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Development of Group B Coxsackievirus As an Oncolytic Virus: Opportunities and Challenges

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Development of Group B Coxsackievirus As an Oncolytic Virus: Opportunities and Challenges viruses Review Development of Group B Coxsackievirus as an Oncolytic Virus: Opportunities and Challenges Huitao Liu 1,2 and Honglin Luo 1,3,* 1 Centre for Heart Lung Innovation, St. Paul’s Hospital—University of British Columbia, Vancouver, BC V6Z 1Y6, Canada; [email protected] 2 Department of Experimental Medicine, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada 3 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada * Correspondence: [email protected] Abstract: Oncolytic viruses have emerged as a promising strategy for cancer therapy due to their dual ability to selectively infect and lyse tumor cells and to induce systemic anti-tumor immunity. Among various candidate viruses, coxsackievirus group B (CVBs) have attracted increasing attention in recent years. CVBs are a group of small, non-enveloped, single-stranded, positive-sense RNA viruses, belonging to species human Enterovirus B in the genus Enterovirus of the family Picornaviridae. Preclinical studies have demonstrated potent anti-tumor activities for CVBs, particularly type 3, against multiple cancer types, including lung, breast, and colorectal cancer. Various approaches have been proposed or applied to enhance the safety and specificity of CVBs towards tumor cells and to further increase their anti-tumor efficacy. This review summarizes current knowledge and strategies for developing CVBs as oncolytic viruses for cancer virotherapy. The challenges arising from these studies and future prospects are also discussed in this review. Citation: Liu, H.; Luo, H. Keywords: coxsackievirus B; oncolytic virus; cancer; virotherapy; cancer; toxicity; anti-tumor immunity Development of Group B Coxsackievirus as an Oncolytic Virus: Opportunities and Challenges. Viruses 2021, 13, 1082. https://doi.org/ 1. Introduction 10.3390/v13061082 Oncolytic virotherapy represents a new and promising option for cancer treatment. This approach uses engineered or naturally occurring viruses, termed oncolytic viruses, to Academic Editor: Caroline Tapparel target and destroy tumor cells while sparing normal cells [1,2]. Current evidence supports that both direct lysis of cancer cells and anti-tumor immunity triggered by viral infection Received: 4 May 2021 contribute to the anti-tumor efficacy of virotherapy [1,2]. Oncolytic viruses selectively Accepted: 3 June 2021 infect and replicate in tumor cells, inducing cell destruction and the consequent release Published: 5 June 2021 and spread of progeny virions to infect adjacent cells. Oncolytic viruses can also stimulate immunogenic cell death through promoting the innate and adaptive immune response. Publisher’s Note: MDPI stays neutral The advantage of virotherapy over other classical cancer therapies (e.g., chemo- and with regard to jurisdictional claims in published maps and institutional affil- radiotherapy) lies in the fact that candidate viruses can be genetically manipulated to iations. increase their potency against specific cancer types. As a milestone in virotherapy, in 2015, the US FDA approved the first oncolytic agent Imlygic (Talimogene laherparepvec, T-Vec) for the treatment of melanoma [3,4]. T-Vec is a modified herpes simplex virus-1 (HSV-1) genetically engineered to encode the im- munostimulatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). Copyright: © 2021 by the authors. Although the survival benefits remain controversial, the approval of T-Vec has promoted Licensee MDPI, Basel, Switzerland. significant interest in the development of oncolytic viruses as either a monotherapy or in This article is an open access article combination with other anti-tumor therapies [3,4]. According to clinicaltrials.gov, there are distributed under the terms and conditions of the Creative Commons currently 105 registered oncolytic viral trials in the USA, 21 in Canada, 18 in Spain, and 15 Attribution (CC BY) license (https:// in France among other top countries (Figure1A). In recent years, the number of initiated creativecommons.org/licenses/by/ clinical studies on virotherapy has increased significantly (Figure1B). 4.0/). Viruses 2021, 13, 1082. https://doi.org/10.3390/v13061082 https://www.mdpi.com/journal/viruses Viruses 2021, 13, 1082 2 of 16 Viruses 2021, 13, 1082 2 of 15 Spain, and 15 in France among other top countries (Figure 1A). In recent years, the number of initiated clinical studies on virotherapy has increased significantly (Figure 1B). A Rank Countries Clinical trials recorded* B 1 United States 105 25 2 Canada 21 y d s l u a t 20 3 Spain 18 i s r t s l l a 4 France 15 a i c i r 15 t n i l l 5 United Kingdom 14 a c c f i o n i 10 r 6 China (mainland) 11 l e c b f 7 Germany 8 o m . 5 u O N 7 Australia 8 N 9 Republic of Korea 7 0 00 1 1 2 2 33 44 5 5 66 77 88 99 00 11 22 33 44 55 6 6 77 88 99 00 11 22 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 10 Japan 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 2 2 2 2 2 2 2 2 2 2 Year2 2 2 2 2 2 2 2 2 2 2 * Same clinical trials may be taken in multiple countries. Years Figure 1.FigureNumber 1. Number of registered of registered clinical clinical trials trials on on oncolytic oncolytic viralviral studies studies from from clinicaltrials.gov clinicaltrials.gov in top in10 topcountries 10 countries (A) from (A) from 2001 to 20212001 (toB ).2021 Note (B). thatNote thethat datathe data of 2021of 2021 only only cover cover clinicalclinical studies studies registered registered until until 31 May 31 [ May2021. Search 2021. keywords Search keywords ‘oncolytic’ and ‘tumor’ found 182 records in total with five excluded for not involving oncolytic virus. ‘oncolytic’ and ‘tumor’ found 182 records in total with five excluded for not involving oncolytic virus. Research in the field of oncolytic RNA viruses has grown rapidly over the past dec- ade.Research Several in RNA the viruses field of that oncolytic exhibit oncolytic RNA viruses activity has hav growne been rapidlytested in overearly theclinical past decade. Severaltrials, RNA which viruses include thatNewcastle exhibit disease oncolytic virus [5], activity measles have virus been [6], vesicular tested in stomatitis early clinical tri- als,virus which (VSV include) [7], Seneca Newcastle valley virus disease [8], reovirus virus [[9],5], respiratory measles virus syncytial [6], virus vesicular [10], po- stomatitis virusliovirus (VSV) [11], [7], and Seneca coxsackievirus valley virus [12]. A [8mong], reovirus enteroviruses, [9], respiratory the PVSRIPO, syncytial a modified virus po- [10], po- liovirusliovirus [11 ],carrying and coxsackievirus an internal ribosomal [12]. Amongentry site enteroviruses,(IRES) of human the rhinovirus PVSRIPO, type a 2 modified poliovirus[11,13,14] carrying, and the CVA21 an internal-based CAVATAK ribosomal [15 entry–19] are site the (IRES) two best of-characterized human rhinovirus onco- type lytic viruses. A number of clinical trials have been conducted on them and shown prom- 2 [11ising,13,14 efficacy.], and theIn 2018, CVA21-based the CAVATAK CAVATAK start-up company, [15–19] are Viralytics, the two was best-characterized acquired by on- colyticMerck viruses. for $394 A million. number This of remarkable clinical trialsnews has have been been very conducted encouraging, on especially them and to shown promisingthose interested efficacy. inIn developing 2018, the enteroviruses CAVATAK for start-up cancer company,therapy. While Viralytics, PVSRIPO was and acquired by MerckCAVATAK for $394 have million.demonstrated This effectiveness remarkable again newsst certain has been tumors, very they encouraging, have less effi- especially to thosecacy against interested other in tumors developing and can sometimes enteroviruses cause foradverse cancer side therapy. effects. Thus, While investiga- PVSRIPO and CAVATAKtion into have additional demonstrated enteroviruses effectiveness is needed. against certain tumors, they have less efficacy Coxsackieviruses are a group of non-enveloped, positive-sense, single-stranded against other tumors and can sometimes cause adverse side effects. Thus, investigation RNA viruses belonging to the species human Enterovirus in the family of Picornaviridae into[20] additional. Coxsackieviruses enteroviruses were isorig needed.inally classified into two groups—A (CVA) and B (CoxsackievirusesCVB)—on the basis of are early a group observation of non-enveloped, of the differences positive-sense, in tissue damage single-stranded induced in RNA virusesnewborn belonging mice [21]. to The the first species report humanon oncolyticEnterovirus CVB was publishedin the family in 1997, of whichPicornaviridae inves- [20]. Coxsackievirusestigated the anti- weretumor originallyproperties of classified CVB1 against into human two groups—A colon cancer (CVA) [22]. Since and then, B (CVB)—on the basisseveral of efforts early by observation different laboratories of the differenceshave been made in tissueto assess damage the oncolytic induced potential in newborn miceand [21 safety]. The of first CVBs report targeting on oncolyticvarious forms CVB of tumor was published in pre-clinical in 1997,studies which [23–30]. investigated In this the review, we summarize the recent progress in developing CVBs, with a focus on CVB3, as anti-tumor properties of CVB1 against human colon cancer [22]. Since then, several efforts an oncolytic virus against different types of cancer. We also discuss the potential barriers by differentand future laboratories perspectives for have the beenclinical made use of toCVBs assess in cancer the oncolytictherapy. potential and safety of CVBs targeting various forms of tumor in pre-clinical studies [23–30]. In this review, we summarize2. Viral Structure the recent and progress Life-Cycle in developing CVBs, with a focus on CVB3, as an oncolytic virus againstThe CVBs different contain types six viral of cancer.types, named We also CVB1 discuss-CVB6, thewhich potential are common barriers human and future perspectivespathogens forassociated the clinical with a usewide of range CVBs of diseases in cancer from therapy.
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