Reovirus mutant jin-3 exhibits lytic and immune-stimulatory effects in preclinical human prostate cancer models

Abstract

Treatment of castration-resistant prostate cancer remains a challenging clinical problem. Despite the promising effects of immunotherapy in other solid cancers, prostate cancer has remained largely unresponsive. Oncolytic viruses represent a promising therapeutic avenue, as oncolytic virus treatment combines tumour cell lysis with activation of the immune system and mounting of effective anti-tumour responses. Mammalian Orthoreoviruses are non-pathogenic human viruses with a preference of lytic replication in human tumour cells. In this study, we evaluated the oncolytic efficacy of the bioselected oncolytic reovirus mutant jin-3 in multiple human prostate cancer models. The jin-3 reovirus displayed efficient infection, replication, and anti-cancer responses in 2D and 3D prostate cancer models, as well as in ex vivo cultured human tumour slices. In addition, the jin-3 reovirus markedly reduced the viability and growth of human cancer cell lines and patient-derived xenografts. The infection induced the expression of mediators of immunogenic cell death, interferon-stimulated genes, and inflammatory cytokines. Taken together, our data demonstrate that the reovirus mutant jin-3 displays tumour tropism, and induces potent oncolytic and immunomodulatory responses in human prostate cancer models. Therefore, jin-3 reovirus represents an attractive candidate for further development as oncolytic agent for treatment of patients with aggressive localised or advanced prostate cancer.

Biomarker screen for efficacy of oncolytic virotherapy in patient-derived pancreatic cancer cultures

“… 53 , 77 , 78 , 79 , 80 For RV jin-3, hallmarks of ICD were found after treatment of patient-derived prostate cancer models. 81 …”

New advances of the androgen receptor in prostate cancer: report from the 1st International Androgen Receptor Symposium

“…In the session’s final talk, Dr. van de Merbel gave an overview of “Patient-derived tumor models for personalized therapeutics in prostate cancer.” Using her data on the oncolytic virus jin-3 reovirus, she described the advantages and pitfalls of PCa models such as syngeneic mice models, 3D prostate organoids, ex vivo slices, and patient-derived xenografts [ 61 , 62 ]. She revealed that oncolytic viruses are powerful in stimulating antitumor immune responses and may potentiate immunotherapy.…”

Oncolyic Virotherapy for Prostate Cancer: Lighting a Fire in Winter

“…Preclinical studies of reovirus against PCa were conducted later than those of Ads. In 2010, Morris et al found that reovirus caused the death of human prostate cancer cells PC-3, LNCaP and Du-145 by apoptosis, and tumor reduction was observed after a single intratumoral injection of the virus in nude mice bearing human prostate cancer xenografts [ 193 ]. Wild-type reovirus binds to cancer cells through the interaction of the viral stinger protein Sigma-1 with sialic acid and junctional adhesion molecule A (JAM-A).…”