Seneca Valley virus replicons are packaged in trans and have the capacity to overcome the limitations of viral transgene expression

Jeffrey D Bryant; Jennifer S Lee; Ana De Almeida; Judy Jacques; Ching-Hung Chang; William Fassler; Christophe Quéva; Lorena Lerner; Edward M Kennedy

doi:10.1016/j.omto.2023.02.005

Seneca Valley virus replicons are packaged in trans and have the capacity to overcome the limitations of viral transgene expression

Mol Ther Oncolytics. 2023 Feb 16:28:321-333. doi: 10.1016/j.omto.2023.02.005. eCollection 2023 Mar 16.

Authors

Jeffrey D Bryant¹, Jennifer S Lee¹, Ana De Almeida¹, Judy Jacques¹, Ching-Hung Chang¹, William Fassler¹, Christophe Quéva¹, Lorena Lerner¹, Edward M Kennedy¹

Affiliation

¹ Oncorus, Inc., Andover, MA 01810, USA.

Abstract

Oncolytic viruses (OVs) promote the anti-tumor immune response as their replication, and the subsequent lysis of tumor cells, triggers the activation of immune-sensing pathways. Arming OVs by expressing transgenes with the potential to promote immune cell recruitment and activation is an attractive strategy to enhance OVs' therapeutic benefit. For picornaviruses, a family of OVs with clinical experience, the expression of a transgene is limited by multiple factors: genome physical packaging limits, high rates of recombination, and viral-mediated inhibition of transgene secretion. Here, we evaluated strategies for arming Seneca Valley virus (SVV) with relevant immunomodulatory transgenes. Specificially in the contex of arming SVV, we evaluated transgene maximum size and stabiltity, transgene secretion, and the impact of transgene inclusion on viral fitness. We find that SVV is not capable of expressing secreted payloads and has a transgene packaging capacity of ∼10% of viral genome size. To enable transgene expression, we developed SVV replicons with greater transgene size capacity and secretion capabilities. SVV replicons can be packaged in trans by virus in co-infected cells to express immunomodulatory transgenes in surrounding cells, thus providing a means to enhance the potential of this therapeutic to augment the anti-tumor immune response.

Keywords: CRE; RNA therapeutics; SVV; Seneca Valley virus; cancer; oncolytic viral therapy; replicon; signal sequence; stable transgene expression; transgene.