathway in vitro and in vivo, similarly to what happens during tumor adaptive immune resistance mechanisms where upon recognition of tumor antigens, TILs produce IFNg, which drives PD-L1 expression in the tumor microenvironment and delivers a suppressive signal to T cells upon binding to PD-1. Incubation of the high-CEA expressing gastric carcinoma cell line (MKN45) with human PBMCs (E:T 10:1) and increasing concentrations of CEA TCB, led to a dose-dependent up-regulation of PD-1 receptor on both CD4+ or CD8+ T cell subsets as well as of PD-L1 on surviving tumor cells as early as 24 h following treatment. PD-1 expression was specific as it did not occur in the absence of CEA-expressing tumor cells or upon treatment with un-targeted control TCB. In vivo studies performed using MKN45 tumor xenografts (MKN45) in fully humanized NOG mice demonstrated that CEA TCB treatment led to increased frequency of intra-tumoral T cells expressing PD-1 and to a strong induction of PD-L1 expression in tumors. Combination of CEA TCB with a PD-L1 blocking antibody showed significant increase of anti-tumor activity as compared to the respective single agents. These preclinical data indicate that CEA TCB treatment leads to up-regulation of the PD-1/PD-L1 immune suppressive pathway and that the combination of CEA TCB with PD-L1 blocking agents results in enhanced anti-tumor activity. Phase Ib clinical trials investigating the combination of CEA TCB and atezolizumab are currently ongoing. Citation Format: Marina Bacac, Tanja Fauti, Sara Colombetti, Linda Fahrni, Valeria Nicolini, Christian Gerdes, Jose Saro, Vaios Karanikas, Christian Klein, Pablo Umana. Combination of CEA TCB, a novel T-cell bispecific antibody for the treatment of solid tumors, with PD-L1 checkpoint blockade. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1494.