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The Emerging Therapeutic Potential of the Oncolytic Immunotherapeutic Pexa-Vec (JX-594)

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The Emerging Therapeutic Potential of the Oncolytic Immunotherapeutic Pexa-Vec (JX-594) Oncolytic Virotherapy Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW The emerging therapeutic potential of the oncolytic immunotherapeutic Pexa-Vec (JX-594) Caroline J Breitbach1 Abstract: Oncolytic immunotherapeutics (OIs) are viruses designed to preferentially replicate John C Bell2,3 in and lyse cancer cells, thereby triggering antitumor immunity. Numerous oncolytic platforms Tae-Ho Hwang1 are currently in clinical development. Here we review preclinical and clinical experience with David H Kirn1 Pexa-Vec (pexastimogene devacirepvec, JX-594). Pexa-Vec is derived from a vaccinia vaccine James Burke1 strain that has been engineered to target cancer cells and express the therapeutic transgene granulocyte macrophage colony-stimulating factor (GM-CSF) in order to stimulate antitumor 1SillaJen Inc, Seoul, South Korea; immunity. Key to its ability to target metastatic disease is the evolution of unique vaccinia virus 2Department of Biochemistry, Microbiology and Immunology, characteristics that allow for effective systemic dissemination. Multiple mechanisms of action University of Ottawa, Ottawa, (MOA) for Pexa-Vec have been demonstrated in preclinical models and patients: 1) tumor cell ON, Canada; 3Centre for Cancer Therapeutics, Ottawa infection and lysis, 2) antitumor immune response induction, and 3) tumor vascular disruption. Hospital Research Institute, This review will summarize data on the Pexa-Vec MOA as well as provide an overview of the Ottawa, ON, Canada Pexa-Vec clinical development program from multiple Phase I studies, Phase II studies in renal cell cancer and colorectal cancer, through Phase IIb clinical testing in patients with advanced hepatocellular carcinoma (primary liver cancer). Keywords: Pexa-Vec, JX-594, oncolytic immunotherapy, hepatocellular carcinoma Vaccinia biology and selective cancer targeting Vaccinia viruses are enveloped double-stranded DNA viruses belonging to the family of Poxviridae and were utilized as vaccines for the eradication of smallpox.1 Pexa-Vec (pexastimogene devacirepvec; JX-594) is a targeted and armed oncolytic and immuno- therapeutic vaccinia virus with disruption of the viral thymidine kinase gene and expres- sion of the human granulocyte macrophage colony-stimulating factor (hGM-CSF) and β-galactosidase transgenes under control of the synthetic early/late and p7.5 promoters, respectively.2–4 Selective targeting of tumor cells by Pexa-Vec is attributed to both engi- neered mechanisms as well as to inherent vaccinia selectivity for cancers.5 Thymidine kinase gene inactivation renders viral replication dependent on the high cellular thymidine kinase activity that is a hallmark of cancer cells.6 Vaccinia vaccine strains have been shown to be inherently tumor targeting.7,8 This may be attributable to the fact that many of the hallmarks of cancer9 (eg, blocks in apoptotic pathways, dysregulation of cell cycle control and immune evasion) are also optimal cellular conditions for successful vaccinia virus replication. Furthermore, vaccinia replication and spread is dependent on epidermal Correspondence: James Burke growth factor receptor (EGFR) signaling,10 a pathway that is activated in most cancers.9 16th floor, 450 Sansome St San Francisco, CA, USA Blocking EGFR signaling inhibits vaccinia replication.11 Indeed, the majority of solid Tel +1 406 850 8160 tumor cell lines tested were susceptible to vaccinia infection. In contrast, leukemia and Fax +1 415 598 2600 Email [email protected] lymphoma cell lines were the only cancer cell types uniformly refractory to infection.5 submit your manuscript | www.dovepress.com Oncolytic Virotherapy 2015:4 25–31 25 Dovepress © 2015 Breitbach et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further http://dx.doi.org/10.2147/OV.S59640 permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Breitbach et al Dovepress Systemic tumor targeting detected (and, thereby, provoke the induction of antibod- and transgene expression ies) after productive Pexa-Vec infection. A dose-dependent Vaccinia viruses, unlike many other viruses, are stable in blood increase in anti-β-galactosidase antibodies was observed in 17 following intravenous (IV) or intratumoral (IT) introduction. patients. Detectable concentrations of granulocyte mac- Vaccinia has evolved to produce an extracellular enveloped rophage colony-stimulating factor (GM-CSF) in plasma were virus form, which provides an additional membrane coat that measured acutely (4–15 days after treatment) in a subset of 17,18 results in resistance to complement and antibody neutraliza- patients receiving IV or IT Pexa-Vec. Together, these data tion following exposure to the systemic vasculature.12–14 This demonstrate that Pexa-Vec leads to successful infection and inherent property results in enhanced effective tumor delivery gene expression in metastatic tumors following systemic following the systemic application of oncolytic vaccinia administration. for the treatment of cancer. This results in highly efficient systemic delivery to and spread between tumor cells after Pexa-Vec mechanisms of action treatment.8,15,16 Based on these preclinical studies, clinical Pexa-Vec mechanisms of actions (MOA) have been evalu- evaluation of oncolytic vaccinia was initiated. IV Pexa-Vec ated in both preclinical and clinical studies (Figure 1 and infusion was well-tolerated up to a dose of 3×107 plaque form- Table 1). Firstly, Pexa-Vec has been shown to selectively ing units per kg (pfu/kg).17 Systemic delivery of Pexa-Vec to infect and amplify within tumors (termed oncolysis).2,17,18 tumors was tested by collecting tumor biopsies in all patients Infection of tumors by viruses results in the release of between 7 and 10 days postinfusion. On this trial, reproduc- damage-associated molecular patterns (DAMPs)19,20 as ible Pexa-Vec delivery to tumors was established at a dose well as pathogen-associated molecular patterns (PAMPs)21 threshold of 1×109 pfu, with tumor biopsies in seven of eight originating from components of the virus particle, result- patients containing detectable Pexa-Vec.17 The induction of ing in an acute inflammatory response. The production and humoral immunity to the Pexa-Vec transgene β-galactosidase release of tumor antigens within this highly stimulatory was also used as a surrogate marker of Pexa-Vec replication context is capable of inducing an adaptive immune response in patients, as high concentrations of the transgene are only against the tumor itself. Protective antitumor immunity has Adaptive Direct cell lysis Vascular shutdown immune response Release of Tumor Pexa-Vec, antigen GM-CSF, Tumor cell death recognition and antigens GM-CSF Tumor cells Activated T cells Cell death Activates VEGF dendritic cells Antigens Vessel wall High TK levels in tumor Pexa-Vec infects tumor- drive Pexa-Vec replication associated endothelial cells Tumor Pexa-Vec infects target cells Pexa-Vec replication Figure 1 Pexa-Vec mechanisms of action. Abbreviations: GM-CSF, granulocyte macrophage colony-stimulating factor; TK, tyrosine kinase; VEGF, vascular endothelial growth factor. 26 submit your manuscript | www.dovepress.com Oncolytic Virotherapy 2015:4 Dovepress Dovepress Pexa-Vec oncolytic immunotherapy Table 1 Overview of oncolytic vaccinia mechanisms of action Mechanism Preclinical Clinical References of action Oncolysis – Selective infection and killing of tumor cells – Selective infection of tumor cells following Breitbach et al;17 demonstrated in vitro and in vivo intratumoral administration or intravenous Kim et al;2 Parato et al;5 infusion Park et al18 Active – Protective antitumor immunity induced – Inflammatory response detected in tumors Heo et al;26 immunotherapy – Complement-dependent cytotoxicity – Complement-dependent cytotoxicity Hwang et al;24 demonstrated; serum transfer exhibits antitumor demonstrated in patient serum from Phase I Kim et al;25 Kirn et al;22 activity in virus naïve rabbits and Phase II trials Mastrangelo et al23 Antivascular – VEGF and FGF-2 driven infection of endothelial cells – Infection of tumor-associated endothelial cells Breitbach et al27 – Infection of tumor-associated vasculature in vivo – Acute reduction in tumor perfusion detected – Functional reduction in tumor blood flow by dynamic magnetic resonance imaging Abbreviations: FGF-2, fibroblast growth factor 2; VEGF, vascular endothelial growth factor. been demonstrated following vaccinia infection of murine tumors revealed reproducible infection of tumor-associated tumors in vivo.22 Inflammation within tumors was detected endothelial cells.27 Furthermore, a subset of HCC patients following IT Pexa-Vec administration in patients with treated with Pexa-Vec by IT injection on a Phase II study melanoma.23,24 Furthermore, functional anticancer immunity exhibited an acute reduction in tumor perfusion as measured in the context of Pexa-Vec treatment was demonstrated in by dynamic magnetic resonance imaging (MRI) 5 days after preclinical models and patients by measuring induction of the initial Pexa-Vec injection. 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