Abstract 349: Oncolytic reovirus variants induce direct oncolysis in human prostate cancer

Abstract

Abstract The acquisition of therapy resistance and the formation of distant metastases represent major problems in prostate cancer. To date, immunotherapeutic approaches have been relatively disappointing in the treatment of prostate cancer. Therapies based on oncolytic viruses are being exploited for several tumor entities and have been studied in multiple clinical trials. Mammalian orthoreovirus is a non-enveloped double stranded RNA virus that has not been linked to serious disease in humans. Reovirus is relatively safe to use and several clinical trials are currently ongoing to study the oncolytic effect of reovirus in various tumor types. Type 3 Dearing (T3D) is a promising candidate for the use as an oncolytic agent. Besides wildtype T3D reovirus (R124), spontaneous mutants Jin1, 2 and 3 were generated which harbor mutations in spike protein Sigma-1. In this way, Jin mutants are able to infect cells independently of the Junction Adhesion Molecule-A (JAM-A) entry receptor on the tumor cell surface, which is often downregulated in different types of cancer. In this study, the direct oncolytic effect of wildtype (R124) and Jin mutant reovirus was examined in human prostate cancer cells in vitro and in our ‘near-patient’ model of ex vivo cultured human prostate cancer tissue slices. Both R124 and Jin3 dose-dependently induced prostate cancer cell death in PC-3M-Pro4luc2, DU145 and 22Rv1 cells in vitro. Interestingly, JAM-A negative cancer cells were insensitive for R124, but were effectively killed by Jin1 mutant, indicating the beneficial effects of the Jin mutant in JAM-A low/negative tumors. Moreover, tumor tissue slices were generated from explanted patient prostate cancer tissues and patient-derived xenografts (PDX) and cultured with reovirus. Oncolytic effects were observed in ex vivo cultured tumor slices upon viral replication and subsequent stimulation of apoptosis. Therefore, ex vivo culture of patient-derived tumor tissue allows the assessment of individual anti-tumor response of the oncolytic virotherapy (i.e. personalized therapeutics). Taken together, our results indicate that both wildtype R124 virus and mutant Jin reovirus can infect and replicate in human prostate cancer cells and patient-derived prostate cancer tissues. The Jin mutants are of particular interest in JAM-A negative tumors. The indirect immunomodulatory effects of reovirus in human prostate cancer are currently ongoing. In conclusion, our selected oncolytic reoviruses may represent a promising novel treatment strategy in human prostate cancer alone or combined with immunostimulatory agents. Citation Format: Arjanneke F. van de Merbel, Geertje van der Horst, Maaike H. van der Mark, Diana J. van den Wollenberg, Jack A. Schalken, Anne Collins, Norman J. Maitland, Rob C. Hoeben, Gabri van der Pluijm. Oncolytic reovirus variants induce direct oncolysis in human prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 349.