An Oncolytic Adenovirus Vector Expressing p14 FAST Protein Induces Widespread Syncytium Formation and Reduces Tumor Growth Rate In Vivo

Josh Del Papa; Julia Petryk; John C Bell; Robin J Parks

doi:10.1016/j.omto.2019.05.001

An Oncolytic Adenovirus Vector Expressing p14 FAST Protein Induces Widespread Syncytium Formation and Reduces Tumor Growth Rate In Vivo

Mol Ther Oncolytics. 2019 May 15:14:107-120. doi: 10.1016/j.omto.2019.05.001. eCollection 2019 Sep 27.

Authors

Josh Del Papa^{1

2

3}, Julia Petryk⁴, John C Bell^{2

3

4}, Robin J Parks^{1

2

3

5}

Affiliations

¹ Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
² Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
³ Department of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
⁴ Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
⁵ Centre for Neuromuscular Disease, University of Ottawa, Ottawa, ON K1N 6N5, Canada.

Abstract

Intratumoral injection of oncolytic viruses provides a direct means of tumor cell destruction for inoperable tumors. Unfortunately, oncolytic vectors based on human adenovirus (HAdV) typically do not spread efficiently throughout the tumor mass, reducing the efficacy of treatment. In this study, we explore the efficacy of a conditionally replicating HAdV vector expressing the p14 Fusion-Associated Small Transmembrane (FAST) protein (CRAdFAST) in both immunocompetent and immunodeficient mouse models of cancer. The p14 FAST protein mediates cell-cell fusion, which may enhance spread of the virus-mediated, tumor cell-killing effect. In the murine 4T1 model of cancer, treatment with CRAdFAST resulted in enhanced cell death compared to vector lacking the p14 FAST gene, but it did not reduce the tumor growth rate in vivo. In the human A549 lung adenocarcinoma model of cancer, CRAdFAST showed significantly improved oncolytic efficacy in vitro and in vivo. In an A549 xenograft tumor model in vivo, CRAdFAST induced tumor cell fusion, which led to the formation of large acellular regions within the tumor and significantly reduced the tumor growth rate compared to control vector. Our results indicate that expression of p14 FAST from an oncolytic HAdV can improve vector efficacy for the treatment of cancer.

Keywords: FAST; adenovirus; cancer; cell fusion; oncolytic.