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

• Published in: Molecular therapy Vol. 26; no. 11; pp. 2567 - 2579
• Main Authors: Ganesh, Shanthi, Shui, Xue, Craig, Kevin P., Park, Jihye, Wang, Weimin, Brown, Bob D., Abrams, Marc T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.11.2018; Elsevier Limited; American Society of Gene & Cell Therapy
• Subjects: Adenocarcinoma; Animal models; Animals; Antigens; Antitumor activity; beta Catenin - antagonists & inhibitors; beta Catenin - genetics; Breast cancer; cancer; Cancer immunotherapy; Cancer therapies; Carcinoma; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - immunology; Carcinoma, Renal Cell - pathology; CD8+ T cells; checkpoint blockade; Chemokines; Combined Modality Therapy; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 Antigen - genetics; CTLA-4 Antigen - immunology; CTLA-4 protein; Cytokines; Cytotoxicity; Drug dosages; DsiRNA; Experiments; Female; Flow cytometry; Growth inhibition; Humans; Immune checkpoint; Immunoglobulins; Immunology; Immunotherapy; Immunotherapy - methods; Kinases; lipid nanoparticle; LNP; Lymphocytes; Lymphocytes T; Mammary gland; Melanoma; Melanoma, Experimental - drug therapy; Melanoma, Experimental - genetics; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Metastases; Metastasis; Mice; Mice, Transgenic; Mutation; Nanoparticles; Neuroblastoma; non-inflamed tumors; Original; PD-1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Response rates; RNA Interference; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; RNA-mediated interference; RNAi; Software; T cell receptors; T-Lymphocytes - immunology; Transgenic mice; Tumors; Wnt protein; Wnt Signaling Pathway - genetics; Wnt1 Protein - genetics; β-Catenin; β-catenin; CD8+ T cells; checkpoint blockade; RNAi; lipid nanoparticle; DsiRNA; immunotherapy; non-inflamed tumors; cancer; LNP
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2018.09.005

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. [Display omitted] Immune checkpoint inhibitors including PD-(L)1 antibodies have shown great potential for treating diverse human cancers, but relatively few patients achieve durable responses. Using murine tumor models, Ganesh et al. demonstrate that co-treatment with an optimized β-catenin-targeting RNAi agent increases sensitivity to immunotherapy by promoting the infiltration of cytotoxic T cells.