Developing Picornaviruses for Cancer Therapy
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cancers Review Developing Picornaviruses for Cancer Therapy Cormac McCarthy 1, Nadishka Jayawardena 1, Laura N. Burga 1,* and Mihnea Bostina 1,2,* 1 Department of Microbiology and Immunology, University of Otago, Dunedin 9016, New Zealand; [email protected] (C.M.); [email protected] (N.J.) 2 Otago Micro and Nano Imaging, University of Otago, Dunedin 9016, New Zealand * Correspondence: [email protected] (L.N.B.); [email protected] (M.B.) Received: 4 April 2019; Accepted: 8 May 2019; Published: 16 May 2019 Abstract: Oncolytic viruses (OVs) form a group of novel anticancer therapeutic agents which selectively infect and lyse cancer cells. Members of several viral families, including Picornaviridae, have been shown to have anticancer activity. Picornaviruses are small icosahedral non-enveloped, positive-sense, single-stranded RNA viruses infecting a wide range of hosts. They possess several advantages for development for cancer therapy: Their genomes do not integrate into host chromosomes, do not encode oncogenes, and are easily manipulated as cDNA. This review focuses on the picornaviruses investigated for anticancer potential and the mechanisms that underpin this specificity. Keywords: picornavirus; oncolytic virotherapy; poliovirus; coxsackievirus; senecavirus 1. Introduction Cancer remains one of the leading causes of death worldwide. Globally, there were around 18 million new cases of cancer in 2018, with up to 9.5 million deaths [1]. Contemporary treatment for cancer usually involves some combination of surgical resection, radiation therapy and/or chemotherapy. While these conventional therapies have improved the prognosis for many cancers, the side-effects are often severe. In addition, some tumours are inoperable or resistant to radio- and chemotherapy, emphasising the need to develop new therapeutic strategies. Oncolytic virotherapy has emerged as a promising way of treating cancers. Broadly speaking, oncolytic viruses are naturally occurring or engineered viruses that selectively infect and lyse cancer cells. Their replication in cancer cells produces progeny viruses which in turn repeat the infection process in neighbouring cells. Furthermore, viral infection can stimulate cytotoxic immune responses against antigen from destroyed cells (Figure1). The efficacy of oncolytic viruses has been shown in many cases to be increased when used in combination with other therapeutic agents. For example, in mouse models of head and neck cancers, Herpes simplex virus-1 has shown increased efficacy when combined with cisplatin [2], and coxsackievirus A21 has greater anti-tumour activity when combined with anti-programmed cell death protein 1 (PD-1) antibodies against metastatic melanoma, bladder cancer, and non-small-cell lung cancer [3]. Oncolytic virotherapy’s roots extend back to early reports of patients with leukaemia and Hodgkin’s disease, who survived concomitant viral infections and showed evidence of clinical remission [4,5]. These observations led to a number of trials from the mid-to-late 20th century, such as West Nile Virus Egypt 101 against various cancers [6], Adenovirus versus cervical carcinomas [7] and Mumps virus against various terminal cancers [8]. Each of these trials showed varying degrees of protective effect. For instance, the trial concerning Adenovirus showed that 26 of 40 inoculations resulted in tumour necrosis [7], and the Mumps virus trial resulted in complete regression of 37 out of 90 trial subjects, as well as 42 instances of growth suppression [8]. In 2015, an important milestone in the endeavour to make oncolytic virotherapy a viable therapy was reached. Cancers 2019, 11, 685; doi:10.3390/cancers11050685 www.mdpi.com/journal/cancers Cancers 2019, 11, 685 2 of 29 Cancers 2019, 11, 685 2 of 29 FigureFigure 1. Oncolytic 1. Oncolytic picornaviruses picornaviruses asas a cancer treatment. treatment. The Theuse useof oncolytic of oncolytic picornaviruses picornaviruses is is highlightedhighlighted by by theirtheir relative relative ease ease of production of production in high in titres high in titres food and in food drug andadministration drug administration (FDA)- (FDA)-approvedapproved cell cell lines. lines. Resulting Resulting mature mature virions virionscan then can be systemically then be systemically administered administered into a patient into a with a tumour. Most picornaviruses display a high tropism to a variety of tumours but not to normal patient with a tumour. Most picornaviruses display a high tropism to a variety of tumours but not to tissues, resulting in intratumoural replication and subsequent cellular death. The new viral progeny normal tissues, resulting in intratumoural replication and subsequent cellular death. The new viral released from lysed cancer cells can then infect neighbouring cancer cells. The mere presence of virus progenyparticles released and fromvirus-induced lysed cancer tumour cells cell can death then mo infectdulates neighbouring the immune cancer system cells. to activate The mere antigen- presence of viruspresenting particles cells and (APC), virus-induced denditric cells tumour (DC), and cell T ce deathlls (TC), modulates which collectively the immune provide system a long-lasting to activate antigen-presentingantitumour activity. cells (APC), denditric cells (DC), and T cells (TC), which collectively provide a long-lasting antitumour activity. This was the approval of the first oncolytic virus, modified Herpes simplex virus-1, also known as ThisTalimogene was the Laherparepvec approval of (T-VEC), the first by oncolytic the US Food virus, and modified Drug AdministrationHerpes simplex (FDA)virus-1, for the alsotreatment known as Talimogeneof malignant Laherparepvec melanomas (T-VEC), [9]. In addition, by the Oncorine, US Food derived and Drug from Administration adenovirus, was (FDA) approved for thein China treatment of malignantin 2005 for melanomas the treatment [ 9of]. head In addition,and neck cancers Oncorine, [10],[11]. derived While fromcancer adenovirus, cells are generally was observed approved in Chinato in be 2005 morefor susceptible the treatment to viral ofinfection head andthan neckhealth cancersy cells, the [10 clinical,11]. Whileuse of oncolytic cancer cells viruses are is generally still observedrelatively to be modest more susceptible[12]. This is todue viral to several infection limiting than conditions: healthy cells, Oncolytic the clinical viruses usehave of to oncolytic be nonpathogenic and genetically stable, while still maintaining infectivity to nonhomogenous cancerous viruses is still relatively modest [12]. This is due to several limiting conditions: Oncolytic viruses cells [13]. They also have to be able to overcome the unfavourable conditions of the tumour have tomicroenvironment, be nonpathogenic including and genetically dense connective stable, tissue, while poor still maintaininglymphatic flow infectivity and increased to nonhomogenous interstitial cancerouspressure cells [14]. [13 ]. They also have to be able to overcome the unfavourable conditions of the tumour microenvironment,Despite the includinginherent cha densellenges connective presented in tissue, producing poor safe lymphatic and effective flow oncolytic and increased viruses, interstitialthere pressureare a [ 14number]. of naturally occurring and engineered viruses that have entered clinical trials. 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These viruses vary greatly with respect to several factor (GM-CSF) (ONCOS-102®), Vaccinia virus engineered to express GM-CSF with thymidine kinase characteristics, including the species, genera, etc. to which they belong, their progress through clinical deleted (PexaVec®), Measles virus engineered to express thyroidal sodium iodide importer (MV-NIS®) trials, cancer types they are used to treat and degree to which they have been engineered. ® and naturallyThere occurringare a number Reovirus of ways to (Reolysin increase the). effectiveness These viruses of oncolytic vary greatly viruses. withOften, respect they are toused several characteristics,in combination including with chemotherapeutics the species, genera, and/or etc. radi to whichation/surgical they belong, techniques their. For progress instance, through Reolysin clinical® trials,in cancer clinical types trials they has been are used combined to treat with and carbop degreelatin to and which paclitaxel they havefor the been treatment engineered. of malignant Theremelanomas are a [15], number and ofPexaVec ways®to in increase clinical thetrials e ffhasectiveness been combined of oncolytic with viruses.sorafenib Often,to combat they are usedhepatocellular in combination carcinoma with chemotherapeutics[16]. Oncolytic viruses and can/or also radiation be engineered/surgical to express techniques. tumour-specific For instance, Reolysinpeptides,® in clinicalwith the purpose trials has of magnifying been combined the immune with response carboplatin against