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Mol Ther. 2018 Nov 7;26(11):2567-2579. doi: 10.1016/j.ymthe.2018.09.005. Epub 2018 Sep 13.

RNAi-Mediated β-Catenin Inhibition Promotes T Cell Infiltration and Antitumor Activity in Combination with Immune Checkpoint Blockade.

Author information

1
Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA. Electronic address: sganesh@dicerna.com.
2
Dicerna Pharmaceuticals, Inc., Cambridge, MA 02140, USA.

Abstract

Wnt/β-catenin signaling mediates cancer immune evasion and resistance to immune checkpoint therapy, in part by blocking cytokines that trigger immune cell recruitment. 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 nanoparticle drug product containing a chemically optimized RNAi trigger targeting CTNNB1, the gene that encodes β-catenin. In syngeneic mouse tumor models, β-catenin inhibition with DCR-BCAT significantly increased T cell infiltration and potentiated the sensitivity of the tumors to checkpoint inhibition. The combination of DCR-BCAT and immunotherapy yielded significantly greater tumor growth inhibition (TGI) compared to monotherapy in B16F10 melanoma, 4T1 mammary carcinoma, Neuro2A neuroblastoma, and Renca renal adenocarcinoma. Response to the RNAi-containing combination therapy was not dependent on Wnt activation status of the tumor. Importantly, this drug combination was associated with elevated levels of biomarkers of T cell-mediated cytotoxicity. Finally, when CTLA-4 and PD-1 antibodies were combined with DCR-BCAT in MMTV-Wnt1 transgenic mice, a genetic model of spontaneous Wnt-driven tumors, complete regressions were achieved in the majority of treated subjects. These data support RNAi-mediated β-catenin inhibition as an effective strategy to increase response rates to cancer immunotherapy.

KEYWORDS:

CD8+ T cells; DsiRNA; LNP; RNAi; cancer; checkpoint blockade; immunotherapy; lipid nanoparticle; non-inflamed tumors; β-catenin

PMID:
30274786
PMCID:
PMC6225018
DOI:
10.1016/j.ymthe.2018.09.005
[Indexed for MEDLINE]
Free PMC Article

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