Abstract LB-075: Increased T cell- activation resulting from the combination of the anti-CEACAM6 function-blocking antibody BAY 1834942 with checkpoint inhibitors targeting either PD-1/PD-L1 or TIM-3

Abstract

Abstract CEACAM6 (CD66c) is a novel immune checkpoint regulator suppressing the activity of effector T cells against tumors. CEACAM6 is expressed on tumor cells of multiple malignancies e.g.adenocarcinomas of the lung, colon, pancreas and stomach. In these tumor types higher CEACAM6 expression is associated with advanced stages and a poor prognosis. In immunohistochemistry analyses on primary tumor tissue slides and tissue microarrays the tumor cell expression of CEACAM6 was found to be independent from that of programmed death ligand 1 (PD-L1). BAY 1834942 is a humanized monoclonal antibody selectively blocking CEACAM6-mediated suppression of human T cells. Because there is no rodent orthologue of CEACAM6, BAY 1834942 was fully characterized in in vitro studies as reported earlier (AACR 2018, abstract nr. 1771). Benchmarking and combination studies showed that CEACAM6-mediated inhibition of T cell activation is apparently non-redundant with the programmed death-receptor 1 (PD-1)/ PD-L1 axis. Combination experiments were performed in co-cultures of PD-1, T cell immunoglobulin and mucin domain 3 (TIM3) and CEACAM1 (CD66a) positive virus antigen-specific T cells and virus peptide-loaded CEACAM6-expressing tumor cells (HCC2935, HCT116-C6 cells). When BAY 1834942 was combined with antibody inhibitors of either PD-1 or PD-L1, we consistently observed enhanced secretion of proinflammatory cytokines by T cells in the presence of PD-L1 positive tumor cells (HCC2935). Unexpectedly, combination of BAY 1834942 with an anti-TIM3 antibody resulted in an even more pronounced, synergistic increase of cytokine secretion. The combined effect of CEACAM6 and TIM-3 blockade was confirmed using survivin peptide-specific T cells as alternative T cell source. In contrast, combination of BAY 1834942 with an anti-CEACAM1 function blocking antibody was not superior to anti-CEACAM1 treatment alone, which is in line with our hypothesis that CEACAM1 is the main T cell receptor for CEACAM6 in our functional assays. In summary, BAY 1834942 is a novel immune checkpoint inhibitor with monotherapy potential for the treatment of patients with CEACAM6-expressing cancers. The data shown here provide a rationale for examining its combination potential with immune checkpoint inhibitors targeting either PD-1, PD-L1 or TIM-3. BAY 1834942 is currently under investigation in Ph1 clinical trials (NCT03596372). Citation Format: Joerg Willuda, Hans-Henning Boehm, Jessica Pinkert, Mark Trautwein, Wolf-Dietrich Doecke, Oliver von Ahsen, Karl Ziegelbauer, Rienk Offringa, Bertolt Kreft, Philipp Beckhove. Increased T cell- activation resulting from the combination of the anti-CEACAM6 function-blocking antibody BAY 1834942 with checkpoint inhibitors targeting either PD-1/PD-L1 or TIM-3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-075.