Abstract 634: RNAi-mediated β-catenin inhibition promotes T-cell infiltration and anti-tumor activity in combination with immune checkpoint blockade

Abstract

Abstract Recent research strongly suggests an important role for Wnt/β-catenin signaling in mediating cancer immune evasion and resistance to immune checkpoint therapy, including anti-PD-1, anti-PD-L1, and anti CTLA-4 antibodies. The mechanism by which Wnt/β-catenin signaling causes checkpoint resistance is believed to involve blocking of specific cytokines which trigger immune cell recruitment to the tumor, resulting in the phenomenon of T-cell exclusion and rendering the tumor to a non-inflamed state. Inhibition of β-catenin may be an effective strategy for increasing the low response rate to these effective medicines in numerous cancer populations. DCR-BCAT is a potent and specific chemically-optimized RNA interference (RNAi) trigger targeting CTNNB1, the gene which encodes β-catenin, formulated in a tumor-selective EnCore lipid nanoparticle. In syngeneic mouse tumor models, β-catenin inhibition promoted T-cell infiltration and significantly improved the sensitivity of the tumors to checkpoint inhibition. The combination of DCR-BCAT and IO therapy yielded significant tumor growth inhibition compared to monotherapy in B16F10 melanoma, 4T1 mammary carcinoma, Neuro2A neuroblastoma and Renca renal adenocarcinoma. Importantly, a significant increase in CD8+ T-cells after DCR-BCAT monotherapy was observed in all models evaluated, including genetically-driven spontaneous MMTV-Wnt1 tumors. These data support clinical development of these combination approaches for this first-in-class RNAi therapeutic. Citation Format: Shanthi Ganesh, Serena Shui, Weimin Wang, Bob D. Brown, Marc Abrams. RNAi-mediated β-catenin inhibition promotes T-cell infiltration and anti-tumor activity in combination with immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 634. doi:10.1158/1538-7445.AM2017-634