Improved oncolytic activity of a reovirus mutant that displays enhanced virus spread due to reduced cell attachment

Francisca Cristi; Maiah Walters; Nashae Narayan; Kate Agopsowicz; Mary M Hitt; Maya Shmulevitz

doi:10.1016/j.omto.2023.100743

Improved oncolytic activity of a reovirus mutant that displays enhanced virus spread due to reduced cell attachment

Mol Ther Oncolytics. 2023 Nov 2:31:100743. doi: 10.1016/j.omto.2023.100743. eCollection 2023 Dec 19.

Authors

Francisca Cristi^{1

2

3}, Maiah Walters¹, Nashae Narayan¹, Kate Agopsowicz^{4

3}, Mary M Hitt^{4

2

3}, Maya Shmulevitz^{1

2

3}

Affiliations

¹ Department of Medical Microbiology and Immunology, University of Alberta, Edmonton AB T6G 2E1, Canada.
² Li Ka Shing Institute of Virology, University of Alberta, Edmonton AB T6G 2E1, Canada.
³ Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton AB T6G 2E1, Canada.
⁴ Department of Oncology, University of Alberta, Edmonton AB T6G 1Z2, Canada.

Abstract

Wild-type reovirus serotype 3 Dearing (T3wt), a non-pathogenic intestinal virus, has shown promise as a cancer therapy in clinical trials, but it would benefit from an increased potency. Given that T3wt is naturally adapted to the intestinal environment (rather than tumors), we genetically modified reovirus to improve its infectivity in cancer cells. Various reovirus mutants were created, and their oncolytic potency was evaluated in vitro using plaque size as a measure of virus fitness in cancer cells. Notably, Super Virus 5 (SV5), carrying five oncolytic mutations, displayed the largest plaques in breast cancer cells among the mutants tested, indicating the potential for enhancing oncolytic potency through the combination of mutations. Furthermore, in a HER2+ murine breast cancer model, mice treated with SV5 exhibited superior tumor reduction and increased survival compared with those treated with PBS or T3wt. Intriguingly, SV5 did not replicate faster than T3wt in cultured cells but demonstrated a farther spread relative to T3wt, attributed to its reduced attachment to cancer cells. These findings highlight the significance of increased virus spread as a crucial mechanism for improving oncolytic virus activity. Thus, genetic modifications of reovirus hold the potential for augmenting its efficacy in cancer therapy.

Keywords: breast cancer; immunotherapy; improved oncolytic potency; improved reovirus mutant; large-plaque-forming virus; oncolytic virus; reovirus; reovirus spread; virus attachment; virus spread.