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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CTLA-4 Antigen / antagonists & inhibitors*
  • CTLA-4 Antigen / genetics
  • CTLA-4 Antigen / immunology
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / immunology
  • Carcinoma, Renal Cell / pathology
  • Combined Modality Therapy
  • Female
  • Humans
  • Immunotherapy / methods
  • Melanoma, Experimental / drug therapy*
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Transgenic
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / immunology
  • RNA Interference
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics
  • T-Lymphocytes / immunology
  • Wnt Signaling Pathway / genetics
  • Wnt1 Protein / genetics
  • beta Catenin / antagonists & inhibitors
  • beta Catenin / genetics*

Substances

  • CTLA-4 Antigen
  • CTNNB1 protein, mouse
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • RNA, Small Interfering
  • Wnt1 Protein
  • Wnt1 protein, mouse
  • beta Catenin