Abstract B03: RNAi-mediated β-catenin inhibition sensitizes noninflamed tumors to immune checkpoint blockade

Abstract

Abstract Anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies are immunotherapeutics which confer benefit to several subpopulations of cancer patients, yet the majority of tumors remain insensitive. Wnt/β-catenin signaling has been strongly implicated in mediating cancer immune evasion and resistance to immune checkpoint therapy. 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. DCR-BCAT is an advanced experimental therapeutic containing a chemically-optimized RNA interference (RNAi) trigger targeting CTNNB1, the gene that encodes β-catenin, formulated in a tumor-selective lipid nanoparticle. To understand the role of β-catenin in immunotherapy, we investigated DCR-BCAT in combination with checkpoint inhibitors in syngeneic murine tumor allograft models. β-catenin inhibition promoted T-cell infiltration and significantly improved sensitivity to anti-PD-1 and anti-CTLA-4 therapy. The combination treatment yielded significant tumor growth inhibition compared to monotherapy in B16F10 melanoma, 4T1 mammary carcinoma, Neuro2A neuroblastoma and Renca renal adenocarcinoma. T-cell mediated cytotoxicity was identified of the primary mechanism of efficacy, as shown by granzyme B and perforin staining. Interestingly, antitumor efficacy in these combination studies was not correlated with Wnt activation status in syngeneic models. Finally and strikingly, when DCR-BCAT was combined with immuotherapy in mice which develop spontaneous Wnt-driven mammary tumors, checkpoint therapy potentiation yielded complete tumor regressions. These data offer proof-of-concept for conversion of non-inflamed tumors to inflamed tumors by β-catenin inhibition, and support clinical evaluation of this combination approach using a first-in-class RNAi-based agent. Citation Format: Shanthi Ganesh, Serena Shui, Weimin Wang, Bob D. Brown, Marc Abrams. RNAi-mediated β-catenin inhibition sensitizes noninflamed tumors to immune checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B03.