Carvedilol targets β-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy

• Published in: Communications biology 2022-02, Vol.5 (1), p.106-12, Article 106
• Main Authors: Hoare, Joseph I., Osmani, Bleona, O’Sullivan, Emily A., Browne, Ashley, Campbell, Nicola, Metcalf, Stephen, Nicolini, Francesco, Saxena, Jayeta, Martin, Sarah A., Lockley, Michelle
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/106; 13/109; 13/21; 13/31; 13/44; 13/51; 38; 38/22; 631/154/51; 64; 64/60; 692/308/153; 692/4028/67/1517/1709; Adenoviridae; Adenoviruses; Adrenergic alpha-1 Receptor Antagonists - pharmacology; Adrenergic alpha-1 Receptor Antagonists - therapeutic use; Animal models; Animals; Antitumor activity; Arrestin; beta-Arrestins - metabolism; Biology; Biomedical and Life Sciences; Carvedilol - pharmacology; Carvedilol - therapeutic use; Cell Line, Tumor; Clinical trials; CRISPR; Cytokines; DNA biosynthesis; Female; Humans; Immunity, Innate; Inflammation; Innate immunity; Life Sciences; Mice; Neoplasms, Experimental - drug therapy; Oncolysis; Oncolytic Virotherapy; Oncolytic Viruses; Ovarian cancer; Ovarian Neoplasms - immunology; Ovarian Neoplasms - therapy; Tumors; Viruses; Xenograft Model Antitumor Assays
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-03041-4

Oncolytic viruses are being tested in clinical trials, including in women with ovarian cancer. We use a drug-repurposing approach to identify existing drugs that enhance the activity of oncolytic adenoviruses. This reveals that carvedilol, a β-arrestin-biased β-blocker, synergises with both wild-type adenovirus and the E1A-CR2-deleted oncolytic adenovirus, dl 922-947. Synergy is not due to β-adrenergic blockade but is dependent on β-arrestins and is reversed by β-arrestin CRISPR gene editing. Co-treatment with dl 922-947 and carvedilol causes increased viral DNA replication, greater viral protein expression and higher titres of infectious viral particles. Carvedilol also enhances viral efficacy in orthotopic, intraperitoneal murine models, achieving more rapid tumour clearance than virus alone. Increased anti-cancer activity is associated with an intratumoural inflammatory cell infiltrate and systemic cytokine release. In summary, carvedilol augments the activity of oncolytic adenoviruses via β-arrestins to re-wire cytokine networks and innate immunity and could therefore improve oncolytic viruses for cancer patient treatment. Hoare et al describe a drug-repurposing approach and report that carvedilol, a β-arrestin-biased β-blocker, exhibits synergistic anti-ovarian cancer effects with oncolytic adenovirus. The study reveals that carvedilol augments the activity of oncolytic adenoviruses via β-arrestins to re-wire cytokine networks and innate immunity, resulting in increased oncolytic activity.