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The Trend in the Development of Oncolytic Virus Therapy
Biomed Sci Letters 2019;25:201-210
Published online September 30, 2019;  https://doi.org/10.15616/BSL.2019.25.3.201
© 2019 The Korean Society For Biomedical Laboratory Sciences.

Sun-Il Kwon†,*

Department of Biomedical Laboratory Science, Deagu Health Science University, Daegu 41453, Korea
Correspondence to: Sun-Il Kwon. Department of Biomedical Laboratory Science, Deagu Health Science University, Youngsong-ro 15 (Taejeon-dong), Buk-ku, Daegu 41453, Korea.
Tel: +82-53-320-1302, Fax: +82-53-320-1450, e-mail: psikwon@dhc.ac.kr
*Professor.
Received July 5, 2019; Revised September 10, 2019; Accepted September 11, 2019.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Abstract
The oncolytic viruses selectively infect and destroy cancer cells, not harming normal cells. The cancer cell materials released by oncolysis, like tumor antigens, stimulate host antitumor immune responses, which is a long-lasting antitumor immunity removing cancer cells in remote parts of the body by a systemic response. Oncolytic viruses armed with transgenes such as cytokines or other immune stimulating factors enhance the immune responses. The first oncolytic virus approved by US-FDA is Imlygic® targeting for melanoma. The oncolytic virus is considered as a revolutionary immunotherapy for tumors together with immune checkpoint inhibitors. A variety of oncolytic viruses are under research in the treatment of kidney cancer, liver cancer, breast cancer, and many others solid tumors. Clinical trials have shown promising results in different types of cancers. Here, we present a brief introduction of various aspects of oncolytic virus, and a review of the current status of oncolytic virus therapy development.
Keywords : Oncolytic virus, Cancer, Virus therapy, Transgenes, Combination therapy
1. 꽌濡

씤媛꾩뿉寃 빐濡떎怨 뿬寃⑥뜕 媛먯뿼꽦 諛붿씠윭뒪媛 씤媛꾩쓽 븫移섎즺젣濡 媛쒕컻릺怨 엳떎. 븫꽭룷뿉 꽑깮쟻쑝濡 移⑦닾븯뿬 븫꽭룷瑜 怨듦꺽븯뒗 븫슜빐諛붿씠윭뒪(oncolytic virus)媛 諛붾줈 洹 寃껋씤뜲, 븫슜빐諛붿씠윭뒪 移섎즺踰뺤 씠젣 쑀留앺븳 븫移섎즺踰뺤쑝濡 씤떇릺怨 엳떎. 븫슜빐諛붿씠윭뒪뒗 젙긽꽭룷뿉뒗 쁺뼢쓣 二쇱 븡怨 븫꽭룷뿉꽌留 꽑깮쟻쑝濡 蹂듭젣릺뼱꽌 븫꽭룷瑜 二쎌씤떎. 븫슜빐諛붿씠윭뒪뒗 쑀쟾怨듯븰쟻쑝濡 留뚮뱾뼱吏嫄곕굹 옄뿰쟻씤 諛붿씠윭뒪媛 洹몃濡 궗슜맂떎. 쑀쟾옄 移섎즺踰뺤뿉꽌뒗 諛붿씠윭뒪媛 떒닚엳 쇅옒 쑀쟾옄쓽 쟾떖泥대줈 궗슜릺吏留 븫슜빐諛붿씠윭뒪 移섎즺踰뺤뿉꽌뒗 븫슜빐諛붿씠윭뒪 옄泥닿 솢꽦 빟臾쇱씠 맂떎. 븫슜빐諛붿씠윭뒪媛 븫꽭룷留뚯쓣 꽑깮쟻쑝濡 젣嫄고븯뒗 듅씠꽦쓣 솗蹂댄븯寃 릺硫댁꽌 븫슜빐諛붿씠윭뒪뒗 븫젙蹂듭쓽 以묒슂븳 룄援щ줈 遺긽븯寃 릺뿀떎. 븫슜빐諛붿씠윭뒪뒗 醫낆뼇 궡뿉 媛먯뿼릺뼱 븫꽭룷瑜 吏곸젒 二쎌씪 肉먮쭔 븘땲씪 씠李⑥쟻쑝濡 빆븫硫댁뿭諛섏쓳쓣 쑀룄븯뿬 슦由 떊泥댁쓽 硫댁뿭怨꾧 닲뼱 엳뒗 븫꽭룷瑜 李얠븘궡뼱 뙆愿댄븯룄濡 븳떎. 븫슜빐諛붿씠윭뒪뒗 쑀슚꽦 삉븳 醫뗫떎. 꽕移섎쪟 醫낆뼇紐⑤뜽 떎뿕뿉꽌 븫슜빐諛붿씠윭뒪뒗 醫낆뼇 궡뿉 떒 븳 踰덈쭔쓽 二쇱궗濡 븫쓣 셿移섑븯湲곕룄 뻽떎(Naik et al., 2012). 븫슜빐諛붿씠윭뒪뒗 븫移섎즺젣濡쒖꽌 옞옱젰씠 쟻吏 븡떎.

꽌援ъ뿉꽌 理쒖큹濡 뿀媛瑜 諛쏆 븫슜빐諛붿씠윭뒪 移섎즺젣뒗 엫由ъ쭅(Imlygic, T-Vec, talimogene laherparepvec)씤뜲, 쓳깋醫 移섎즺젣濡 2015뀈 誘멸뎅뿉꽌, 2016뀈 쑀읇뿉꽌 媛곴컖 뙋留ㅼ듅씤쓣 諛쏆븯떎(Greig, 2016). 엫由ъ쭅 蹂묒썝꽦씠 뾾룄濡 쑀쟾쟻쑝濡 議곗옉븳 뿤瑜댄럹뒪 諛붿씠윭뒪(herpes simplex virus)뿉 granulocyte-macrophage colony stimulating factor (GM-CSF) 쑀쟾옄瑜 궫엯븳 寃껋씠떎. 엫由ъ쭅쓣 븫꽭룷 遺쐞뿉 援냼 二쇱궗븯硫 씠 옱議고빀 諛붿씠윭뒪뒗 븫꽭룷 궡뿉꽌 利앹떇븯寃 릺뒗뜲, 異⑸텇엳 利앹떇븯怨 굹硫 븫꽭룷瑜 뙆뿴떆궎硫댁꽌 諛뽰쑝濡 굹삩떎. 씠븣 諛붿씠윭뒪媛 깮꽦븳 硫댁뿭諛섏쓳쓣 쑀룄븯뒗 GM-CSF媛 룞떆뿉 諛⑹텧릺뼱 닔吏긽꽭룷 寃고빀븳떎. 씠 썑 닔吏긽꽭룷뒗 醫낆뼇쑝濡 諛쒖깮븳 븫꽭룷瑜 씤떇븯뿬 硫댁뿭꽭룷뿉寃 젙蹂대 쟾떖븯怨, 닚李⑥쟻쑝濡 硫댁뿭怨꾨뒗 뒪뒪濡 醫낆뼇꽭룷瑜 怨듦꺽븯寃 맂떎. 엫由ъ쭅 2二 媛꾧꺽쓽 醫낆뼇 궡 援냼 닾뿬濡 二쇱궗 遺쐞뿉꽌 47%쓽 셿쟾愿빐瑜 씠猷⑥뿀怨, 룞떆뿉 쟾떊 硫댁뿭諛섏쓳쑝濡 썝嫄곕━ 鍮꾧컧뿼븫뿉꽌 9%쓽 셿쟾愿빐瑜 씠猷⑥뿀떎(Andtbacka et al., 2016). 떎瑜 硫댁뿭愿臾몄뼲젣젣 蹂묒슜 닾뿬瑜 븳 떆뿕뿉꽌뒗 뜑슧 뼢긽맂 슚怨쇰 蹂댁뿬二쇱뿀떎(Puzanov et al., 2016; Maroun et al., 2017).

쁽옱 꽭怨꾩쟻쑝濡 떎닔쓽 븫슜빐諛붿씠윭뒪 移섎즺젣 썑蹂닿 醫낆뼇紐⑤뜽 떎뿕룞臾쇨낵 씤媛꾩쓣 긽쑝濡 엫긽떆뿕씠 吏꾪뻾릺怨 엳뼱꽌, 븵쑝濡 깉濡쒖슫 븫슜빐諛붿씠윭뒪 移섎즺젣媛 벑옣븷 寃껋쑝濡 삁긽맂떎(Lundstrom, 2018). 蹂 뿰援щ뒗 醫낆뼇쓽 移섎즺뿉꽌 븫슜빐諛붿씠윭뒪쓽 以묒슂꽦씠 而ㅼ졇 媛먯뿉 뵲씪 븫슜빐諛붿씠윭뒪 移섎즺젣 愿젴맂 뿰援 媛쒕컻쓽 쓲由꾩쓣 議곕쭩빐 蹂닿퀬옄 븳떎.

2. 븫슜빐諛붿씠윭뒪 移섎즺젣 媛쒕컻쓽 뿭궗쟻씤 怨쇱젙

2-1. 빆븫移섎즺젣 媛쒕컻쓽 뿭궗

쟾넻쟻쑝濡 궗슜릺뼱 삩 솕븰빆븫젣瑜 젣1꽭 빆븫젣씪怨 븯뒗뜲, 꽭룷룆꽦 빆븫젣濡쒖꽌 젙긽꽭룷蹂대떎 鍮좊Ⅴ寃 옄씪뒗 븫꽭룷瑜 꽑깮쟻쑝濡 二쎌씠뒗 諛⑸쾿씠떎. 븫꽭룷뒗 젙긽꽭룷뿉 鍮꾪븯뿬 遺꾩뿴씠 솗꽦븯뿬 꽭룷二쇨린媛 鍮좊Ⅸ뜲, 꽭룷二쇨린 以 DNA 빀꽦떆湲곗쓽 꽭룷瑜 꽑깮쟻쑝濡 젣嫄고븯뿬 븫쓽 꽦옣쓣 뼲젣븳떎.

븫꽭룷뿉 븳 꽑깮꽦쓣 넂뿬 遺옉슜쓣 以꾩씤 빆븫젣瑜 2꽭 빆븫젣씪怨 븳떎. 씠뱾 븫꽭룷뿉 듅씠쟻쑝濡 議댁옱븯뒗 遺꾩옄깮臾쇳븰쟻씤 몴쟻쓣 씠슜븯湲 븣臾몄뿉 몴쟻移섎즺젣씪怨 遺瑜몃떎. 몴쟻移섎즺젣뒗 븫꽭룷뿉꽌 李⑤퀎쟻쑝濡 怨쇰떎 諛쒗쁽릺뒗 듅젙 떒諛깆쭏씠굹 듅젙 쑀쟾옄쓽 蹂솕瑜 몴쟻쑝濡 궪븘꽌 븫쓽 꽦옣怨 諛쒖깮뿉 愿뿬븯뒗 떊샇瑜 李⑤떒븿쑝濡쒖뜥 븫꽭룷瑜 二쎌씤떎.

슦由 紐몄쓽 硫댁뿭泥닿퀎瑜 솢꽦솕떆耳쒖꽌 硫댁뿭꽭룷媛 븫꽭룷瑜 젣嫄고븯寃 븯뒗 硫댁뿭빆븫젣瑜 3꽭 빆븫젣씪怨 遺瑜몃떎. 硫댁뿭빆븫젣뒗 슦由 옄떊쓽 硫댁뿭꽭룷瑜 씠슜븯뿬 꽑깮쟻쑝濡 븫꽭룷瑜 怨듦꺽븯寃 留뚮뱶뒗뜲, 硫댁뿭꽭룷媛 븫꽭룷瑜 듅씠쟻쑝濡 씤떇븯뿬 뒪뒪濡 移섎즺븯룄濡 룙뒗 諛⑹떇씠떎. 젣3꽭 硫댁뿭移섎즺젣濡쒕뒗 븫슜빐諛붿씠윭뒪(oncolytic virus), 硫댁뿭愿臾몄뼲젣젣(immune check point inhibitor), CAR-T (chimeric antigen receptor T cells) 移섎즺젣 벑씠 룷븿맂떎(Kwon, 2017).

理쒓렐 10뿬뀈 룞븞 빆븫젣쓽 媛쒕컻 二쇰줈 씤媛꾩쓽 硫댁뿭諛섏쓳뿉 湲곕컲쓣 몦 硫댁뿭빆븫移섎즺젣媛 二쇰쪟瑜 씠猷④퀬 엳떎. 硫댁뿭빆븫젣뒗 몴쟻移섎즺젣 뜑遺덉뼱 븫移섎즺 諛⑸쾿쓽 쓲由꾩쓣 諛붽씀怨 엳떎. 븫슜빐諛붿씠윭뒪뒗 빆븫硫댁뿭湲곕뒫 솢꽦솕 痢〓㈃뿉꽌룄 二쇰ぉ쓣 諛쏄퀬 엳떎(Bommareddy et al., 2018).

2-2. 븫슜빐諛붿씠윭뒪 移섎즺젣 媛쒕컻 怨쇱젙

븫슜빐諛붿씠윭뒪 移섎즺踰뺤쓽 媛쒕뀗 긽떦엳 삤옖 湲곌컙 議댁옱빐솕떎. 씠誘 삤옒 쟾遺꽣 궗엺뱾 떖븳 룆媛먯쓣 븪嫄곕굹 떎瑜 媛먯뿼吏덊솚쓣 븪 썑뿉 媛걫 諛깊삁蹂묒씠 媛먯そ媛숈씠 궗씪議뚮떎嫄곕굹 떎瑜 醫낆뼇씠 쁽엳 쐞異뺣릺뿀떎뒗 궗떎쓣 寃쏀뿕쟻쑝濡 븣븯떎. 諛붿씠윭뒪쓽 쟾떊꽦 媛먯뿼 썑뿉 醫낆뼇씠 以꾩뼱뱶뒗 쁽긽 뿬윭 援곕뜲꽌 옄二 愿李곕릺뿀떎(Smith et al., 1956). 븫슜빐諛붿씠윭뒪 移섎즺젣 媛쒕컻 씠윭븳 愿李곗뿉꽌 鍮꾨’맂떎. 1949뀈 22紐낆쓽 샇吏궓蹂 솚옄媛 媛꾩뿼 諛붿씠윭뒪瑜 븿쑀븯뒗 삁泥씠굹 議곗쭅 異붿텧臾쇰줈 移섎즺瑜 諛쏆븯떎(Hoster et al., 1949). 1950뀈遺꽣 1980뀈源뚯 蹂대떎 븞쟾븯怨 슚怨쇱쟻씤 寃곌낵瑜 뼸湲 쐞븯뿬 닔留롮 끂젰씠 寃쎌<릺뿀쑝굹 蹂꾨떎瑜 엫긽쟻 꽦怨쇨 뾾씠 留됱쓣 궡졇떎. 씠뒗 二쇰줈 諛붿씠윭뒪쓽 룆꽦쓣 議곗젅븯嫄곕굹 醫낆뼇 듅씠꽦쓣 솗蹂댄븯뒗 諛⑸쾿씠 洹몃븣源뚯 誘몃퉬븯뿬 諛붿씠윭뒪 泥섏튂 諛⑸쾿씠 븞쟾븯吏 븡븯湲 븣臾몄씠뿀떎. 洹몃윭굹 1980뀈뿉 뱾뼱꽌 쑀쟾怨듯븰씠 諛쒕떖븯硫댁꽌 븫슜빐諛붿씠윭뒪 移섎즺踰뺤뿉 븳 愿떖씠 떎떆 遺긽븯怨, 洹 썑 30뿬뀈媛 愿꾨ぉ븷 留뚰븳 吏꾩쟾씠 씠猷⑥뼱議뚮떎(Howells et al., 2017).

1950뀈遺꽣 1990뀈源뚯뒗 빞깮삎 諛붿씠윭뒪굹 빟룆솕맂 諛붿씠윭뒪濡 븫移섎즺瑜 떆룄븯떎. 二쇰줈 궗슜맂 諛붿씠윭뒪뒗 媛꾩뿼 諛붿씠윭뒪, 썾뒪듃굹씪뿴蹂 諛붿씠윭뒪, 솴뿴蹂 諛붿씠윭뒪, 럢湲곗뿴蹂 諛붿씠윭뒪 벑씠뿀뒗뜲 移섎즺젣濡쒖꽌 슚슜媛移섎뒗 궙븯떎.

遺遺꾩쓽 븫꽭룷뒗 諛붿씠윭뒪 媛먯뿼뿉 븳 諛⑹뼱 湲곗쟾(삁瑜 뱾硫, 踰좏-씤꽣럹濡 떊샇쟾떖寃쎈줈)씠 넀긽릺뼱 엳뼱꽌, 諛붿씠윭뒪뒗 젙긽꽭룷蹂대떎 븫꽭룷뿉꽌 썾뵮 옒 蹂듭젣맂떎. 洹몃윭誘濡 븫꽭룷뿉꽌 諛붿씠윭뒪瑜 蹂듭젣떆궎뒗 씪 鍮꾧탳쟻 돩슫 씪씠떎. 젙옉 뼱젮슫 臾몄젣뒗 諛붿씠윭뒪媛 븫꽭룷뿉꽌뒗 蹂듭젣媛 옒 릺硫댁꽌 젙긽꽭룷뿉꽌뒗 蹂듭젣媛 릺吏 븡寃 븯뒗 寃껋씠떎. 븫꽭룷 듅씠쟻씤 蹂듭젣瑜 씠猷④린 쐞븯뿬 씤媛꾩뿉寃 蹂묒썝꽦씠 뾾뒗 諛붿씠윭뒪瑜 꽑蹂꾪븯嫄곕굹, 諛붿씠윭뒪 寃뚮냸쓣 쑀쟾怨듯븰쟻쑝濡 議곗옉븯硫 맂떎. 蹂묒썝꽦씠 뾾뒗 諛붿씠윭뒪쓽 삁뒗 젅삱由ъ떊(Reolysin)씤뜲, 젅삤諛붿씠윭뒪(Reovirus)쓽 빞깮삎 蹂씠二쇰줈 Ras 떊샇쟾떖寃쎈줈媛 솢꽦솕맂 븫꽭룷뿉꽌뒗 븫궡긽(oncolytic) 듅꽦쓣 媛吏 諛섎㈃ 젙긽꽭룷뿉꽌뒗 蹂묒썝꽦씠 嫄곗쓽 뾾떎. 諛붿씠윭뒪 寃뚮냸쓣 議곗옉븷 븣뿉뒗 諛붿씠윭뒪 蹂듭젣瑜 뾼寃⑺븯寃 넻젣븯뒗 쟾왂쓣 벖떎. 쑀쟾怨듯븰쟻쑝濡 thymidine kinase뿉 룎뿰蹂씠瑜 씪쑝궓 Herpes simplex virus type I (HSV-1)뒗 븫꽭룷뿉꽌留 듅씠쟻쑝濡 蹂듭젣瑜 븯硫, 뇤醫낆뼇쓽 移섎즺뿉룄 쑀슜븳 寃껋쑝濡 諛앺議뚮떎(Martuza et al., 1991). 씠 怨좊Т쟻씤 뿰援 寃곌낵뒗 븫슜빐諛붿씠윭뒪 移섎즺젣 媛쒕컻뿉 諛붿씠윭뒪 寃뚮냸 뵒옄씤쓣 쟻洹뱀쟻쑝濡 룄엯븯寃 븯떎. 븫슜빐諛붿씠윭뒪 移섎즺젣 媛쒕컻怨 愿젴븯뿬 媛옣 以묒슂븳 諛쒓껄 ’븫슜빐 怨쇱젙 以묒뿉 쟾떊쟻씤 醫낆뼇 듅씠硫댁뿭(systemic tumor-specific immunity)씠 슚怨쇱쟻쑝濡 쑀룄맂떎’뒗 젏씠떎. 씠 쁽긽 紐⑤뱺 븫슜빐諛붿씠윭뒪 移섎즺뿉꽌 븫솚옄쓽 깮議댁쓣 뿰옣떆궎뒗 以묒슂븳 듅吏뺤쑝濡 씤떇릺怨 엳떎(Fukuhara et al., 2016).

쑀쟾怨듯븰쟻쑝濡 議곗옉맂 븫슜빐諛붿씠윭뒪 移섎즺젣濡 삩肄붾┛(OncorineTM)怨 엫由ъ쭅(ImlygicTM)씠 엳떎. 삩肄붾┛ 몢寃쎈븫怨 떇룄븫移섎즺젣濡 2005뀈뿉 以묎뎅뿉꽌 뙋留ㅺ 듅씤릺뿀떎(Garber, 2006). 꽭룷뒗 諛붿씠윭뒪뿉 媛먯뿼릺硫 p53 떒諛깆쭏쓽 以묒옱뿉 쓽빐 꽭룷二쇨린瑜 뒭異붽퀬 꽭룷옄硫몄궗(apoptosis)瑜 씪쑝耳쒖꽌 諛붿씠윭뒪쓽 利앹떇쓣 留됰뒗떎. 븘뜲끂諛붿씠윭뒪쓽 E1B 쑀쟾옄 궛臾쇱 닕二쇱쓽 p53 쑀쟾옄 궛臾쇱뿉 寃고빀븯뿬 씠瑜 遺덊솢꽦솕 떆궡쑝濡쒖뜥, 닕二쇱꽭룷媛 諛붿씠윭뒪 蹂듭젣瑜 뼲젣븯뒗 寃껋쓣 諛⑺빐븳떎. 삩肄붾┛ 븘뜲끂諛붿씠윭뒪뿉꽌 E1B 궛臾쇱쓽 쑀쟾옄瑜 젣嫄고븳 寃껋씠떎. 뵲씪꽌 E1B 궛臾쇱쓽 諛쒗쁽씠 寃곗뿬맂 삩肄붾┛ p53 궛臾쇱씠 뾾뒗 븫꽭룷(遺遺꾩쓽 븫꽭룷뒗 룎뿰蹂씠뿉 쓽빐 p53 궛臾쇱씠 뾾떎)瑜 留뚮굹硫 蹂듭젣뒫젰쓣 쑀吏븯뒗 諛섎㈃, 젙긽쟻쑝濡 p53 궛臾쇱쓣 깮궛븯뒗 젙긽꽭룷瑜 留뚮굹硫 p53 궛臾쇱뿉 쓽븯뿬 諛붿씠윭뒪쓽 蹂듭젣뒫젰뿉 젣빟쓣 諛쏄쾶 맂떎(Vollmer et al., 1999). 삩肄붾┛ 移섎즺젣濡쒖꽌 뜑 씠긽 솗옣릺吏 紐삵븯怨 洹 궗슜씠 븘吏곴퉴吏 以묎뎅 궡뿉 援븳릺뼱 엳떎.

엫由ъ쭅 쑀쟾怨듯븰쟻쑝濡 議곗옉맂 herpes simplex virus-1 (HSV-1)씠떎. 몢 媛쒖쓽 쑀쟾옄(γ-34.5 諛 α-47)媛 젣嫄곕릺뼱 엳怨 씤媛꾩쓽 GM-CSF (Granulocyte-macrophage colony-stimulating factor, 怨쇰┰援 떇꽭룷 肄쒕줈땲 옄洹 씤옄) 쑀쟾옄媛 젣嫄곕맂 遺쐞뿉 異붽릺뼱 엳떎. 엫由ъ쭅 븫꽭룷뿉꽌 利앹떇븯뿬 븫꽭룷瑜 꽣듃由ш퀬, 硫댁뿭諛섏쓳쓣 옄洹뱁븯뿬 븫꽭룷瑜 떎떆 怨듦꺽븯룄濡 꽕怨꾨릺뿀떎(Hu et al., 2006; Fukuhara et al., 2016).

3. 븫슜빐諛붿씠윭뒪 듅꽦怨 몴쟻씤 移섎즺젣

3-1. 븫슜빐諛붿씠윭뒪 移섎즺젣쓽 씪諛섏쟻씤 듅꽦

씪諛섏쟻쑝濡 븫슜빐諛붿씠윭뒪瑜 꽕怨꾪븷 븣뒗 뿬윭 媛吏瑜 슂냼瑜 怨좊젮빐빞 븯吏留 理쒖냼븳 5媛吏 議곌굔뿉뒗 遺빀븯뿬빞 븳떎. 씠 5媛吏 議곌굔쑝濡쒕뒗 몴쟻 醫낆뼇뿉 븳 듅씠꽦쓣 媛吏怨, 媛먯뿼맂 醫낆뼇꽭룷瑜 二쎌씠뒗 뙆愿대젰쓣 媛吏硫, 빆醫낆뼇硫댁뿭쓣 쑀룄븯뒗 뒫젰쓣 蹂댁쑀븯怨, 遺옉슜쓣 理쒖냼솕븯怨, 諛붿씠윭뒪媛 媛吏뒗 蹂몄뿰쓽 媛먯뿼젰씠 蹂듭썝븯吏 紐삵븯룄濡 빐빞 븯뒗 寃껋씠떎(Maroun et al., 2017).

븫슜빐諛붿씠윭뒪뒗 븫쓣 슜빐븯뿬 븫쓣 移섎즺븯뒗 몴쟻 諛붿씠윭뒪 移섎즺(targeted oncolytic virotherapy) 諛⑸쾿씠떎. 솕븰쟻 샊 빆泥 몴쟻빆븫젣泥섎읆 븫슜빐諛붿씠윭뒪뒗 젙긽꽭룷 援щ텇씠 릺뒗 醫낆뼇꽭룷 궡쓽 鍮꾩젙긽쟻씤 遺쐞瑜 몴쟻쑝濡 궪뒗떎. 븫슜빐諛붿씠윭뒪뒗 븫꽭룷뿉꽌 솢꽦솕맂 쑀쟾궗寃쎈줈굹, 븫꽭룷뿉꽌 냼떎맂 醫낆뼇뼲젣씤옄湲곕뒫쓣 몴쟻쑝濡 궪븘 醫낆뼇꽭룷瑜 꽑깮븳떎. 븫슜빐諛붿씠윭뒪뒗 醫낃눼 궡뿉꽌 꽑깮쟻쑝濡 蹂듭젣릺뼱 븫꽭룷瑜 슜빐븳떎. 蹂듭젣맂 뵺 諛붿씠윭뒪뒗 씤젒 議곗쭅쓣 넻빐 솗궛릺뼱 癒 怨녹뿉 엳뒗 醫낆뼇꽭룷룄 닚李⑥쟻쑝濡 二쎌씤떎(Fig. 1) (Davola and Mossman, 2019).

Fig. 1.

Action mechanism of oncolytic virus (OV). OVs destroy selectively cancer cells while having minimal effect on healthy cells. OVs attack tumor cells by two different mechanisms; direct tumor cell lysis and indirect augmentation of host immune activity (Davola and Mossman, 2019).



븫슜빐諛붿씠윭뒪뿉뒗 쑀쟾옄 議곗옉쓣 넻빐 뿬윭 媛吏 移섎즺 紐⑹쟻쓽 쑀쟾옄(transgene)媛 궫엯릺뼱 엳떎. 씠 쑀쟾옄뱾씠 諛쒗쁽릺뼱 醫낆뼇 듅씠쟻 꽭룷룆꽦 T-由쇳봽援щ 쑀룄븯嫄곕굹, 醫낆뼇꽭룷瑜 吏곸젒 궗硫몄떆궓떎. 삁瑜 뱾硫 GM-CSF 媛숈 궗씠넗移댁씤 쑀쟾옄瑜 諛쒗쁽떆耳쒖꽌 醫낆뼇꽭룷뿉 븳 硫댁뿭諛섏쓳쓣 利앷컯떆궎嫄곕굹, 쟾援ъ빟臾(pro-drug) 쟾솚슚냼 쑀쟾옄媛 洹 궛臾쇰줈뜥 二쇰 醫낆뼇꽭룷瑜 二쎌씤떎. 븫슜빐諛붿씠윭뒪뿉 떊깮삁愿뼲젣 愿젴 쑀쟾옄瑜 룄엯븯뿬 醫낆뼇삁愿쓣 李⑤떒쓣 븯뿬 醫낆뼇쓣 愿댁궗떆궎湲곕룄 븳떎(Woo and Hu, 2015). 醫낆뼇꽭룷媛 슜빐맆 븣뒗 醫낆뼇愿젴빆썝(tumor-associated antigen)怨 媛숈 硫댁뿭쑀諛쒕Ъ吏덉씠 遺꾨퉬릺뼱 빆醫낆뼇硫댁뿭諛섏쓳씠 쑀룄맂떎(Fig. 1) (Davola and Mossman, 2019).

諛붿씠윭뒪媛 꽭룷瑜 媛먯뿼떆궗 븣뒗 젙긽꽭룷뒗 뵾븯怨 醫낆뼇꽭룷留 몴쟻쑝濡 궪븘 移⑦닾떆궎뒗 寃껋씠 醫뗭뜲, 洹 移⑦닾 湲곗쟾뿉뒗 뿬윭 媛吏媛 엳떎. 諛깆떆땲븘 諛붿씠윭뒪뒗 닔슜泥대 넻븯뒗 떊 궡룷옉슜쑝濡 꽭룷뿉 뱾뼱媛꾨떎. 븘뜲끂諛붿씠윭뒪뒗 븘뜲끂諛붿씠윭뒪 닔슜泥대굹 씤뀒洹몃┛, CD46뿉 寃고빀븯硫 닕二쇱꽭룷濡 뱾뼱媛怨, 뿤瑜댄럹뒪諛붿씠윭뒪뒗 뿤瑜댄럹뒪諛붿씠윭뒪 엯옣以묒옱옄(entry mediator) 寃고빀븯뿬 뱾뼱媛꾨떎.

3-2. 몴쟻씤 븫슜빐諛붿씠윭뒪 移섎즺젣

븫슜빐諛붿씠윭뒪 移섎즺젣 슜쑝濡 떎뼇븳 醫낅쪟쓽 諛붿씠윭뒪媛 꽭怨꾩쟻쑝濡 뿰援щ릺怨 엳떎.

쁽옱 엫긽떆뿕씠 吏꾪뻾릺怨 엳뒗 諛붿씠윭뒪濡쒕뒗 Herpes simplex virus, Adenovirus, Measles virus, Vaccinia virus, Reo-virus, Coxsackievirus, Parvovirus, Poliovirus, Rhinovirus 벑씠 엳떎(Table 1, Raja et al., 2018). 꽌援ъ뿉꽌 쑀씪븯寃 뙋留ㅺ 씠猷⑥뼱吏 엫由ъ쭅怨 뙋留ㅼ듅씤뿉 洹쇱젒븳 寃껋쑝濡 뿬寃⑥뒗 럺궗踰↔낵 젅삱由ъ떊쓣 몴쟻씤 삁濡 궡렣蹂닿퀬옄 븳떎.

Current and recently completed trial I and II using oncolytic viruses (Raja et al., 2018)

Virus Strain Targeted malignancy
Herpes simplex virus I Talimogene Laherparepvec (T-Vec) Breast, Melanoma and pancreatic
TBI-1401 (HF10) Superficial solid tumors and melanoma
G207 Glioma
HSV1716 Mesothelioma, Bone, Sarcomas and neuroblastomas

Adenovirus/Herpes ADV/HSV-tk Breast and NSCLC
Simplex virus

Adenovirus LOAd703 PancreaticNSCLC
CG0070 Bladder
ColoAd1 (Enadenotucirev) Colorectal, NSCLC, Bladder, Epithelial
Renal cell and ovarian
ONCOS-102 Advanced solid tumors and melanoma
DNX-2401 Brain
VCN-01 Advanced solid tumors and pancreatic
Ad-MAGEA3 and MG1-MAGEA3 NSCLC and advanced solid tumors
NSC-CRAd-Survivin-pk7 Glioma
Ad5-yCD/mutTKSR39rep-hIL12 Prostate
Ad5-yCD/mutTKSR39rep-ADP NSCLC

Measles MV-NIS Breast, Head and neck, Ovarian, Nerve sheath, Mesothelioma and multiple myeloma

Vaccinia GL-ONC1 Advanced solid tumors, Head and neck and ovarian
Pexastimogene devacirepvec (Pexa-Vec) Hepatocellular, Head and neck, Colorectal, Advanced solid tumors, Blue cell, Melanoma, Lung and renal cell

Reovirus REOLYSIN Colorectal, Bladder, Pancreatic, Multiple myeloma, Plasma cell cytoma, Ovarian and peritoneal

Coxsackievirus CVA21 (CAVATAK) Melanoma and NSCLC

Parvovirus H-1PV (ParvOryx) Glioblastoma multiforme

Polio/Rhinovirus PVSRIPO Glioma


3-2-1. 쑀쟾옄 議곗옉 븫슜빐諛붿씠윭뒪 엫由ъ쭅(T-vec)

엫由ъ쭅 herpes simplex virus-1 (HSV-1)瑜 議곗옉븯뿬 뵒옄씤븳 寃껋씤뜲, γ-34.5 쑀쟾옄 α-47 쑀쟾옄瑜 寃곗떎떆耳곗쑝硫, transgene쑝濡쒖꽌 human granulocyte macrophage colony-stimulating factor (GM-CSF)瑜 γ-34.5 寃곗떎 遺쐞뿉 궫엯븯떎.

젙긽쟻씤 닕二쇱꽭룷뒗 諛붿씠윭뒪뿉 媛먯뿼릺硫 떒諛깆쭏빀꽦쓣 李⑤떒(shut-off)븯뿬 諛붿씠윭뒪쓽 利앹떇쓣 留됱븘 옄떊쓣 諛⑹뼱븳떎. HSV-1뿉 궡옱맂 γ-34.5 쑀쟾옄쓽 뿭븷 媛먯뿼 썑 닕二쇱꽭룷쓽 떒諛깆쭏빀꽦 李⑤떒옉슜쓣 臾댄슚솕떆耳쒖꽌 옄湲 蹂듭젣瑜 썝솢븯寃 븯뒗 寃껋씠떎. HSV-1뿉 γ-34.5瑜 遺덊솢꽦솕떆궎硫 젙긽꽭룷뿉꽌뒗 닕二쇱꽭룷쓽 떒諛깆쭏빀꽦 李⑤떒옉슜쑝濡 諛붿씠윭뒪쓽 蹂듭젣媛 뼱젮썙吏꾨떎. 遺遺꾩쓽 븫꽭룷뿉뒗 떒諛깆쭏빀꽦 李⑤떒諛섏쓳씠 뾾떎. 뵲씪꽌 γ-34.5 쑀쟾옄媛 寃곗넀맂 HSV-1(엫由ъ쭅) 젙긽꽭룷뿉꽌뒗 蹂듭젣媛 뼱젮슫 諛섎㈃ 븫꽭룷뿉꽌뒗 옒 利앹떇븯寃 맂떎. 利 γ-34.5 쑀쟾옄 寃곗넀 諛붿씠윭뒪뿉寃 醫낆뼇꽭룷뿉 꽑깮쟻씤 蹂듭젣뒫젰쓣 遺뿬븳떎.

α47 쑀쟾옄뒗 빆썝젣떆 愿젴맂 닔넚泥(transporter)뿉 湲명빆븯뿬 洹 옉슜쓣 뼲젣븳떎. α47씠 寃곗떎맂 諛붿씠윭뒪뒗 媛먯뿼맂 븫꽭룷뿉꽌 MHC class I쓽 諛쒗쁽쓣 利앷떆궎寃 맂떎. 媛먯뿼맂 醫낆뼇꽭룷쓽 MHC class I 諛쒗쁽 利앷뒗 寃곌낵쟻쑝濡 醫낆뼇 硫댁뿭諛섏쓳 쑀룄瑜 媛뺥솕떆궓떎. α47 寃곗떎 삉븳 씤洹 US11 쑀쟾옄쓽 利됯컖쟻씤 議곌린 諛쒗쁽쓣 씪쑝궎뒗뜲, 씠뒗 븫꽭룷뿉꽌 諛붿씠윭뒪쓽 蹂듭젣瑜 利앷떆궓떎.

GM-CSF뒗 빆醫낆뼇硫댁뿭쓽 쑀룄瑜 媛뺥솕븯湲 쐞븯뿬 궫엯릺뿀뒗뜲, 씤媛꾩쓽 GM-CSF 쑀쟾옄 몢 媛쒓 γ-34.5 寃곗떎 遺쐞뿉 쐞移섑븳떎. GM-CSF뒗 議곗젅 궗씠넗移댁씤쑝濡쒖꽌 뿼利 遺쐞뿉꽌 닔吏긽꽭룷쓽 異뺤쟻쓣 옄洹뱁븯怨, 빆썝젣떆꽭룷쓽 湲곕뒫쓣 珥됱쭊븯怨, T-꽭룷 諛섏쓳쓣 珥됰컻븳떎. 븫슜빐諛붿씠윭뒪 쑀쟾泥댁뿉 GM-CSF瑜 꽔 寃쎌슦 룞臾쇱떎뿕뿉꽌 醫낆뼇쓽 媛먯냼 쟾泥 깮議댁쑉쓽 쑀쓽븳 利앷媛 愿李곕릺뿀떎(Agarwalla and Aghi, 2012; Kohlhapp and Kaufman, 2016).

엫由ъ쭅 쑀諛⑹븫, 몢寃쎈븫, 쐞옣愿怨꾩븫, 븙꽦쓳깋醫 솚옄瑜 긽쑝濡 븳 븞쟾꽦 떆뿕뿉꽌 醫낆뼇 궡 닾뿬 떆 紐⑤뱺 솚옄뿉寃뚯꽌 옒 愿슜릺뿀떎(Hu et al., 2006; Fukuhara et al., 2016).

3-2-2. 쑀쟾옄 議곗옉 븫슜빐諛붿씠윭뒪 럺궗踰(Pexa-Vec, pexastimogene devacirepvec, JX-594)

럺궗踰≪ 쑀쟾怨듯븰쟻쑝濡 議곗옉맂 諛깆떆땲븘 諛붿씠윭뒪(vaccinia virus)씠떎. 踰≪떆땲븘 諛붿씠윭뒪뒗 옄뿰쟻쑝濡 젙긽꽭룷蹂대떎 븫꽭룷뿉꽌 뜑 옒 利앹떇븯뒗 怨좎쑀쓽 醫낆뼇移쒗솕꽦쓣 媛吏怨 엳떎. 븫꽭룷 二쇰쓽 떊깮삁愿 깉湲곌 돩썙 踰≪떆땲븘 諛붿씠윭뒪쓽 移⑦닾媛 슜씠븯떎. 삉븳 븫꽭룷뒗 利앹떇瑜좎씠 넂븘꽌 諛붿씠윭뒪 蹂듭젣뿉 븘슂븳 돱겢젅삤떆뱶 쓣 留뚮뱾뼱 踰≪떆땲븘 諛붿씠윭뒪뿉寃 蹂듭젣븯湲 醫뗭 솚寃쎌쓣 젣怨듯븳떎.

럺궗踰≪쓽 諛깆떆땲븘 諛붿씠윭뒪뒗 떚誘몃뵖씤궛솕슚냼(thymidine kinase)媛 룎뿰蹂씠濡 遺덊솢꽦솕 릺뼱 엳떎. 븫꽭룷뒗 솢諛쒗븳 蹂듭젣濡 씤븯뿬 떚誘몃뵖씤궛솕슚냼媛 異⑸텇엳 諛쒗쁽릺뼱 遺꾨퉬맂떎. 떚誘몃뵖씤궛솕슚냼瑜 留뚮뱾吏 紐삵븯뒗 럺궗踰≪ 븫꽭룷뿉꽌뒗 씠 슚냼瑜 씠슜븯뿬 利앹떇븷 닔 엳떎. 洹몃윭굹 젙긽쟻씤 닕二쇱꽭룷뿉꽌뒗 떚誘몃뵖씤궛솕슚냼媛 遺議깊븯誘濡 럺궗踰≪ 利앹떇씠 뼱졄떎. 럺궗踰≪ 븫꽭룷留뚯쓣 꽑깮쟻쑝濡 怨듦꺽븯뿬 뙆愿댄븯뒗뜲, 씠 怨쇱젙뿉꽌 遺꾩텧맂 븫꽭룷 듅씠 臾쇱쭏뱾씠 泥대궡 硫댁뿭諛섏쓳쓣 뿰뇙쟻쑝濡 珥됱쭊떆耳 븫꽭룷瑜 怨듦꺽븳떎. 럺궗踰≪뿉뒗 씤媛 GM-CSF 쑀쟾옄룄 궫엯릺뼱 엳떎. GM-CSF 궛臾쇱 醫낆뼇 듅씠 빆醫낆뼇硫댁뿭諛섏쓳쓣 옄洹뱁븳떎. 럺궗踰≪뿉뒗 Lac-Z 쑀쟾옄媛 留덉빱濡 궫엯릺뿀떎(Parato et al., 2012).

諛깆떆땲븘 諛붿씠윭뒪 궗슜쓽 옣젏 젙留 닾뿬뿉꽌 븞젙쟻씠怨, 꽭룷룆꽦씠 媛뺥븯硫, 깮諛깆떊쑝濡쒖꽌 븞쟾꽦씠 슦닔븯떎뒗 젏씠떎. 럺궗踰≪ 쁽옱 媛꾩꽭룷븫醫(hepatocellular carcinoma)뿉 븯뿬 떒룆 샊 蹂묒슜쑝濡 엫긽2긽怨 3긽 떆뿕씠 吏꾪뻾 以묒씠떎(Fukuhara et al., 2016; Yamada et al., 2018; Guo et al., 2019). 럺궗踰≪ 븳援쓽 ’떊씪젨’궗뿉꽌 媛쒕컻쓣 二쇰룄븯怨 엳떎.

3-2-3. 옄뿰쟻씤 븫슜빐諛붿씠윭뒪 젅삱由ъ떊(Reolysin)

蹂댄넻 븫移섎즺뿉 궗슜릺뒗 諛붿씠윭뒪뒗 궗엺뿉寃 蹂묒썝꽦씠 뾾룄濡 쑀쟾옄瑜 議곗옉븳 寃껋씠떎. 洹몃윭굹 Reovirus쓽 寃쎌슦뿉뒗 議곗옉씠 뾾씠 옄뿰쟻씤 긽깭쓽 諛붿씠윭뒪瑜 洹몃濡 移섎즺뿉 궗슜븳떎. Reovirus뒗 씠以묎떏 RNA 諛붿씠윭뒪씤뜲 젙긽꽭룷蹂대떎 醫낆뼇꽭룷뿉꽌 蹂듭젣媛 옒맂떎. Reovirus쓽 븫슜빐 듅꽦 Ras 떊샇쟾떖 솢꽦뿉 쓽議댄븳떎. 젅삱由ъ떊(Reolysin) Reovirus쓽 T3D strain씤뜲 빆븫젣濡쒖꽌 留롮씠 뿰援щ릺뿀쑝硫 쁽옱 옄뿰쟻씤 諛붿씠윭뒪 긽깭濡 엫긽뿰援ъ뿉 궗슜릺怨 엳떎(Gong et al., 2016). 쟾씠 怨좏삎븫, 쓳깋醫, 몢寃쎈븫 벑쓽 利앹긽뿉 븯뿬 엫긽2긽 떆뿕씠 셿猷뚮릺뿀쑝硫, 몢寃쎈븫뿉 빐꽌뒗 엫긽3긽 뿰援ш 吏꾪뻾릺怨 엳怨,쟾씠꽦 쑀諛⑹븫, 룓븫, 痍뚯옣븫뿉룄 엫긽떆뿕씠 吏꾪뻾릺怨좎엳떎(Fukuhara et al., 2016; Eissa et al., 2018). 젅삱由ъ떊 罹먮굹떎 罹섍굅由 냼옱쓽 깮紐낃났븰湲곗뾽 삩肄쒕━떛뒪 諛붿씠삤뀒겕(Oncolytics Biotech)뿉꽌 媛쒕컻븯怨 엳떎.

4. 븫슜빐諛붿씠윭뒪쓽 빆븫슚怨 利앹쭊 諛⑸쾿

4-1. 븫꽭룷 꽑깮쟻씤 媛먯뿼 諛 吏곸젒쟻씤 븫꽭룷 슜빐(direct cancer cell lysis)

諛붿씠윭뒪媛 븫꽭룷뿉留 媛먯뿼릺뼱 蹂듭젣 利앹떇씠 릺뒗 꽑깮꽦 븫슜빐諛붿씠윭뒪뿉꽌 媛옣 以묒슂븳 슂냼씠떎. Reo-virus굹 New Castle virus 벑 옄뿰쟻쑝濡 醫낆뼇꽭룷瑜 꽑깮쟻쑝濡 媛먯뿼떆궎뒗 듅吏뺤씠 엳떎. p53 쑀쟾옄쓽 遺덊솢꽦솕굹 꽭룷궗硫 븯 벑 븫꽭룷 듅쑀쓽 蹂솕媛 씠뱾 諛붿씠윭뒪쓽 蹂듭젣 怨쇱젙뿉 쑀由ы븯寃 옉슜븯뿬 깮湲곕뒗 쁽긽씠떎. 떎瑜 諛붿씠윭뒪쓽 寃쎌슦뿉뒗 蹂삎怨 議곗옉쓣 넻븯뿬 醫낆뼇꽭룷뿉 꽑깮쟻 媛먯뿼쓣 쑀룄븳떎(Cho et al., 2013). 媛 諛붿씠윭뒪뒗 醫낆뼇꽭룷瑜 듅씠쟻쑝濡 몴쟻솕븯湲 쐞븯뿬 뿬윭 媛吏 썝由щ 궗슜븳떎. 諛붿씠윭뒪뿉 뵲씪 miRNA 몴쟻, 씤꽣럹濡 寃고븿, Ras signaling, thymidine kinase 寃곗떎 벑쓽 룄援щ 궗슜븯뿬, 븫슜빐諛붿씠윭뒪媛 븫꽭룷뿉 듅씠쟻쑝濡 媛먯뿼릺룄濡 븳떎. Thymidine kinase媛 寃곗떎맂 諛붿씠윭뒪쓽 寃쎌슦뿉뒗 빑궛쓽 빀꽦씠 솗꽦븳 븫꽭룷뿉꽌留 꽑깮쟻쑝濡 옄湲곗옄떊쓣 蹂듭젣븯뿬 留롮 鍮꾨━삩쓣 깮꽦븳 썑 븫꽭룷瑜 슜빐떆궓떎. 슜빐맂 븫꽭룷뿉꽌 諛⑹텧맂 鍮꾨━삩 二쇰쓽 븫꽭룷뿉 닚李⑥쟻쑝濡 媛먯뿼릺뼱 떎떆 븫슜빐 옉슜쓣 씪쑝궓떎.

슜빐맂 븫꽭룷뿉 쓽빐 끂異쒕맂 븫꽭룷 臾쇱쭏뱾 빆썝젣떆꽭룷뿉 쓽븯뿬 룷쉷맂 떎쓬 醫낆뼇 듅씠쟻씤 T-꽭룷 諛섏쓳쓣 쑀諛쒖떆궓떎. 쟾떊쟻씤 T-꽭룷 諛섏쓳쑝濡 씤븯뿬 硫由 쐞移섑븳 媛숈 醫낅쪟쓽 醫낆뼇룄 諛쒓껄븯뿬 2李⑥쟻쑝濡 怨듦꺽븯寃 맂떎.

4-2. 硫댁뿭 利앷컯 湲곕뒫(enhancing immunogenicity) 遺뿬

븫슜빐諛붿씠윭뒪뒗 吏곸젒 븫꽭룷瑜 궗硫몄떆궎뒗 옉슜쓣 븯吏留 씠뿉 뜑븯뿬 NK 꽭룷 T 꽭룷濡 씤븳 硫댁뿭솢꽦솕瑜 쑀룄븯뿬 빆븫뒫젰쓣 利앷컯떆궓떎. 븫슜빐諛붿씠윭뒪瑜 留뚮뱾 븣뒗 硫댁뿭湲곕뒫쓣 利앹쭊떆궎뒗 쑀쟾옄瑜 븫슜빐諛붿씠윭뒪 踰≫꽣뿉 궫엯븯뿬 臾댁옣떆궓떎. 硫댁뿭젰 利앹쭊쓣 쐞븳 臾댁옣(arming)쑝濡 GM-CSF, interleukin (IL)-2, IL-4, IL-10, IL-15, interferon (INF)-α, INF-β, INF-γ 벑쓽 쑀쟾옄媛 궗슜맂떎. 씠 궫엯 쑀쟾옄媛 깮꽦븯뒗 臾쇱쭏뱾 꽭룷룆꽦 硫댁뿭꽭룷(cytotoxic immune effector cells)뱾씠 옉룞븯뿬 2李⑥쟻쑝濡 굹癒몄 븫꽭룷瑜 젣嫄고븯룄濡 븳떎(Kim, 2017).

4-3. 醫낆뼇 듅씠쟻 뼲젣 쑀쟾옄쓽 궫엯(insertion of tumor suppressor genes)

醫낆뼇쓽 꽦옣뿉뒗 삁愿떊깮씠 븘슂븯떎. 삁븸쓣 넻븯뿬 궛냼 쁺뼇遺꾩씠 怨듦툒릺吏 븡쑝硫 븫꽭룷뒗 궗硫명븳떎. 븫꽭룷뿉 삁븸怨듦툒쓣 李⑤떒븯湲 쐞븯뿬 삁愿떊깮쓣 뼲젣븯뒗 쑀쟾옄굹 뼲젣臾쇱쭏 愿젴 쑀쟾옄瑜 븫슜빐諛붿씠윭뒪뿉 궫엯븳떎. Vascular endothelial growth factor (VEGF), endostatin, angiostatin, vasculostatin, fibroblast growth factor receptor 벑怨 愿젴맂 쑀쟾옄굹 microRNA瑜 궫엯븯湲곕룄 븳떎(Kim, 2017). 諛붿씠윭뒪瑜 궗슜븯湲 쐞빐꽌뒗 諛붿씠윭뒪쓽 깮솢궗瑜 옒 씠빐븯怨, 젒醫 媛뒫븳 理쒕 諛붿씠윭뒪 냽룄瑜 븣븘빞 븯硫, 諛붿씠윭뒪瑜 젣嫄고븯湲 쐞븳 빆諛붿씠윭뒪젣쓽 議댁옱룄 솗蹂대릺뼱빞 븳떎. 쑀쟾옄쓽 議곗옉룄 슜씠븯뿬빞 븯硫, 씤泥 닾뿬 떆 諛쒖깮븯뒗 硫댁뿭썝꽦, 빞깮삎 諛붿씠윭뒪쓽 蹂묒썝꽦룄 怨좊젮븯뿬빞 븳떎(Kim, 2017; Maroun et al., 2017).

4-4. 븫슜빐諛붿씠윭뒪쓽 젣븳

븫슜빐諛붿씠윭뒪뒗 빞깮삎 紐⑥껜 諛붿씠윭뒪쓽 듅꽦쓣 媛吏怨 엳뒗뜲 씠寃껋씠 옣젏씠굹 떒젏쑝濡 옉슜븳떎. HSV-1뿉꽌 쑀옒븳 T-vec(엫由ъ쭅)쓽 寃쎌슦 꽭룷媛 솗궛 떆 諛붿씠윭뒪 삁利앹쓣 씪쑝궎吏 븡뒗떎. 뵲씪꽌 T-vec 蹂묐 궡遺(intralesional)뿉留 닾뿬븯硫 젙留 二쇱궗슜쑝濡쒕뒗 궗슜븯吏 븡뒗떎. T-vec쓽 援吏쟻씤 蹂묐 궡遺 닾뿬媛 쟾떊쟻씤 빆醫낆뼇硫댁뿭쓣 쑀룄븯뿬 썝嫄곕━ 蹂묒냼뿉꽌룄 슚怨쇨 굹궗떎. 씠 쟾떊쟻씤 빆醫낆뼇硫댁뿭諛섏쓳 HSV-1 諛붿씠윭뒪 옄泥댁쓽 빆醫낆뼇硫댁뿭 쑀룄 듅꽦뿉 湲곗씤븳 寃껋쑝濡 뿬寃⑥쭊떎(Varghese et al., 2006).

븫슜빐諛붿씠윭뒪 移섎즺뿉꽌 以묒슂븳 愿떖 移섎즺슚怨쇨 닚솚빆泥댁뿉 쓽빐꽌 媛먯냼맆 닔 엳떎뒗 젏씠떎. 諛붿씠윭뒪 삁利앹쓣 씪쑝궎뒗 諛붿씠윭뒪뒗 以묓솕빆泥댁쓽 怨듦꺽쓣 떦븯湲 돺떎. 젙留 닾뿬븳 諛붿씠윭뒪뒗 씠쟾뿉 移섎즺瑜 諛쏆븯嫄곕굹 諛깆떊쓣 닾뿬 諛쏆 솚옄뿉寃뚮뒗 빆醫낆뼇슚怨쇨 젣븳쟻씪 닔 엳떎. 닚솚빆泥댁뿉 쓽븳 슚怨 媛먯냼뒗 븫슜빐諛붿씠윭뒪瑜 젙留 닾뿬븳 솉뿭쓣 븪븯뜕 솚옄뿉寃뚯꽌 愿李곕릺뿀떎(Russell et al., 2014). 닚솚빆泥댁뿉 쓽븳 諛⑺빐瑜 洹밸났븯湲 쐞빐꽌 reovirus濡 룞臾쇱떎뿕쓣 빐蹂 寃곌낵, 쟾떊쟻씤 移섎즺瑜 쐞빐꽌뒗 reovirus瑜, 삁泥 궡뿉꽌 以묓솕빆泥 닔以씠 삱씪媛湲 쟾뿉, 泥 二 궡뿉 鍮좊Ⅴ寃 諛섎났븯뿬 怨좎슜웾쑝濡 닾뿬븯뒗 寃껋씠 諛붾엺吏곹븯떎(Gong et al., 2016).

븫슜빐諛붿씠윭뒪瑜 諛섎났븯뿬 닾뿬븯硫 諛붿씠윭뒪뿉 븳 硫댁뿭씠 깮寃⑥꽌 移섎즺瑜 吏냽븯湲 옒뱾떎. 硫댁뿭湲곕뒫씠 留롮씠 빟솕맂 留먭린븫쓽 寃쎌슦 븫슜빐諛붿씠윭뒪瑜 닾뿬빐룄 릺뒗吏 븘吏 寃利앹씠 遺덉땐遺꾪븯떎. 삉븳 븫슜빐諛붿씠윭뒪瑜 닾뿬빐룄 紐⑤뱺 븫꽭룷媛 궗硫명븯뒗 寃껋 븘땲떎. 븫꽭룷뒗 떎뼇븳 룎뿰蹂씠瑜 븯誘濡 븫슜빐諛붿씠윭뒪 移섎즺뿉룄 궡븘궓뒗 븫꽭룷媛 궓븘 엳쓣 닔 엳떎.

5. 븫슜빐諛붿씠윭뒪쓽 援궡쇅 媛쒕컻 쁽솴

5-1. 븫슜빐諛붿씠윭뒪쓽 꽭怨꾩쟻씤 엫긽떆뿕 쁽솴

ClinicalTrials.gov(誘멸뎅 NIH, US National Library of Medicine 궛븯 湲곌뎄, https://www.clinicaltrials.gov/)뒗 쟾꽭怨꾩뿉꽌 닔뻾릺怨 엳뒗 엫긽떆뿕쓣 珥앸쭩씪븯뿬 database瑜 援ъ텞븯怨 엳떎. 떒뼱 ’oncolytic’쓣 궎썙뱶濡 寃깋빐蹂 寃곌낵 2019뀈 6썡 23씪 쁽옱 97嫄댁쓽 븫슜빐諛붿씠윭뒪 엫긽떆뿕씠 吏꾪뻾릺怨 엳뒗 寃껋쑝濡 굹궗떎. 엫긽1긽 珥덇린媛 1嫄,엫긽1긽씠 69嫄, 엫긽2긽씠 37嫄, 엫긽3긽씠 5嫄, phase not applicable씠 2嫄댁쑝濡 굹궗떎. 떎瑜 phase쓽 엫긽떆뿕씠 룞떆뿉 吏꾪뻾릺怨 엳뒗 寃쎌슦媛 엳뼱꽌 媛쒕퀎 嫄댁닔쓽 빀씠 珥앷굔닔瑜 긽쉶븯뒗 寃껋쑝濡 異붿젙맂떎.

엫긽떆뿕쓽 쟻쓳利앹쑝濡쒕뒗 諛⑷킅븫, 뇤븫, 몢寃쎈븫, 떊옣븫, 媛꾩븫, 쓳깋醫, 痍뚯옣븫, 쟾由쎌꽑븫 벑씠 엳떎. 궗슜릺뒗 諛붿씠윭뒪濡쒕뒗 뿤瑜댄럹뒪諛붿씠윭뒪, 븘뜲끂諛붿씠윭뒪, 솉뿭諛붿씠윭뒪, 諛깆떆땲븘諛붿씠윭뒪, 젅삤諛붿씠윭뒪, 냼븘留덈퉬諛붿씠윭뒪, 肄뺤궗궎諛붿씠윭뒪, 뙆瑜대낫諛붿씠윭뒪, 젅듃濡쒕컮씠윭뒪 벑씠 엳떎. 젅삤諛붿씠윭뒪, 肄뺤궗궎諛붿씠윭뒪, 뙆瑜대낫諛붿씠윭뒪쓽 寃쎌슦뿉뒗 빞깮삎 諛붿씠윭뒪瑜 洹몃濡 궗슜븯怨, 냼븘留덈퉬諛붿씠윭뒪쓽 寃쎌슦 빟룆솕맂 諛붿씠윭뒪瑜 궗슜븯떎. 떎瑜 諛붿씠윭뒪뱾 諛붿씠윭뒪뿉 뵲씪 thymidine kinase 寃곗떎, GM-CSF 궫엯 벑쓽 떎뼇븳 쑀쟾쟻씤 議곗옉쓣 媛븯뿬 궗슜븯떎(Lawler et al., 2017; Lundstrom, 2018; Bommareddy et al., 2018).

5-2. 븫슜빐諛붿씠윭뒪쓽 援궡 媛쒕컻 쁽솴

援궡뿉꽌룄 뿬윭 뾽泥닿 븫슜빐諛붿씠윭뒪 移섎즺젣瑜 媛쒕컻븯怨 엳떎. 븵뿉꽌 뼵湲됲븳 寃껋쿂읆 럺궗踰≪ 슦由щ굹씪쓽 떊씪젨뿉꽌 媛쒕컻븯怨 엳떎. 럺궗踰≪ 슦몢諛붿씠윭뒪瑜 씠슜븳 媛꾩븫移섎즺젣씠떎. ClinicalTrials.gov뿉 쓽븯硫 럺궗踰≪ 2019뀈 6썡 쁽옱 엫긽1긽 떆뿕 10嫄, 엫긽2긽 떆뿕 9嫄, 엫긽3긽 떆뿕씠 1嫄댁씠 吏꾪뻾 以묒씠떎. 럺궗踰≪ 硫댁뿭愿臾몄뼲젣젣씤 샃떚蹂댁 媛숈 떎瑜 移섎즺젣쓽 蹂묒슜 닾뿬 엫긽떆뿕룄 吏꾪뻾 以묒씠떎. 떆뿕 以묒씤 쟻쓳利앹쑝濡쒕뒗 옣븫 · 쐞븫 떞룄븫 · 痍뚯옣븫 · 湲고 怨좏삎븫쓽 媛 쟾씠 諛 硫댁뿭愿臾몄뼲젣젣 궡꽦 怨좏삎븫 벑씠떎. 떊씪젨 룆由쎌쟻 뜲씠꽣 紐⑤땲꽣留곸쐞썝쉶(Independent Data Monitoring Commitee, DMC)쓽 엫긽以묐떒 沅뚭퀬瑜 諛쏆븘꽌 럺궗踰≪쓽 媛꾩븫 솚옄瑜 긽쑝濡 븳 엫긽3긽쓣 議곌린뿉 醫낅즺븳떎怨 2019뀈 8썡 4씪 諛쒗몴븯떎. 洹몃윭굹 떎瑜 쟻쓳利앹쓽 蹂묒슜 닾뿬 엫긽떆뿕 怨꾩냽 吏꾪뻾븳떎怨 븳떎.

肄붿삤濡깆깮紐낃낵븰 룺뒪諛붿씠윭뒪瑜 씠슜븳 븫슜빐諛붿씠윭뒪 臾쇱쭏씤 KLS-3020쓽 룞臾쇱떎뿕쓣 吏꾪뻾 以묒씠硫, 2019뀈 以 엫긽1긽 떆뿕뿉 吏꾩엯븷 삁젙씠떎. KLS-3020 븫 룞臾 紐⑤뜽뿉 1쉶 닾뿬留뚯쑝濡쒕룄 븫쓽 꽦옣씠 쁽엳 媛먯냼맖씠 솗씤맂 諛 엳떎. 룞궗뒗 醫낆뼇궡긽 諛붿씠윭뒪 移섎즺슚뒫쓣 利앷떆궗 닔 엳뒗 룺뒪諛붿씠윭뒪 봽濡쒕え꽣뿉 븳 듅뿀瑜 痍⑤뱷뻽떎怨 2019뀈 6썡 15씪 諛앺삍떎.

뿬由뒪誘몄뒪뒗 옄궗뿉꽌 遺꾨━븳 빞깮삎 젅삤諛붿씠윭뒪瑜 쐞븫移섎즺뿉 쟻슜떆궎뒗 뿰援щ 븯怨 엳떎. 젅삤諛붿씠윭뒪뒗 샇씉湲, 옣愿뿉 議댁옱븯뒗 臾댄빐븳 諛붿씠윭뒪씤뜲, 빞깮삎 샊 빟룆솕맂 젅삤諛붿씠윭뒪瑜 洹몃濡 궗슜빐 븫移섎즺뿉 궗슜븳떎. 젅삤諛붿씠윭뒪뒗 젙긽꽭룷뿉뒗 媛먯뿼씠 옒 씪뼱굹吏 븡뒗 諛섎㈃ 븫꽭룷뿉뒗 듅씠쟻쑝濡 媛먯뿼씠 씪뼱궇 닔 엳뼱꽌 븫꽭룷瑜 슚怨쇱쟻쑝濡 궗硫몄떆궗 닔 엳떎. 罹먮굹떎쓽 젅삱由ъ떊 誘멸뎅 냼븘뿉寃뚯꽌 遺꾨━맂 젅삤諛붿씠윭뒪 삁泥3삎 뜲뼱留(Reovirus type 3 Dearing)씤 諛섎㈃, 뿬由뒪誘몄뒪쓽 젅삤諛붿씠윭뒪뒗 븳援쓽 냼븘뿉寃뚯꽌 룆옄쟻쑝濡 遺꾨━븳 寃껋씠떎.

吏꾨찓뵒떊 븳뼇븰援 븰궡 踰ㅼ쿂쉶궗濡 異쒕컻븯뿬 븫슜빐諛붿씠윭뒪瑜 媛쒕컻븯怨 엳떎. 醫낆뼇꽭룷뿉 듅씠쟻씤 븫슜빐 븘뜲끂諛붿씠윭뒪瑜 뿰援ы븯怨 엳뒗뜲, 씠 쉶궗뒗 떎뼇븳 븫슜빐 븘뜲끂諛붿씠윭뒪瑜 媛쒕컻븯湲 쐞븳 湲곗큹쟻씤 뵆옯뤌쓣 援ъ텞븯怨 엳떎. 醫낆뼇 듅씠꽦쓣 넂씠湲 쐞븳 移섎즺 쑀쟾옄 궫엯 벑쓽 쑀쟾옄 議곗옉쓣 븯怨, 궗씠넗移댁씤쓣 諛쒗쁽떆궎怨, 硫댁뿭 뼲젣쟻씤 醫낆뼇쓽 誘몄꽭솚寃쎌쓣 洹밸났븯湲 쐞븳 硫댁뿭移섎즺諛⑸쾿쓣 깘깋븯怨, 씤泥 以묓솕빆泥댁 떥슦湲 쐞븳 굹끂뙆떚겢 諛붿씠윭뒪 엯옄瑜 媛쒕컻븯뒗 벑쓽 뿰援щ 븯怨 엳떎. 吏꾨찓뵒떊 봽濡쒕え꽣瑜 媛쒕웾븯怨 移섎즺 쑀쟾옄瑜 룞떆뿉 뿬윭 媛쒕 궫엯븯뿬 移섎즺슚쑉쓣 넂씠뒗 떆룄룄 븳떎. 諛붿씠윭뒪瑜 肄뷀똿븯뿬 쟾떊 닾뿬슜 諛붿씠윭뒪 湲곗닠룄 솗蹂댄뻽떎. 肄뷀똿쑝濡 紐몄냽 硫댁뿭꽭룷뱾씠 諛붿씠윭뒪瑜 룆냼濡 씤떇븯吏 紐삵븯寃 쐞옣븯뿬 삁븸 닾뿬 떆 깮議댁쑉쓣 넂떎. 떎瑜 빆븫諛붿씠윭뒪뿉 鍮꾪빐 媛꾨룆꽦룄 궙異붿뿀떎怨 븳떎. 쟾떊 닾뿬슜 빆븫諛붿씠윭뒪 移섎즺젣뒗 븫移섎즺 諛⑹떇뿉 吏꾩쟾쓣 媛졇삱 寃껋쑝濡 湲곕맂떎.

씠쇅뿉룄 떎닔쓽 諛붿씠삤 踰ㅼ쿂쉶궗뱾씠 븫슜빐諛붿씠윭뒪 뿰援 媛쒕컻뿉 吏꾩엯븯怨 엳떎.

6. 寃곕줎 諛 끉쓽

븫移섎즺쓽 諛⑹떇씠 諛붾뚭퀬 엳떎. 2꽭 몴쟻移섎즺젣 3꽭 硫댁뿭빆븫젣쓽 벑옣쑝濡 븫移섎즺쓽 룄援ш 떎뼇빐吏硫댁꽌 씠 臾닿린뱾쓣 뵲濡 샊 媛숈씠 꽎뼱꽌 궗슜븯뿬 移섎즺슚怨쇰 넂씠뒗 諛⑸쾿씠 떆룄릺怨 엳떎. 젣 1, 2, 3 꽭 븿븫젣瑜 쟻젅엳 媛숈씠 닾뿬븯뒗 蹂묒슜移섎즺踰뺤쑝濡 移섎즺슚怨쇨 利앹쭊맂 궗濡媛 留롮씠 蹂닿퀬릺뿀떎. 븫슜빐諛붿씠윭뒪룄 떎瑜 몴쟻移섎즺젣 샊 硫댁뿭愿臾몄뼲젣젣굹 CAR-T 꽭룷 벑쓽 떎瑜 硫댁뿭빆븫젣 蹂묒슜 닾뿬븯뿬 떆꼫吏瑜 넂씠뒗 엫긽떆뿕쓣 븯怨 엳떎. 븫슜빐諛붿씠윭뒪씤 럺궗踰≪쓽 寃쎌슦 怨좏삎븫怨 쑀諛⑹븫, 뿰議곗쭅 쑁醫낆쓣 긽쑝濡 샃떚蹂, 뿬蹂댁씠 벑쓽 떎瑜 硫댁뿭빆븫젣 蹂묒슜 닾뿬뿉꽌 移섎즺슚怨쇨 利앹쭊맂떎뒗 寃곌낵媛 굹솕떎. 硫댁뿭移섎즺踰뺤쓣 蹂묒슜븷 븣뒗 硫댁뿭뒫젰씠 삩쟾븳 醫낆뼇移섎즺쓽 珥덇린뿉 떆뻾븯뒗 寃껋씠 슚怨쇨 媛옣 醫뗫떎怨 븳떎.

븫쓣 移섎즺븯뒗뜲 寃る뒗 뼱젮 以묒쓽 븯굹뒗 쟾넻쟻씤 븫移섎즺 諛⑸쾿쑝濡쒕뒗 븫以꾧린꽭룷(cancer stem cells)瑜 紐⑤몢 젣嫄고븯湲 뼱졄떎뒗 젏씠떎. 븫以꾧린꽭룷뒗 옞蹂듭긽깭瑜 쑀吏븯뿬 쟾넻쟻씤 븫移섎즺젣뿉 븯뿬 젙긽꽭룷泥섎읆 빆쓣 굹궡怨 궡븘궓븘꽌 븫쓽 옱諛쒖쓣 씪쑝궓떎. 븫슜빐諛붿씠윭뒪뒗 옞蹂듭긽깭씤 븫以꾧린꽭룷瑜 李얠븘媛꽌 젣嫄고븷 옞옱젰쓣 媛吏怨 엳떎. 理쒓렐 떎닔쓽 떎瑜 醫낆뼇뿉꽌 븫슜빐諛붿씠윭뒪뒗 븫以꾧린꽭룷瑜 슚怨쇱쟻쑝濡 젣嫄고븯떎(Chaurasiya et al., 2018). 깮紐낆뿰옣씠 븘땶 븫쓽 셿移섍 移섎즺쓽 紐⑹쟻씪 븣 븫슜빐諛붿씠윭뒪瑜 솢슜븷 닔 엳뒗 媛뒫꽦씠 뿿蹂댁씤떎.

븫슜빐諛붿씠윭뒪뿉 쟻젅븳 뿬윭 媛吏 湲곕뒫쟻씤 쟾씠 쑀쟾옄(transgene)瑜 깙옱븯硫 븫슜빐諛붿씠윭뒪뿉 떎뼇븳 빆醫낆뼇湲곕뒫쓣 遺뿬븷 닔 엳떎. 떎뼇븳 醫낅쪟쓽 븫슜빐諛붿씠윭뒪 移섎즺젣 (pool)씠 留뚮뱾뼱吏硫 誘몃옒뿉뒗 醫낆뼇쓽 醫낅쪟 吏꾪뻾젙룄뿉 뵲씪꽌 쟻빀븳 議고빀쓽 븫슜빐諛붿씠윭뒪瑜 꽑깮븷 닔 엳쓣 寃껋씠떎.

븫슜빐諛붿씠윭뒪뿉뒗 洹밸났빐빞븷 옣踰쎌씠 븘吏 留롮씠 궓븘엳吏留, 떎뼇븳 븫슜빐諛붿씠윭뒪 移섎즺젣쓽 媛쒕컻씠 吏꾪뻾 以묒씤 寃껋 怨좊Т쟻씤 궗떎씠떎. 븫슜빐諛붿씠윭뒪뒗 빆븫硫댁뿭쓽 솢꽦룄 硫댁뿉꽌 떎瑜 빆븫젣뿉 鍮꾪빐 슦닔븯뿬 移섎즺슚怨쇨 醫뗪쾶 굹삱 寃껋쑝濡 湲곕맂떎. 븫슜빐諛붿씠윭뒪뒗 빆븫 硫댁뿭솢꽦怨 愿젴맂 湲곕뒫뿉꽌 1꽭 솕븰빆븫젣, 2꽭 몴쟻빆븫젣, 洹몃━怨 3꽭 硫댁뿭빆븫젣씤 硫댁뿭愿臾몄뼲젣젣, T-꽭룷 移섎즺젣 벑怨 鍮꾧탳 떆 넂 솢꽦룄瑜 蹂댁떎(Bommareddy et al., 2018). 移섎즺 諛⑸쾿씠 솗由쎈맂 湲곗〈쓽 諛⑸쾿怨 媛숈씠 궗슜맆 寃쎌슦 移섎즺슚怨쇨 뜑슧 넂븘吏 寃껋쑝濡 삁긽맂떎. 옒 븣젮吏 삁濡쒕뒗 硫댁뿭愿臾몄뼲젣젣쓽 蹂묒슜 닾뿬씠떎. 븫슜빐諛붿씠윭뒪 媛먯뿼 빆醫낆뼇硫댁뿭諛섏쓳쓣 옄洹뱁븯뿬 硫댁뿭愿臾몄뼲젣젣쓽 슚怨쇰 利앹쭊떆궓떎. 씠뿉 뵲씪 븫슜빐諛붿씠윭뒪 硫댁뿭愿臾몄뼲젣젣瑜 蹂묒슜 닾뿬븯뒗 엫긽떆뿕씠 꽭怨꾩쟻쑝濡 닔뻾릺怨 엳떎(Sivanandam et al., 2019). 븫슜빐諛붿씠윭뒪 移섎즺젣쓽 媛쒕컻씠 吏꾩쟾릺뼱꽌 醫낆뼇移섎즺뿉 쑀슜븳 꽑깮씠 릺怨, 븫移섎즺쓽 씗留앹씠 릺뼱 二쇨린瑜 湲곕븳떎.

ACKNOWLEDGEMENT

None.

CONFLICT OF INTEREST

The author certifies that I have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

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