Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963

Abstract

Replication-selective oncolytic viruses (virotherapeutics) are being developed as novel cancer therapies with unique mechanisms of action, but limitations in i.v. delivery to tumors and systemic efficacy have highlighted the need for improved agents for this therapeutic class to realize its potential. Here we describe the rational, stepwise design and evaluation of a systemically effective virotherapeutic (JX-963). We first identified a highly potent poxvirus strain that also trafficked efficiently to human tumors after i.v. administration. This strain was then engineered to target cancer cells with activation of the transcription factor E2F and the EGFR pathway by deletion of the thymidine kinase and vaccinia growth factor genes. For induction of tumor-specific cytotoxic T lymphocytes, we further engineered the virus to express human GM-CSF. JX-963 was more potent than the previously used virotherapeutic Onyx-015 adenovirus and as potent as wild-type vaccinia in all cancer cell lines tested. Significant cancer selectivity of JX-963 was demonstrated in vitro in human tumor cell lines, in vivo in tumor-bearing rabbits, and in primary human surgical samples ex vivo. Intravenous administration led to systemic efficacy against both primary carcinomas and widespread organ-based metastases in immunocompetent mice and rabbits. JX-963 therefore holds promise as a rationally designed, targeted virotherapeutic for the systemic treatment of cancer in humans and warrants clinical testing.

Gene therapy progress and prospects cancer: oncolytic viruses

“…Two recent publications illustrate this concept. 31,55 The first article describes rational species and strain selection and genetic engineering based on updated knowledge. As described before, poxvirus was selected for this study based on human data showing that systemic delivery of poxvirus is safe and can induce significant tumor responses.…”

“…Intravenous administration led to systemic efficacy against both primary carcinomas and widespread organ-based metastases in immunocompetent animals. 55 The second study describes the use of a vaccinia virus background that selectively targets IFN pathway resistance in tumor cells. Further engineering with TK deletion and IFN-b insertion results in a multimechanistic oncolytic vaccinia virus.…”

“…Several recent publications described the use of this approach. 27,55,57,58 The results of oncolytic viruses on ex vivo tissues and its clinical outcome correlation have yet to be established, but researchers are encouraged to include explants studies whenever possible to maximize clinical relevance. Future clinical developments might include pre-/post-treatment ex vivo assessment of infectivity, cytopathic effects and viral replication.…”

Integrating the biological characteristics of oncolytic viruses and immune cells can optimize therapeutic benefits of cell-based delivery

“…Among the different viruses that have been studied, vaccinia virus strains have a number of characteristics that contribute to their enhanced potential as oncolytic agents; vaccinia viruses demonstrate rapid spread, potent cytolytic ability, a broad range of host cell tropism, a large capacity for genetic payload and a high degree of specificity for tumor targets produced through selective deletion of viral genes. 14,15 These agents also display some degree of systemic delivery potential to the tumor, primarily due to their evolved ability to travel relatively undetected within the blood. However, because they possess the ability to infect a broad range of cell types, only a small amount of virus delivered intravenously will infect the tumor, with the majority undergoing nonpermissive or abortive infections of non-tumor tissue.…”

“…However, because they possess the ability to infect a broad range of cell types, only a small amount of virus delivered intravenously will infect the tumor, with the majority undergoing nonpermissive or abortive infections of non-tumor tissue. Therefore, despite the promising results of vaccina virusbased cancer therapies, [14][15][16][17][18] it appears that for effective treatment of cancers it will be necessary to both improve methods of delivery and use of vaccinia in therapeutic combinations.…”