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

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.

Power and Promise of Next-Generation Sequencing in Liquid Biopsies and Cancer Control

“…112 -115 Cancer-related mutations, including single-nucleotide mutations, copy number changes, methylation changes, and DNA fragmentation patterns have been detected in cfDNA of patients with various cancer by NGS technology (Figure 3). 74,116 -118…”

“…120 Mutations from tumors can be used to monitor clinical progress and detect residual lesions after treatment. 116,121 -123 Abnormal methylation signals in cfDNA molecules enable detection of ultra-early tumors, and genome-wide methylation histological analysis of plasma DNA tissue location can be used as a “whole-body molecular imaging” method to identify potential tissue origins of mutations detected in cfDNA. 124 -127…”

Identification of human adenovirus replication inhibitors from a library of small molecules targeting cellular epigenetic regulators

“…Ad-late/RFP was used to perform the initial screen, and the construction of this virus was described previously ( Saha and Parks, 2019 ). Ad-late/RFP is based on HAdV-5, and contains an intact E1 region, but has the E3 region replaced by the monomeric red fluorescent protein (RFP) coding sequence with an upstream splice acceptor site, which places RFP expression under the control of the viral MLP ( Del Papa et al, 2019 ; Saha and Parks, 2019 ). The virus was propagated in 293 cells and purified by cesium chloride buoyant density centrifugation using standard procedures ( Ross and Parks, 2009 ).…”

Viruses as tools in gene therapy, vaccine development, and cancer treatment

“…In addition, paOAd also showed a therapeutic effect on cancer stem cells [ 42 ]. Expression of p14 FAST from adenovirus can induce widespread syncytium formation, reduce the tumor growth rate, and improve vector efficacy for cancer treatment [ 28 ]. An oncolytic adenovirus, Delta-24-RGDOX, expressing the immune co-stimulator OX40 ligand (OX40L) showed tumor-specific activation of lymphocytes and proliferation of CD8 + T cells specific for tumor-associated antigens, resulting in immunity [ 57 ].…”